基于网络药理学探讨圣草酚对树突状细胞成熟的影响及分子机制Effect of Eriodictyolon the Maturation of Dendritic Cell and the Molecular Mechanism Based on Network Pharmacology
刘晓颖,阿力木·艾麦尔,樊栩,王为兰,王新绘,李金耀
摘要(Abstract):
为探讨圣草酚对树突状细胞(dendritic cell, DC)成熟影响及其分子作用机制,基于网络药理学,通过多个数据平台获得圣草酚对DC、免疫抑制及炎症反应的相关靶点.采用Cytoscape 3.6.1软件构建活性成分潜在靶点网络,并利用String平台构建蛋白相互作用(PPI)网络.利用Metascape平台进行GO和KEGG富集分析,利用Autodock Vina软件进行分子对接.不同浓度(210μM、280μM和350μM)圣草酚单独或与细菌脂多糖(LPS)联用处理DC,流式细胞术检测细胞表面分子表达,ELISA检测细胞因子表达,Western blot检测基质金属蛋白MMP9的表达.获得圣草酚作用靶点96个,DC相关72个,免疫抑制相关14个,炎症反应相关48个,共有核心靶点包括AKT1、SRC、MMP9及MMP2等,主要关联氧化应激及细胞迁移等生物学过程,涉及癌症的信号通路、Ras信号通路、表皮生长因子受体酪氨酸激酶抑制剂抗性、c型凝集素受体信号通路、肿瘤坏死因子信号通路等信号通路.分子对接显示,圣草酚与MMP9具有更强的结合作用.体外实验显示,圣草酚能显著抑制LPS诱导的DC表面分子CD40(P<0.01)和CD86(P<0.001)、细胞因子TNF-α(P<0.001)及IL-6(P<0.001)以及基质金属蛋白酶MMP9(P<0.01)的表达.圣草酚通过抑制DC表面共刺激分子CD40和CD86、促炎细胞因子TNF-α和IL-6表达及MMP9等抑制DC成熟及迁移.
关键词(KeyWords): 圣草酚;树突状细胞;网络药理学;免疫抑制
基金项目(Foundation): 国家自然科学基金(31760260);; 新疆大学博士科研启动基金(BS160261)
作者(Author): 刘晓颖,阿力木·艾麦尔,樊栩,王为兰,王新绘,李金耀
DOI: 10.13568/j.cnki.651094.651316.2021.04.10.0002
参考文献(References):
- [1]LI J,WANG X,WANG W,et al.Pleurotus ferulae water extract enhances the maturation and function of murine bone marrowderived dendritic cells through TLR4 signaling pathway[J].Vaccine,2015,33(16):1923-1933.
- [2]BOLTJES A,WIJK F V.Human dendritic cell functional specialization in steady-state and infammation[J].Frontiers in Immunology,2014,5:131.
- [3]AZEGULI H,LI J Y,ZHOU F F,et al.Capparis spinosa fruit ethanol extracts exert different effects on the maturation of dendritic cells[J].Molecules,2017,22(1):97.
- [4]LIN M K,YU Y L,CHEN K C,et al.Kaempferol from Semen cuscutae attenuates the immune function of dendritic cells[J].Immunobiology,2011,216(10):1103-1109.
- [5]ZHAO Y,LI J,YU K,et al.Sinomenine inhibits maturation of monocyte-derived dendritic cells through blocking activation of NF-kappa B[J].International Immunopharmacology,2007,7(5):637-645.
- [6]LIU L,LIAO P,WANG B,et al.Oral administration of baicalin and geniposide induces regression of atherosclerosis via inhibiting dendritic cells in Apo E-knockout mice[J].International Immunopharmacology,2014,20(1):197-204.
- [7]CHEN C A,LIU C K,HSU M L,et al.Daphnoretin modulates differentiation and maturation of human dendritic cells through down-regulation of c-Jun N-terminal kinase[J].International Immunopharmacology,2017,51:25-30.
