Vincamine as an agonist of G protein-coupled receptor 40 effectively ameliorates pulmonary fibrosis in mice.

Autor: Zhao T; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China., Zhou Z; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Zhao S; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China., Wan H; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China., Li H; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China., Hou J; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China., Wang J; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing 210023, China., Qian M; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: qianmy@njucm.edu.cn., Shen X; Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing 210023, China. Electronic address: xshen@njucm.edu.cn.
Jazyk: angličtina
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2023 Sep; Vol. 118, pp. 154919. Date of Electronic Publication: 2023 Jun 17.
DOI: 10.1016/j.phymed.2023.154919
Abstrakt: Background: Pulmonary fibrosis (PF) is an irreversible and fatal lung disease with limited therapeutic options. G protein-coupled receptor 40 (GPR40) has been developed as a promising therapeutic target for metabolic disorders and functions potently in varied pathological and physiological processes. Vincamine (Vin) is a monoterpenoid indole alkaloid originated from Madagascar periwinkle and was reported as a GPR40 agonist in our previous work.
Purpose: Here, we aimed to clarify the role of GPR40 in PF pathogenesis by using the determined GPR40 agonist Vin as a probe and explore the potential of Vin in ameliorating PF in mice.
Methods: Pulmonary GPR40 expression alterations were assessed in both PF patients and bleomycin-induced PF mice (PF mice). Vin was used to evaluate the therapeutic potential of GPR40 activation for PF and the underlying mechanism was intensively investigated by assays against GPR40 knockout (Ffar1 -/- ) mice and the cells transfected with si-GPR40 in vitro.
Results: Pulmonary GPR40 expression level was highly downregulated in PF patients and PF mice. Pulmonary GPR40 deletion (Ffar1 -/- ) exacerbated pulmonary fibrosis as evidenced by the increases in mortality, dysfunctional lung index, activated myofibroblasts and extracellular matrix (ECM) deposition in PF mice. Vin-mediated pulmonary GPR40 activation ameliorated PF-like pathology in mice. Mechanistically, Vin suppressed ECM deposition by GPR40/β-arrestin2/SMAD3 pathway, repressed inflammatory response by GPR40/NF-κB/NLRP3 pathway and inhibited angiogenesis by decreasing GPR40-mediated vascular endothelial growth factor (VEGF) expression in the region of interface to normal parenchyma in pulmonary fibrotic tissues of mice.
Conclusion: Pulmonary GPR40 activation shows promise as a therapeutic strategy for PF and Vin exhibits high potential in treating this disease.
Competing Interests: Declaration of Competing Interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier GmbH. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: