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Free Radic Biol Med. 2019 Nov 21. pii: S0891-5849(19)31609-0. doi: 10.1016/j.freeradbiomed.2019.11.026. [Epub ahead of print]

Trans-4,4'-dihydroxystilbene ameliorates cigarette smoke-induced progression of chronic obstructive pulmonary disease via inhibiting oxidative stress and inflammatory response.

Author information

1
Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China.
2
State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou, People's Republic of China.
3
Department of Pharmacy, Jinan Maternity and Child Care Hospital, Jinan, People's Republic of China.
4
Department of Health Management, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, People's Republic of China.
5
Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China. Electronic address: shentao@sdu.edu.cn.

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease resulted from airflow obstructions, and there is a driving requirement for novel and effective preventive and therapeutic agents of COPD. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been regarded to be a promising therapeutic target for COPD. Resveratrol is a natural Nrf2 activator with antioxidant and anti-inflammatory properties, however, its application is limited by its relative low efficiency and poor bioavailability. Herein, based on the skeleton of resveratrol, trans-4,4'-dihydroxystilbene (DHS) has been firstly identified to be an Nrf2 activator, which is more potent than the well-known sulforaphane (SF) and resveratrol. Our results indicate that DHS blocks Nrf2 ubiquitylation through specifically reacting with Cys151 cysteine in Keap1 protein to activate Nrf2-regulated defensive response, and thus enhances intracellular antioxidant capability. Furthermore, DHS relieves lipopolysaccharide (LPS)-stimulated inflammatory response via inhibition of NF-κB. Importantly, DHS significantly ameliorates pathological alterations (e.g. infiltration of leukocytes and fibrosis), downregulates the levels of oxidant biomarkers malondialdehyde (MDA) and 8-oxo-7,8-dihydro-2'-deoxyguanosin (8-oxo-dG), and inhibits the overproductions of inflammatory mediators [e.g. tumor necrosis factor α (TNF-α), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9)] in a cigarette smoke (CS)-induced pulmonary impairment mice model. Taken together, this study demonstrates that DHS attenuates the CS-induced pulmonary impairments through inhibitions of oxidative stress and inflammatory response targeting Nrf2 and NF-κB in vitro and in vivo, and could be developed into a preventive agent against pulmonary impairments induced by CS.

KEYWORDS:

4,4′-Dihydroxystilbene; Chronic obstructive pulmonary disease; Inflammatory response; NF-κB; Nrf2; Oxidative stress

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