Dihydroquercetin suppresses cigarette smoke induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease by activating Nrf2-mediated pathway

Xiangming Liu; Yiming Ma; Lijuan Luo; Dandan Zong; Herui Li; Zihang Zeng; Yanan Cui; Weiwei Meng; Yan Chen

doi:10.1016/j.phymed.2021.153894

Dihydroquercetin suppresses cigarette smoke induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease by activating Nrf2-mediated pathway

Phytomedicine. 2022 Feb:96:153894. doi: 10.1016/j.phymed.2021.153894. Epub 2021 Dec 14.

Authors

Xiangming Liu¹, Yiming Ma¹, Lijuan Luo¹, Dandan Zong¹, Herui Li¹, Zihang Zeng¹, Yanan Cui¹, Weiwei Meng¹, Yan Chen²

Affiliations

¹ Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China.
² Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China. Electronic address: chenyan99727@csu.edu.cn.

PMID: 34942457
DOI: 10.1016/j.phymed.2021.153894

Abstract

Background: Dihydroquercetin (DHQ) is a flavonoid with strong anti-inflammatory and antioxidant effects. However, its protective activity against cigarette smoke-induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease and its underlying mechanisms remain unclear.

Purpose: The present study was conducted to investigate the protective role of DHQ in the pathogenesis of COPD in vivo and in vitro.

Methods: A cigarette smoke-induced COPD mouse model was established by cigarette smoke (CS) exposure combined with intraperitoneal injection of cigarette smoke extract (CSE). During the modeling process, the mice were intraperitoneally injected with DHQ daily. HBE cells were cultured with CSE with or without pretreatment with DHQ (40, 80 μM) or ML385 (10 μM). Cell viability was assessed by a cell counting kit 8 (CCK-8). The contents of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by MDA and SOD assay kits, respectively, and reactive oxygen species (ROS) generation was detected by DCFH-DA assays. Protein expression levels of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPx4) and nuclear factor erythroid 2-related factor 2 (Nrf2) were measured by western blot. Lipid peroxidation was determined by C11-BODIPY staining. Transmission electron microscopy was used to observe the morphological features of the mitochondria.

Results: Treatment with DHQ significantly elevated ferroptosis-related protein (SLC7A11 and GPx4) expression in vivo and in vitro. The mRNA levels of SLC7A11 and GPx4 were also increased after DHQ treatment. The excessive MDA and ROS production and depleted SOD activity induced by CSE were reversed by DHQ. DHQ notably reduced the increased lipid peroxidation induced by CSE in HBE cells. In addition, treatment with DHQ attenuated the morphological changes in the mitochondria caused by CSE. Moreover, we also found that DHQ increased the levels of Nrf2 in a concentration-dependent manner in the cigarette smoke-induced COPD mouse model and CSE-treated HBE cells. Additionally, after administering an Nrf2-specific inhibitor, ML385, to HBE cells, the elevated SLC7A11 and GPx4 mRNA and protein levels induced by DHQ were reversed. Moreover, ML385 treatment attenuated the protective effect of DHQ on lipid peroxidation.

Conclusion: Our results show that treatment with DHQ significantly reverses the ferroptosis induced by cigarette smoke both in vivo and in vitro via a Nrf2-dependent signaling pathway.

Keywords: Cigarette smoke; Dihydroquercetin; Ferroptosis; Oxidative stress.

MeSH terms

Animals
Ferroptosis*
Mice
NF-E2-Related Factor 2 / metabolism
Oxidative Stress
Pulmonary Disease, Chronic Obstructive* / drug therapy
Quercetin / analogs & derivatives
Smoke / adverse effects
Smoking

Substances

NF-E2-Related Factor 2
Smoke
Quercetin
taxifolin