Therapeutic Effect Of Diterpenoids And Stilbenes Against Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease(COPD)is a chronic inflammation of the respiratory system caused by airflow obstruction.Tobacco exposure and burning of biomass fuels increase the risk of COPD morbidity.The high smoking rate and the environmental pollution caused by urbanization in China have led to an increase in the morbidity of COPD.In addition,hormones are mainly used for clinical treatment of COPD,which have the deficiency of immunosuppression and can not be taken for a long time.There is a requirement for new and effective COPD preventive and therapeutic agents.Nuclear factor-erythroid 2-related factor 2(Nrf2)is an important regulatory factor for maintaining redox homeostasis in vivo,and nuclear transcription factor-KB(NF-κB)is a key transcription factor that regulates inflammatory responses in vivo.Given the roles of oxidative stress and inflammatory response in the pathogenesis of COPD,Nrf2 and NF-κB are considered as potential therapeutic targets for COPD.Natural products and their derivatives are important sources of innovative drugs and are important for discovering COPD preventive and therapeutic drugs.Based on Nrf2 and NF-κB signaling pathways,this article has carried out the research on diterpenes and stilbenes against chronic obstructive pulmonary disease,including the following two contents:1.Activation of the Nrf2 pathway and the protective effect by the isopimarane-type diterpene botrysphin D(BD)Diterpenes are important sources of innovative drugs.In our previous research,a library of natural terpenoids has been established and evaluated for its Nrf2 induction potential.It was found that the isopimarane-type diterpene BD activated Nrf2 from mRNA and protein levels and could inhibit As(III)-induced oxidative stress and cell death.Herein,its molecular mechanism and protective effect on intracellular oxidative damage were further revealed.The results showed that:(1)BD promoted Nrf2 nuclear translocation and inhibited ubiquitination;(2)Protein kinases(PERK,PI3K,PKC,and MEK1/2)were involved in the regulation of Nrf2 by BD;(3)BD counteracted cell death caused by As(III)and played a protective role in an Nrf2-dependent manner.The novelties of this study include:(1)BD is identified to be an Nrf2 activator for the first time;(2)BD attenuates arsenic-induced oxidative stress in human lung epithelial cells;(3)BD is verified to be a potential preventive agent against oxidative stress-induced damage in human lung tissue.It provides a new structural backbone for the search of Nrf2/ARE activators,which can be chemically modified to discover effective Nrf2 activators2.Inhibition of trans-4,4’-dihydroxystilbene against cigarette smoke-induced chronic obstructive pulmonary diseaseResveratrol is a natural Nrf2 activator with anti-inflammatory and antioxidant properties.However,its application is limited by its relative low activity and poor bioavailability.Herein,based on the skeleton of resveratrol,a series of stilbene derivatives were synthesized,and their Nrf2 inducting abilities were evaluated using luciferase reporter gene experiments,and a potent active stilbene,DHS,was obtained We carried out an in-depth evaluation on its mechanism of activation and its in vitro and in vivo activities,and found that:(1)DHS blocked Nrf2 ubiquitination by specifically reacting with Cysl51 in Keapl,thereby activating the Nrf2 defense response and enhancing intracellular antioxidant capacity.(2)DHS relieved the inflammatory response stimulated by lipopolysaccharide(LPS)by inhibition of NF-κB.(3)In a cigarette smoke(CS)induced pulmonary impairment mice model,DHS obsviously ameliorated pathological alterations(e.g.fibrosis and infiltration of leukocytes),downregulated the contents of oxidative biomarkers[e.g.8-oxo-7,8-dihydro-2’-deoxyguanosin(8-oxo-dG)and malondialdehyde(MDA)],and inhibited excessive productions of inflammatory mediators[e.g.matrix metalloproteinase 9(MMP-9),cyclooxygenase 2(COX-2)and tumor necrosis factor alpha(TNF-α)].This study showed that DHS inhibited oxidative stress and inflammatory response by targeting Nrf2 and NF-κB in vivo and in vitro,thereby attenuating CS-induced pulmonary impairmentThe innovations of this subject include:(1)DHS is identified as an Nrf2 activator for the first time;(2)DHS activates Nrf2 by reacting with Cys151 in Keapl;(3)DHS inhibits inflammatory response by inhibition of NF-κB;(4)DHS could inhibit the progression of chronic obstructive pulmonary disease induced by cigarette smoke.DHS has the potential to be developed as a preventive agent for cigarette smoke-induced COPD.In this paper,the antioxidative and protective mechanisms of the isopimarane-type diterpene BD were deeply investigated.In addition,the anti-inflammatory and anti-oxidant activities and related mechanisms of the stilbene DHS were evaluated systematically in vivo and in vitro.These have injected new strength into the development of preventive and therapeutic agents for COPD.