Glycnsisitin A:A promising bicyclic peptide against heart failure that facilitates TFRC-mediated uptake of iron in cardiomyocytes

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外文摘要：Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in China.As the monarch drug of Zhigancao decoction,the bioactive molecules of licorice against heart diseases remain elusive.We established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides,glycnsisitins A-C(1-3),with distinctive C-C and C-O-C side-chain-to-side-chain linkages from the roots of Glycyrrhiza uralensis(Licorice).Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin(DOX)-induced cardiomyocyte injury.Glycnsisitin A treatment not only reduced the mortality of heart failure(HF)mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial fibrosis.Gene set enrichment analysis(GSEA)of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the myocardium.Mechanistically,glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor(TFRC),which caused increased uptake of iron in cardiomyocytes.These findings highlight the key role of bicyclic peptides as bioactive molecules of Zhi-gancao decoction for the treatment of HF,and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.

外文关键词：

Glycyrrhiza uralensisBicyclic peptidesMyocardial energy metabolismIron homeostasisTFRC

作者：

Jichao Zhou、Yuanyuan Liu、Xiaoli Wei、Meng Yuan、Xu Zhang、Lingfeng Qin、Bing Cui、Pingping Li、Jing Zhang、Ziming Feng、Jianshuang Jiang、Xiang Yuan、Ruibing Xu、Zhimeng Zhang、Peicheng Zhang、Xiaowei Zhang、Yanan Yang

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作者单位：

State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100050,China

基金：

Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences,ChinaChinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences,ChinaChinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences,ChinaBeijing Outstanding Young Scientist Program,ChinaChinese Academy of Medical Sciences(CAMS)Central Publicinterest Scientific Institution Basal Research Fund

项目编号：

2022-I2M-2-0022021-I2M-1-0162022-I2M-1-014BJJWZYJH012019100230282018PT35004

出版年：

2024

DOI：

10.1016/j.apsb.2024.02.026

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(7)