Gracillin relieves pulmonary fibrosis by suppressing the STAT3 axis

Mengyao Xie; Lehe Yang; Jiayun Cheng; Hongyan Qu; Yanting Gu; Cheng Ding; Xiaomei Xu; Chengguang Zhao; Xiaoying Huang; Liangxing Wang

doi:10.1016/j.jep.2023.116704

Gracillin relieves pulmonary fibrosis by suppressing the STAT3 axis

J Ethnopharmacol. 2023 Nov 15:316:116704. doi: 10.1016/j.jep.2023.116704. Epub 2023 May 29.

Authors

Affiliations

¹ Pulmonary Division, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325035, China.
² The Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China.
³ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
⁴ Pulmonary Division, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325035, China. Electronic address: huangxiaoying@wmu.edu.cn.
⁵ Pulmonary Division, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325035, China. Electronic address: wangliangxing@wzhospital.cn.

PMID: 37257706
DOI: 10.1016/j.jep.2023.116704

Abstract

Ethnopharmacological relevance: Pulmonary fibrosis (PF) is a persistent and refractory illness accompanied by inflammation and fibrosis. Gracillin, a natural steroidal saponin, is one of the components of Dioscorea quinqueloba which has been used in herbal medicines for treating some inflammatory diseases. Therefore, it may be a potential drug candidate for PF management.

Aim of the study: This study aims to elucidate and verify the anti-pulmonary fibrosis effect of gracillin.

Methods: We established an in vivo model of PF by treatment of mice with bleomycin (BLM) and an in vitro model by treatment of NIH-3T3 cells with TGF-β1. Pathological changes to the structure of lung tissue, pulmonary function, inflammatory exudation of bronchoalveolar lavage fluid (BALF) and deposition of collagen were detected in vivo, and extracellular matrix (ECM) deposition and migration were evaluated in vitro. The significance of gracillin on STAT3 phosphorylation and nuclear translocation were evaluated by western blotting, immunohistochemistry and immunofluorescence assays. The STAT3 transcriptional activity was quantified with a dual-luciferase reporter assay. Recovery experiments were performed by plasmid-directed overexpression of STAT3.

Results: We found that gracillin could improve pulmonary function, reduce lung inflammation and mitigate collagen deposition to ameliorate BLM-induced PF in mice. Gracillin also suppressed TGF-β1-induced increases in ECM deposition biomarkers, including COL1A1, fibronectin, α-SMA, N-cad and vimentin, and repressed migration in NIH-3T3 cells. Additionally, gracillin suppressed the phosphorylation, nuclear translocation and transcriptional action of STAT3. Furthermore, the decreased ECM deposition and migration upon gracillin treatment were abrogated upon overexpression of STAT3 in NIH-3T3 cells.

Conclusions: Gracillin protects against PF by inhibiting the STAT3 axis, providing a safe and efficacious approach to treating PF.

Keywords: Gracillin; Inhibitor; Pulmonary ﬁbrosis; STAT3.

MeSH terms

Animals
Bleomycin
Collagen
Lung
Mice
Pulmonary Fibrosis* / chemically induced
Pulmonary Fibrosis* / drug therapy
Pulmonary Fibrosis* / pathology
Transforming Growth Factor beta1* / pharmacology

Substances

Transforming Growth Factor beta1
gracillin
Collagen
Bleomycin