Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1

Abstract Aconitum carmichaelii (Fuzi) is a traditional Chinese medicine that has been widely used in the clinic to save the dying life for over several thousand years. However, the medicinal components of Fuzi in treating vascular senescence (VS) and its potential mechanism remain unclear. In this s...

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Main Authors: Zhongxiao Lin, Hao He, Yu Xian, Jianghong Cai, Qinyang Ge, Minghao Guo, Quan Zheng, Xiaoyan Liu, Chengke Mo, Xin Zhang, Wei Qi, Youming Zhang, Lu Liang, Xi‐Yong Yu, Yi Zhun Zhu
Format: Article
Language:English
Published: Wiley 2023-10-01
Series:MedComm
Subjects:
Online Access:https://doi.org/10.1002/mco2.338
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author Zhongxiao Lin
Hao He
Yu Xian
Jianghong Cai
Qinyang Ge
Minghao Guo
Quan Zheng
Xiaoyan Liu
Chengke Mo
Xin Zhang
Wei Qi
Youming Zhang
Lu Liang
Xi‐Yong Yu
Yi Zhun Zhu
author_facet Zhongxiao Lin
Hao He
Yu Xian
Jianghong Cai
Qinyang Ge
Minghao Guo
Quan Zheng
Xiaoyan Liu
Chengke Mo
Xin Zhang
Wei Qi
Youming Zhang
Lu Liang
Xi‐Yong Yu
Yi Zhun Zhu
author_sort Zhongxiao Lin
collection DOAJ
description Abstract Aconitum carmichaelii (Fuzi) is a traditional Chinese medicine that has been widely used in the clinic to save the dying life for over several thousand years. However, the medicinal components of Fuzi in treating vascular senescence (VS) and its potential mechanism remain unclear. In this study, a network pharmacology method was used to explore the possible components and further validated by experiments to get a candidate compound, deoxyandrographolide (DA). DA restrains aging biomarkers, such as p16, p21, γH2A.X, and p53 in vitro and in vivo blood co‐culture studies. Histone deacetylase 1 (HDAC1), mouse double minute2 (MDM2), cyclin‐dependent kinase 4, and mechanistic target of rapamycin kinase (mTOR) are predicted to be the possible targets of DA based on virtual screening. Subsequent bio‐layer interferometry results indicated that DA showed good affinity capability with HDAC1. DA enhances the protein expression of HDAC1 in the angiotensin II‐induced senescence process by inhibiting its ubiquitination degradation. Loss of HDAC1 by CRISPR/Cas9 leads to the disappearance of DA's anti‐aging property. The enhancement of HDAC1 represses H3K4me3 (a biomarker of chromosomal activity) and improves chromosome stability. RNA sequencing results also confirmed our hypothesis. Our evidence illuminated that DA may achieve as a novel compound in the treatment of VS by improving chromosome stability.
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spelling doaj.art-e5df6e66d2864bbd9abc38d5897086052023-10-16T15:20:40ZengWileyMedComm2688-26632023-10-0145n/an/a10.1002/mco2.338Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1Zhongxiao Lin0Hao He1Yu Xian2Jianghong Cai3Qinyang Ge4Minghao Guo5Quan Zheng6Xiaoyan Liu7Chengke Mo8Xin Zhang9Wei Qi10Youming Zhang11Lu Liang12Xi‐Yong Yu13Yi Zhun Zhu14State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaGuangzhou Twelfth People's Hospital GuangzhouChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaCAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic Biology Shenzhen Institute of Advanced Technology Chinese Academy of Sciences ShenzhenChinaDepartment of Pharmacology Shanghai Key Laboratory of Bioactive Small Molecules School of Pharmacy Fudan University ShanghaiChinaGuangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology The NMPA and State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences and The Fifth Affiliated Hospital Guangzhou Medical University GuangzhouChinaState Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology MacauChinaAbstract Aconitum carmichaelii (Fuzi) is a traditional Chinese medicine that has been widely used in the clinic to save the dying life for over several thousand years. However, the medicinal components of Fuzi in treating vascular senescence (VS) and its potential mechanism remain unclear. In this study, a network pharmacology method was used to explore the possible components and further validated by experiments to get a candidate compound, deoxyandrographolide (DA). DA restrains aging biomarkers, such as p16, p21, γH2A.X, and p53 in vitro and in vivo blood co‐culture studies. Histone deacetylase 1 (HDAC1), mouse double minute2 (MDM2), cyclin‐dependent kinase 4, and mechanistic target of rapamycin kinase (mTOR) are predicted to be the possible targets of DA based on virtual screening. Subsequent bio‐layer interferometry results indicated that DA showed good affinity capability with HDAC1. DA enhances the protein expression of HDAC1 in the angiotensin II‐induced senescence process by inhibiting its ubiquitination degradation. Loss of HDAC1 by CRISPR/Cas9 leads to the disappearance of DA's anti‐aging property. The enhancement of HDAC1 represses H3K4me3 (a biomarker of chromosomal activity) and improves chromosome stability. RNA sequencing results also confirmed our hypothesis. Our evidence illuminated that DA may achieve as a novel compound in the treatment of VS by improving chromosome stability.https://doi.org/10.1002/mco2.338deoxyandrographolideepigeneticFuziHDAC1network pharmacology
spellingShingle Zhongxiao Lin
Hao He
Yu Xian
Jianghong Cai
Qinyang Ge
Minghao Guo
Quan Zheng
Xiaoyan Liu
Chengke Mo
Xin Zhang
Wei Qi
Youming Zhang
Lu Liang
Xi‐Yong Yu
Yi Zhun Zhu
Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1
MedComm
deoxyandrographolide
epigenetic
Fuzi
HDAC1
network pharmacology
title Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1
title_full Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1
title_fullStr Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1
title_full_unstemmed Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1
title_short Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1
title_sort discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting hdac1
topic deoxyandrographolide
epigenetic
Fuzi
HDAC1
network pharmacology
url https://doi.org/10.1002/mco2.338
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