How to cite item

Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity

   
@article{APS10647,
	author = {Dong Huang and Ying-yuan Zhao and Rui-min Wang and Wei Li and Fang-yu Yuan and Xue-long Yan and Xiao Yang and Gui-hua Tang and Sheng Yin and Hui-chang Bi},
	title = {Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity},
	journal = {Acta Pharmacologica Sinica},
	volume = {43},
	number = {8},
	year = {2022},
	keywords = {},
	abstract = {Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg−1. d−1, ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10647}
}