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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.

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


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.


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

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