{"title":"The main active components of Prunella vulgaris L. alleviate myocardial ischemia-reperfusion injury by inhibiting oxidative stress and ferroptosis via the NRF2/GPX4 pathway.","authors":"Ling Leng, Peijie Li, Rui Liu, Opoku Bonsu Francis, Shaofei Song, Yunchan Sui, Yanze Yang, Yucheng Wang, Xiaoyu Sun, Rong Miao, Qing Yuan, Xue Li, Wenzhi Yang, Xiumei Gao, Qilong Wang","doi":"10.1016/j.jep.2025.119630","DOIUrl":null,"url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Prunella vulgaris L. (PV) is a widely distributed medicinal and edible plant used in traditional Chinese medicine for its anti-tumor, anti-inflammatory, anti-oxidant, hypoglycemic, and anti-hypertensive effects. Despite the numerous studies reporting on its cardiovascular protective effects, it is still not known whether PV could relieve myocardial ischemia-reperfusion (MI/R) injury.</p><p><strong>Aim of the study: </strong>To investigate the effects of PV on MI/R injury and explore the underlying mechanism of action.</p><p><strong>Materials and methods: </strong>Sprague-Dawley rats were orally administrated with the aqueous extract of P. vulgaris for 7 days before MI/R injury was induced. Echocardiography, infarct staining, and TUNEL assay were used to evaluate the protective effect of P. vulgaris. H<sub>2</sub>O<sub>2</sub>- and RSL3-stimulated H9C2 rat myocardial cells were used to explore the underlying mechanism. Ultra-high-performance liquid chromatography/mass spectrometer analysis was used to identify the chemical constituents of P. vulgaris. AutoDock was used to predict the binding affinity and the interactions between the main active compounds and Keap1. Nuclear factor erythroid 2-related factor 2 (Nrf2) knock-out mice were used to confirm whether the protective effect of P. vulgaris was mediated by Nrf2.</p><p><strong>Results: </strong>P. vulgaris improved left ventricular systolic function and decreased the myocardial infarction area, which in turn helps alleviate MI/R injury. PV also increased the level of Nrf2 proteins and promoted the expression of HO-1, SOD, and GSH, thus upregulating the activity of the antioxidant system. The molecular docking simulations indicated that rosmarinic acid, salviaflaside, ursolic acid, and protocatechuic acid from P. vulgaris could strongly bind to Keap1 protein with good binding affinities. Additionally, ursolic acid was found to elevate NRF2 protein levels as well as promote NRF2 nuclear translocation. Moreover, the cardiac protective effect of PV or ursolic acid disappeared in NRF2-/- mice, indicating that this protective effect was mediated by NRF2. Besides, PV also increased the protein levels of GPX4 in MI/R rat or mice models, and this upregulation disappeared in NRF2-/- mice. Results from the RSL-3-induced ferroptosis H9C2 cell model showed that ursolic acid was the main active component of PV that protects cardiomyocytes against ferroptosis.</p><p><strong>Conclusions: </strong>Collectively, the findings indicate that PV could alleviate MI/R injury by inhibiting oxidative stress and ferroptosis via the NRF2/GPX4 pathway, and ursolic acid is the main active component responsible for mediating both antioxidative and anti-ferroptosis effects, suggesting its potential use as a therapeutic agent against MI/R injury.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"119630"},"PeriodicalIF":4.8000,"publicationDate":"2025-03-13","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.2025.119630","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
The main active components of Prunella vulgaris L. alleviate myocardial ischemia-reperfusion injury by inhibiting oxidative stress and ferroptosis via the NRF2/GPX4 pathway.
Ethnopharmacological relevance: Prunella vulgaris L. (PV) is a widely distributed medicinal and edible plant used in traditional Chinese medicine for its anti-tumor, anti-inflammatory, anti-oxidant, hypoglycemic, and anti-hypertensive effects. Despite the numerous studies reporting on its cardiovascular protective effects, it is still not known whether PV could relieve myocardial ischemia-reperfusion (MI/R) injury.
Aim of the study: To investigate the effects of PV on MI/R injury and explore the underlying mechanism of action.
Materials and methods: Sprague-Dawley rats were orally administrated with the aqueous extract of P. vulgaris for 7 days before MI/R injury was induced. Echocardiography, infarct staining, and TUNEL assay were used to evaluate the protective effect of P. vulgaris. H2O2- and RSL3-stimulated H9C2 rat myocardial cells were used to explore the underlying mechanism. Ultra-high-performance liquid chromatography/mass spectrometer analysis was used to identify the chemical constituents of P. vulgaris. AutoDock was used to predict the binding affinity and the interactions between the main active compounds and Keap1. Nuclear factor erythroid 2-related factor 2 (Nrf2) knock-out mice were used to confirm whether the protective effect of P. vulgaris was mediated by Nrf2.
Results: P. vulgaris improved left ventricular systolic function and decreased the myocardial infarction area, which in turn helps alleviate MI/R injury. PV also increased the level of Nrf2 proteins and promoted the expression of HO-1, SOD, and GSH, thus upregulating the activity of the antioxidant system. The molecular docking simulations indicated that rosmarinic acid, salviaflaside, ursolic acid, and protocatechuic acid from P. vulgaris could strongly bind to Keap1 protein with good binding affinities. Additionally, ursolic acid was found to elevate NRF2 protein levels as well as promote NRF2 nuclear translocation. Moreover, the cardiac protective effect of PV or ursolic acid disappeared in NRF2-/- mice, indicating that this protective effect was mediated by NRF2. Besides, PV also increased the protein levels of GPX4 in MI/R rat or mice models, and this upregulation disappeared in NRF2-/- mice. Results from the RSL-3-induced ferroptosis H9C2 cell model showed that ursolic acid was the main active component of PV that protects cardiomyocytes against ferroptosis.
Conclusions: Collectively, the findings indicate that PV could alleviate MI/R injury by inhibiting oxidative stress and ferroptosis via the NRF2/GPX4 pathway, and ursolic acid is the main active component responsible for mediating both antioxidative and anti-ferroptosis effects, suggesting its potential use as a therapeutic agent against MI/R injury.
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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