{"title":"膳食抗氧化剂通过蛋白激酶amp活化α (AMPKα)和核因子，红细胞2样2 （NRF2）途径相互作用减轻抗生素诱导的线粒体功能障碍。","authors":"Jingyan Zhao, Bing Shang, Sha Xu, Danfeng Zheng, Xiaofang Zhang, Jiawen Lv, Yaqiong Dong, Xiaoda Yang","doi":"10.1111/bph.70191","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and purpose: </strong>Antibiotics and ibuprofen combinations cause mitochondrial toxicity and hepatotoxicity. This study investigated whether dietary antioxidants could protect against this damage via protein kinase AMP-activated alpha (AMPKα)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways.</p><p><strong>Experimental approach: </strong>Human umbilical vein endothelial cells (HUVECs) were treated with antibiotics (kanamycin, azithromycin, ampicillin or ciprofloxacin) plus ibuprofen with or without antioxidants. Azithromycin/ibuprofen induced hepatotoxicity was evaluated in C57BL/6J mice. Mitochondrial parameters including morphology, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ<sub>m</sub>) and key proteins (mitofusin 2, AMPKα, glycogen synthase kinase 3 beta [GSK3B], NRF2 and haem oxygenase 1 [HO1]) were analysed.</p><p><strong>Key results: </strong>Antibiotics/ibuprofen combinations triggered mitochondrial fission, ROS overproduction and mitofusin 2 down-regulation. Four antioxidants, that is, coniferaldehyde, raspberry ketone, gastrodin and eugenol, restored mitochondrial function and morphology. Coniferaldehyde and raspberry ketone effectively prevented in vivo hepatotoxicity and inflammation. Moreover, coniferaldehyde/raspberry ketone activated NRF2/HO1 while restoring AMPKα/GSK3B signalling.</p><p><strong>Conclusions and implications: </strong>Coniferaldehyde and raspberry ketone showed potent rescue effects in vitro against all antibiotic models and in vivo against azithromycin/ibuprofen-induced hepatotoxicity through AMPKα-GSK3B/NRF2-HO1 modulation, with favourable safety profiles.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dietary antioxidants alleviate antibiotic-induced mitochondrial dysfunction through protein kinase AMP-activated alpha (AMPKα) and nuclear factor, erythroid 2 like 2 (NRF2) pathway interaction.\",\"authors\":\"Jingyan Zhao, Bing Shang, Sha Xu, Danfeng Zheng, Xiaofang Zhang, Jiawen Lv, Yaqiong Dong, Xiaoda Yang\",\"doi\":\"10.1111/bph.70191\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and purpose: </strong>Antibiotics and ibuprofen combinations cause mitochondrial toxicity and hepatotoxicity. This study investigated whether dietary antioxidants could protect against this damage via protein kinase AMP-activated alpha (AMPKα)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways.</p><p><strong>Experimental approach: </strong>Human umbilical vein endothelial cells (HUVECs) were treated with antibiotics (kanamycin, azithromycin, ampicillin or ciprofloxacin) plus ibuprofen with or without antioxidants. Azithromycin/ibuprofen induced hepatotoxicity was evaluated in C57BL/6J mice. Mitochondrial parameters including morphology, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ<sub>m</sub>) and key proteins (mitofusin 2, AMPKα, glycogen synthase kinase 3 beta [GSK3B], NRF2 and haem oxygenase 1 [HO1]) were analysed.</p><p><strong>Key results: </strong>Antibiotics/ibuprofen combinations triggered mitochondrial fission, ROS overproduction and mitofusin 2 down-regulation. Four antioxidants, that is, coniferaldehyde, raspberry ketone, gastrodin and eugenol, restored mitochondrial function and morphology. Coniferaldehyde and raspberry ketone effectively prevented in vivo hepatotoxicity and inflammation. Moreover, coniferaldehyde/raspberry ketone activated NRF2/HO1 while restoring AMPKα/GSK3B signalling.</p><p><strong>Conclusions and implications: </strong>Coniferaldehyde and raspberry ketone showed potent rescue effects in vitro against all antibiotic models and in vivo against azithromycin/ibuprofen-induced hepatotoxicity through AMPKα-GSK3B/NRF2-HO1 modulation, with favourable safety profiles.</p>\",\"PeriodicalId\":9262,\"journal\":{\"name\":\"British Journal of Pharmacology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.7000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/bph.70191\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/bph.70191","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Dietary antioxidants alleviate antibiotic-induced mitochondrial dysfunction through protein kinase AMP-activated alpha (AMPKα) and nuclear factor, erythroid 2 like 2 (NRF2) pathway interaction.
Background and purpose: Antibiotics and ibuprofen combinations cause mitochondrial toxicity and hepatotoxicity. This study investigated whether dietary antioxidants could protect against this damage via protein kinase AMP-activated alpha (AMPKα)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways.
Experimental approach: Human umbilical vein endothelial cells (HUVECs) were treated with antibiotics (kanamycin, azithromycin, ampicillin or ciprofloxacin) plus ibuprofen with or without antioxidants. Azithromycin/ibuprofen induced hepatotoxicity was evaluated in C57BL/6J mice. Mitochondrial parameters including morphology, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and key proteins (mitofusin 2, AMPKα, glycogen synthase kinase 3 beta [GSK3B], NRF2 and haem oxygenase 1 [HO1]) were analysed.
Key results: Antibiotics/ibuprofen combinations triggered mitochondrial fission, ROS overproduction and mitofusin 2 down-regulation. Four antioxidants, that is, coniferaldehyde, raspberry ketone, gastrodin and eugenol, restored mitochondrial function and morphology. Coniferaldehyde and raspberry ketone effectively prevented in vivo hepatotoxicity and inflammation. Moreover, coniferaldehyde/raspberry ketone activated NRF2/HO1 while restoring AMPKα/GSK3B signalling.
Conclusions and implications: Coniferaldehyde and raspberry ketone showed potent rescue effects in vitro against all antibiotic models and in vivo against azithromycin/ibuprofen-induced hepatotoxicity through AMPKα-GSK3B/NRF2-HO1 modulation, with favourable safety profiles.
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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