Planta Med 2023; 89(15): 1444-1456 DOI: 10.1055/a-2114-5371
Biological and Pharmacological Activity
Original Papers
Bioassay-Guided Fractionation and Biological Activity of Cardenolides from Streptocaulon juventas
Yunhui Xu‡
2
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
,
Jian Xu‡
1
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
,
Wanfang Zhu‡
3
College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
,
Yanling Yan
4
Departments of Clinical & Translational Sciences, Biomedical Sciences and Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United
States
,
Xueyang Jiang
5
Department of Medicinal Chemistry, Anhui University of Chinese Medicine, Hefei, China
,
Zijian Xie
2
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
,
Feng Feng
1
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
,
Jie Zhang
1
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
› Author AffiliationsThis work was supported by the American Heart Association (AHA) postdoctoral fellowship (#18POST33990237), the National Institutes of Health (HL109015), and the Marshall
Institute for Interdisciplinary Research (MIIR) fund.
The discovery that Na/K-ATPase acts as a signal transducer led us to investigate the structural diversity of cardiotonic steroids and study their ligand effects. By applying Na/K-ATPase
activity assay-guided fractionation, we isolated a total of 20 cardiotonic steroids from Streptocaulon juventas, including an undescribed juventasoside B (10) and 19 known
cardiotonic steroids. Their structures have been elucidated. Using our platform of purified Na/K-ATPase and an LLC-PK1 cell model, we found that 10, at a concentration that induces
less than 10% Na/K-ATPase inhibition, can stimulate the Na/K-ATPase/Src receptor complex and selectively activate downstream pathways, ultimately altering prostate cancer cell growth. By
assessing the ligand effect of the isolated cardiotonic steroids, we found that the regulation of cell viability by the isolated cardiotonic steroids was not associated with their inhibitory
potencies against Na/K-ATPase activity but reflected their ligand-binding affinity to the Na/K-ATPase receptor. Based on this discovery, we identified a unique active cardiotonic steroid,
digitoxigenin (1), and verified that it can protect LLC-PK1 cells from hypoxic injury, implicating its potential use in ischemia/reperfusion injury and inducing collagen synthesis in
primary human dermal fibroblast cells, and implicating that compound 2 is the molecular basis of the wound healing activity of S. juventas.
Identification of bioactive fractions from S. juventas as well as the ESI-MS, 1H NMR, 13C NMR, HSQC, 1H-1H COSY, and HMBC of
compound 10 and 1H NMR spectra of compounds 1 – 9 and 11 – 20 are available as Supporting Information.
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