Bioassay-Guided Fractionation and Biological Activity of Cardenolides from Streptocaulon juventas

Yunhui Xu; Jian Xu; Wanfang Zhu; Yanling Yan; Xueyang Jiang; Zijian Xie; Feng Feng; Jie Zhang

doi:10.1055/a-2114-5371

Planta Medica, Table of Contents

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‡

²Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

,

Jian Xu‡

¹Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China

,

Wanfang Zhu‡

³College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China

,

Yanling Yan

⁴Departments of Clinical & Translational Sciences, Biomedical Sciences and Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States

,

Xueyang Jiang

⁵Department of Medicinal Chemistry, Anhui University of Chinese Medicine, Hefei, China

,

Zijian Xie

²Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

,

Feng Feng

¹Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China

,

Jie Zhang

¹Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China

› Author Affiliations

Abstract

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.

Key words

Streptocaulon juventas - Asclepiadaceace - cardiotonic steroids - Na/K-ATPase

Full Text

References

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