- [8]ZHANG R Z,YU S J,BAI H,et al.TCM-mesh:the database and analytical system for network pharmacology analysis for TCMpreparations[J].Scientific Reports,2017,7(1):2821.
- [9]WANG Z,LAN Y,CHEN M,et al.Eriodictyol,not its glucuronide metabolites,attenuates acetaminopheninduced hepatotoxicity[J].Molecular Pharmaceutics,2017,14(9):2937-2951.
- [10]ISLAM A,ISLAM S,RAHMAN K,et al.The pharmacological and biological roles of eriodictyol[J].Archives of Pharmacal Research,2020,43(6):582-592.
- [11]WANG Y S,CHEN Y,CHEN Y,et al.Eriodictyol inhibits IL-1β-induced infammatory response in human osteoarthritis chondrocytes[J].Biomedicine&Pharmacotherapy,2018,107:1128-1134.
- [12]WANG R,SHEN L.Effect of eriodictyol on Nrf2/HO-1 pathway in mice experimental colitis[J].Chinese Journal of Immunology,2020,36(8):928-932.
- [13]WANG X,DENG R,DONG J,et al.Eriodictyol ameliorates lipopolysaccharide-induced acute lung injury by suppressing the infammatory COX-2/NLRP3/NF-κB pathway in mice[J].Journal of Biochemical and Molecular Toxicology,2020,34(3):e22434.
- [14]OSMAN M,TORTORELLA M,LONDEI M,et al.Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases define the migratory characteristics of human monocyte-derived dendritic cells[J].Immunology,2002,105:73-82.
- [15]ZOZULYA A L,REINKE E,BAIU D C,et al.Dendritic cell transmigration through brain microvessel endothelium is regulated by MIP-1αchemokine and matrix metalloproteinases[J].The Journal of Immunology,2007,178(1):520-529.
- [16]SOUSA C R E.Dendritic cells in a mature age[J].Nature Reviews Immunology,2006,6(6):476-483.
- [17]YU S M,KIM S J.Withaferin A-caused production of intracellular reactive oxygen species modulates apoptosis via PI3K/Akt and JNKinase in rabbit articular chondrocytes[J].Journal of Korean Medical Science,2014,29(8):1042-1053.
- [18]SUGIMORI K,MATSUI K,MOTOMURA H,et al.BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-κB activation[J].Journal of Bone&Mineral Metabolism,2005,23(6):411-419.
- [19]LEE K N,SEO M C,BAE I H,et al.COMP-Ang1,a variant of angiopoietin1,inhibits serum-deprived apoptosis of mesenchymal cells via PI3K/Akt and mitogen-activated protein kinase pathways[J].Pharmacology,2010,86(5/6):327-335.
- [20]LI X,WANG Y.Cinnamaldehyde attenuates the progression of rheumatoid arthritis through down-regulation of PI3K/Akt signaling pathway[J].Infammation,2020,43(9746):1729-1741.
- [21]XIANG M,LIU T T,TAN W Y,et al.Effects of kinsenoside,a potential immunosuppressive drug for autoimmune hepatitis,on dendritic cells/CD8+T cells communication in mice[J].Hepatology,2016,64(6):2135-2150.
- [22]LIU Y C,YAN X N.Eriodictyol inhibits survival and infammatory responses and promotes apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through AKT/FOXO1 signaling[J].Journal of Cellular Biochemistry,2019,120(9):14628-14635.
- [23]LIU J F,CHEN P C,CHANG T M,et al.Thrombospondin-2 stimulates MMP-9 production and promotes osteosarcoma metastasis via the PLC,PKC,c-Src and NF-κB activation[J].Journal of Cellular and Molecular Medicine,2020,24(21):12826-12839.
- [24]ALAMGEER,UMME H H,AMBEREN M U,et al.Phytochemicals targeting matrix metalloproteinases regulating tissue degradation in infammation and rheumatoid arthritis[J].Phytomedicine,2020,66:153134.