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Andrographolide restores steroid sensitivity to block LPS/IFNγ-induced IL-27 and airway hyper-responsiveness in mice

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中国药理学与毒理学杂志 2015年第S1期29卷 50-51页

作者： Wu-pengLIAO WanShunDanielTAN wai-shiufredwong Department of Pharmacology Yong Loo Lin School of Medicine National University Health System Singapore Immunology Program Life Science Institute National University of Singapore Singapore

OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential mediator *** investigated whether andrographolide,apreviously demonstrated anti-inflammatory bioactive molecule extracted from the plant Andrographis paniculata,could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR viaits anti-oxidative *** Mouse macrophage cell line Raw264.7,mouse primary pulmonary monocyte/macrophage,and BALB/c mouse were treated with LPS/IFN-γ,in the presence and absence of increasing doses of dexamethasone and/or *** and protein levels of IL-27 in vitro and in vivo were examined,and mouse AHR was *** Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 and AHR in *** significantly facilitated the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 level in macrophage cell line and primary monocyte/macrophage,mouse bronchoalveolar lavage fluid and lung tissue,and furthermore on the incurring ***/IFN-γdid not impede nuclear translocation of glucocorticoid receptors but diminishthe protein level of histone deacetylase-2(HDAC2),an essential epigenetic enzymeresponsible for steroid anti-inflammatory *** at low doses(5μmol·L-1 in vitro;1mg·kg-1,ip in vivo)restored nuclear HDAC2 protein levels both in cells and in mouse lungs,possibly via suppression of PI3K/Akt signaling pathway and up-regulation of the anti-oxidative transcription factor *** Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.

关键词： IL-27 andrographolide LPS IFN-γ airway hyper-respo

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Anti-malarial drug,artesunate,as a novel therapeutic drug target for airway wall remodeling in asthma

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中国药理学与毒理学杂志 2015年第S1期29卷 54-55页

作者： SherylTAN BenjaminONG ChangCHENG WanxingEugeneHO JohnK.CTAM AlastairG.STEWART TrudiHARRIS wai-shiufredwong ThaiTRAN Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Saw Swee Hock School of Public Health National University Health System Singapore Department of Surgery Yong Loo Lin School of Medicine National University of Singapore Singapore Department of Pharmacology University of Melbourne Australia

OBJECTIVE Airway wall remodeling(AWR),which refers to structural changes in the airway,is a key characteristic of *** smooth muscle(ASM)cell hypertrophy and hyperplasia contributes to ***,which are used as first line therapy for the treatment of asthma,reduce ASM proliferation but the magnitude of their anti-proliferative actions is dependent on the mitogen ***,glucocorticoid therapy is accompanied by many side ***,a semi-synthetic artemisinin derivative,has been widely used to treat malaria with minimal *** has been shown to attenuate allergic airway inflammation in ***,its role in treating AWR in asthma is not *** this study,we hypothesize that artesunate has anti-proliferative actions on ASM cells,potentially reversing *** and RESULTS Quiescent primary human ASM cells were pre-treated(1h)with artesunate(3,10,30μmol·L-1)before being stimulated with either FBS(10%)or thrombin(0.3U·mL-1).Following 48 h stimulation with mitogen,cells were counted using a ***(Dex,100nmol·L-1)was used as a positive *** concentration-dependently reduced cell number and the magnitude of inhibition appeared to be non-mitogen ***,we examined the effect of artesunate on two important signalling proteins involved in cell proliferation,ERK1/2phosphorylation and cyclin D1 protein *** reduced cyclin D1 protein levels significantly following 20 h stimulation with either thrombin or FBS but had no effect on ERK1/2 phosphorylation following 6h ***,artesunate(30μmol·L-1),but not Dex,inhibited the phosphorylation of Akt,which is upstream of cyclin ***,we show that the inhibitory effect of artesunate,but not Dex,on ASM cell number is retained at least 24h post-treatment following stimulation with *** an acute murine model of allergic asthma,artesunate treatment decreased sm-α-actin positive cells and cyclin D1 protein

关键词： asthma airway wall remodeling PI3K cyclin D1

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Vitamin E isoform γ-tocotrienol alleviates cigarette smoke-induced chronic obstructive pulmonary disease

