Isoliquiritin targeting m5C RNA methylation improves mitophagy in doxorubicin-induced myocardial cardiotoxicity.

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL
Jiaqi Fu, Li Cheng, Jie Zhang, Runjie Sun, Manya Yu, Muyun Wu, Suzhen Li, Xing Cui
{"title":"Isoliquiritin targeting m5C RNA methylation improves mitophagy in doxorubicin-induced myocardial cardiotoxicity.","authors":"Jiaqi Fu, Li Cheng, Jie Zhang, Runjie Sun, Manya Yu, Muyun Wu, Suzhen Li, Xing Cui","doi":"10.1016/j.phymed.2024.156293","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin (DOX)-induced myocardial cardiotoxicity (DIC) severely limits its clinical application, and there is no optimal therapeutic agent available. Recent studies revealed that activation of BNIP3-mediated mitophagy and the inhibition of m5C RNA methylation played a crucial role in DIC. Isoliquiritin (ISL) has remarkable cardiac protective effect. But its potential mechanisms against DIC still remains unknown.</p><p><strong>Purpose: </strong>To investigate the therapeutic effect and potential mechanism of Isoliquiritin(ISL) on doxorubicin(DOX)-induced myocardial cardiotoxicity(DIC).</p><p><strong>Methods: </strong>Bioinformatics analyses and network pharmacology were carried out to identify effective target of ISL against DIC. Molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The mechanism of ISL regulating mitophagy through M5C methylation to improve DIC was demonstrated in vitro and in vivo experiments. The methylation modification was verified by MeRIP-qPCR. Cell model of DIC was constructed to evaluate mitochondrial function by measuring cell viability, myocardial enzyme level, mitochondrial quality, mCherry-EGFP analysis and TEM morphometry with the application of mitophagy inhibitor (Baf A1) and inducer (CCCP). Myocardial injury in mice with DIC was assessed by survival rate, myocardial enzyme level, HE staining, echocardiography and detection of mitophagy markers.</p><p><strong>Results: </strong>The decreased level of m5C writer TRDMT1 and mitochondrial marker (BNIP3) were chosen for the research. After the docking and SPR verification between ISL and TRDMT1, the improvement of ISL on TRDMT1 and TRDMT1-associated m5C level of BNIP3 was identified. In vitro and in vivo experiments showed that the cardiac markers, heart function, and mitochondrial function were recovered after ISL application. Meanwhile, the results manifested that there was blocked autophagy flow indicated by mCherry-EGFP analysis, then the suppressed mitophagy caused the mitochondria damage associated cell death. ISL could alleviate the autophagy block, and Baf A1 couldn't influnce the ISL effect. Compared to CCCP group, Mitochondrial maker TOMM20 significantly elevated treated with both CCCP and DOX, indicating that DOX impaired mitophagy for clearing damaged mitochondrial proteins. After ISL treated, a higher level of co-localization between mitochondrial and BNIP3 was observed, inducing restoration of mitochondrial function.</p><p><strong>Conclusion: </strong>This study showed that ISL may exert cardioprotective role restoring BNIP3-mediated mitophagy by targeting TRDMT1 to alleviate DOX-induced macro-autophagy-dependent protein homeostasis and acquired blocking of mitophagy, providing a new idea for the clinical treatment of DIC.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156293"},"PeriodicalIF":6.7000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.phymed.2024.156293","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Doxorubicin (DOX)-induced myocardial cardiotoxicity (DIC) severely limits its clinical application, and there is no optimal therapeutic agent available. Recent studies revealed that activation of BNIP3-mediated mitophagy and the inhibition of m5C RNA methylation played a crucial role in DIC. Isoliquiritin (ISL) has remarkable cardiac protective effect. But its potential mechanisms against DIC still remains unknown.

Purpose: To investigate the therapeutic effect and potential mechanism of Isoliquiritin(ISL) on doxorubicin(DOX)-induced myocardial cardiotoxicity(DIC).

Methods: Bioinformatics analyses and network pharmacology were carried out to identify effective target of ISL against DIC. Molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The mechanism of ISL regulating mitophagy through M5C methylation to improve DIC was demonstrated in vitro and in vivo experiments. The methylation modification was verified by MeRIP-qPCR. Cell model of DIC was constructed to evaluate mitochondrial function by measuring cell viability, myocardial enzyme level, mitochondrial quality, mCherry-EGFP analysis and TEM morphometry with the application of mitophagy inhibitor (Baf A1) and inducer (CCCP). Myocardial injury in mice with DIC was assessed by survival rate, myocardial enzyme level, HE staining, echocardiography and detection of mitophagy markers.

Results: The decreased level of m5C writer TRDMT1 and mitochondrial marker (BNIP3) were chosen for the research. After the docking and SPR verification between ISL and TRDMT1, the improvement of ISL on TRDMT1 and TRDMT1-associated m5C level of BNIP3 was identified. In vitro and in vivo experiments showed that the cardiac markers, heart function, and mitochondrial function were recovered after ISL application. Meanwhile, the results manifested that there was blocked autophagy flow indicated by mCherry-EGFP analysis, then the suppressed mitophagy caused the mitochondria damage associated cell death. ISL could alleviate the autophagy block, and Baf A1 couldn't influnce the ISL effect. Compared to CCCP group, Mitochondrial maker TOMM20 significantly elevated treated with both CCCP and DOX, indicating that DOX impaired mitophagy for clearing damaged mitochondrial proteins. After ISL treated, a higher level of co-localization between mitochondrial and BNIP3 was observed, inducing restoration of mitochondrial function.

Conclusion: This study showed that ISL may exert cardioprotective role restoring BNIP3-mediated mitophagy by targeting TRDMT1 to alleviate DOX-induced macro-autophagy-dependent protein homeostasis and acquired blocking of mitophagy, providing a new idea for the clinical treatment of DIC.

求助全文
约1分钟内获得全文 求助全文
来源期刊
Phytomedicine
Phytomedicine 医学-药学
CiteScore
10.30
自引率
5.10%
发文量
670
审稿时长
91 days
期刊介绍: Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信