2. Academic Validation
  3. Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1

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

  • MedComm (2020). 2023 Aug 17;4(5):e338. doi: 10.1002/mco2.338.
Zhongxiao Lin 1 2,  Hao He 1,  Yu Xian 1,  Jianghong Cai 1,  Qinyang Ge 1,  Minghao Guo 1,  Quan Zheng 1,  Xiaoyan Liu 1,  Chengke Mo 3,  Xin Zhang 1,  Wei Qi 1,  Youming Zhang 4,  Lu Liang 5,  Xi-Yong Yu 2,  Yi Zhun Zhu 1 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macau University of Science and Technology Macau China.
  • 2 Guangzhou 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 Guangzhou China.
  • 3 Guangzhou Twelfth People's Hospital Guangzhou China.
  • 4 CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic Biology Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen China.
  • 5 Department of Pharmacology Shanghai Key Laboratory of Bioactive Small Molecules School of Pharmacy Fudan University Shanghai China.
PMID: 37600507 DOI: 10.1002/mco2.338
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.

Keywords

Fuzi; HDAC1; deoxyandrographolide; epigenetic; network pharmacology.

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