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中国药理学与毒理学杂志 2015年第S1期29卷 51-51页

作者： HongYongPEH WanShunDanielTAN TzeKheeCHAN ChenWeiPOW ChoonNamONG wai-shiufredwong Department of Pharmacology Yong Loo Lin School of Medicine National University Health System Singapore Immunology Program Life Science Institute National University of Singapore Singapore-MIT Alliance for Research and Technology Singapore Saw Swee Hock School of Public Health National University Health System Singapore

OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the *** E isoformγ-tocotrienol possesses both anti-oxidative and anti-inflammatory *** hypothesized thatγ-tocotrienol may have protective effects against *** BALB/c mice were exposedto cigarette smoke daily for 2 weeks with oralγ-tocotrienol treatment in the second *** lavage(BAL)fluid was assessed for total and differential cell counts,oxidative damage biomarkers,and cytokine *** tissues were examined for the expression of antioxidants and pro-inflammatory *** order to measure changes in lung functions in COPD,another set of mice was exposed to cigarette smoke for 2 months with oralγ-tocotrienol treatment in the last 2 ***γ-Tocotrienol dose-dependently abated cigarette smoke-induced elevation of BAL fluid total and neutrophil cell counts,cytokine and chemokine(IL-1β,IL-6,IL-17,LIX,G-CSF,KC,RANTES and VEGF)levels,as well as oxidative/nitrosative damage biomarker(advanced oxidation of protein products,8-isoprostane,8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine)levels.γ-Tocotrienol promoted total lung antioxidant capacity and endogenous antioxidant activities of superoxide dismutase,catalase and glutathione *** importantly,γ-tocotrienol markedly restored work of breathing and lung functions(total lung capacity,static compliance and FEV100/FVC)in chronic experimental ***,γ-tocotrienol demonstrated better anti-oxidative,anti-inflammatory,and restoration of lung functions in COPD than *** We have shown for the first time the efficacy of vitamin E isomerγ-tocotrienol in protection against cigarette smoke-induced COPD by direct neutralization of free radicals,abating oxidative damage,and restoring antioxidants activities,coupled with anti-inflammatory actions in the inflamed airways.

关键词： cigarette smoke inflammation oxidative damage lung

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Non-typeable haemophilus influenzae-induced exacerbation on a cigarette smoke lung injury model:Protective effect of andrographolide

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中国药理学与毒理学杂志 2015年第S1期29卷 54-54页

作者： Wan-shunDanielTAN Hong-yonPEH Chu-huiPANG Wu-pengLIAO Tze-kheeCHAN Suk-hiangLAU VincentT.K.CHOW wai-shiufredwong Immunology Program Life Science Institute National University of Singapore Department of Pharmacology Yong Loo Lin School of Medicine National University Health System Interdisciplinary Research Group in Infectious Diseases Singapore-MIT Alliance for Research and Technology Department of Microbiology Yong Loo Lin School of Medicine National University of Singapore

OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD *** Female BALB/c mice,6-8-week-old,were exposed to 4% 3R4 FCS delivered using aperistaltic pump daily for 2 weeks to induce an acute lung injury *** 2 weeks of smoking,mice were inoculated intratracheally with NTHi to induce exacerbation on the *** were sacrificed 48 h after last bacteria challenge and lung samples were collected for various *** After developing a 2-week CS acute lung injury model exacerbated by NTHi,the CS+NTHi group was shown to have a higher inflammatory response,higher bacterial clearance,an upregulation of MMP12 mRNA levels and decrease in TIMP1 mRNA levels in the *** of Andrographolide suppressed BALF lung cellular infiltrates,TNF-α,CXCL1/KC,IL-1βand 8-OHdG protein levels,together with increased HO-1 and GR mRNA levels and decreased MMP-8 and MMP-9 mRNA *** was able to ameliorate lung histopathology as observed with H&E staining and inflammation *** was also shown to reduce Keap-1 level in lungs without affecting DJ-1 *** This study demonstrates the protective effect of andrographolide in a novel 2-week CS acute lung injury model exacerbated by NTHi and presents it as a potential therapeutic for COPD.

关键词： COPD haemophilus influenzae smoke andrographolide

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