干预实验性自身免疫性脑脊髓膜炎的天然产物及其作用机制
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摘要
实验性自身免疫性脑脊髓膜炎(experimentalautoimmuneencephalomyelitis,EAE)模型是研究人类多发性硬化(multiplesclerosis,MS)的经典动物模型,研究发现诸多天然产物具有干预EAE的作用。对近10年报道的具有干预EAE活性的生物碱类、黄酮类、萜类、多酚类等天然产物及其作用机制进行综述,为MS等神经自身免疫性疾病临床研究和治疗提供参考。
Experimental autoimmune encephalomyelitis(EAE) is a classic animal model for the study of human multiple sclerosis(MS). A number of studies have found that natural compounds possessed effects on the treatment of EAE. In this paper, we consulted related literatures, classified natural compounds such as alkaloids, flavonoids, terpenoids, and polyphenols, and explained the treatment mechanisms against EAE of Chinese materia medica, and to provide references for clinical research and treatment of neurological autoimmune diseases such as MS.
Experimental autoimmune encephalomyelitis(EAE) is a classic animal model for the study of human multiple sclerosis(MS). A number of studies have found that natural compounds possessed effects on the treatment of EAE. In this paper, we consulted related literatures, classified natural compounds such as alkaloids, flavonoids, terpenoids, and polyphenols, and explained the treatment mechanisms against EAE of Chinese materia medica, and to provide references for clinical research and treatment of neurological autoimmune diseases such as MS.
引文
[1]Simon G,Estelle B.Experimental autoimmune encephalomyelitis(EAE)as animal models of multiple sclerosis(MS)[J].CSH Perspect Med,2018,doi:10.1101/cshperspect.a028977.
[2]Constantinescu C S,Farooqi N,O'Brien K.et al.Experimental autoimmune encephalomyelitis(EAE)as a model for multiple sclerosis(MS)[J].Brit J Pharmacol,2011,164(4):1079-1106.
[3]Ziemssen T,Ziemssen F.The role of the humoral immune system in multiple sclerosis(MS)and its animal model experimental autoimmune encephalomyelitis(EAE)[J].Autoimmu Rev,2005,4(7):460-467.
[4]Liu N,Kan Q C,Zhang X J,et al.Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis[J].Exper Mol Pathol,2014,97(3):470-476.
[5]Zhang M L,Zhang X J,Kang J,et al.Matrine promotes NT3 expression in CNS cells inexperimental autoimmune encephalomyelitis[J].Neurosci Lett,2017,doi:10.1016/j.neulet.2017.04.005.
[6]Zhao X,Zhang X,Lv Y,et al.Matrine downregulates IL-33/ST2 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis[J].Immunol Lett,2016,doi:10.1016/j.imlet.2016.08.007.
[7]Zhu L,Pan Q X,Zhang X J,et al.Protective effects of matrine on experimental autoimmune encephalomyelitis via regulation of ProNGF and NGF signaling[J].Exper Mol Pathol,2016,doi:10.1016/j.yexmp.2015.12.006.
[8]Zhang S,Kan Q C,Xu Y,et al.Inhibitory effect of matrine on blood-brain barrier disruption for the treatment of experimental autoimmune encephalomyelitis[J].Med Inflamm,2013,doi:10.1155/2013/736085.
[9]Ma X,Jiang Y,Wu A,et al.Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6mice[J].PLoS One,2010,5(10):e13489.
[10]Jiang Y,Wu A,Zhu C,et al.The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis[J].Neurol Res,2013,35(4):360-368.
[11]Zeng Y,Gu B,Ji X,et al.Sinomenine,an antirheumatic alkaloid,ameliorates clinical signs of disease in the Lewis rat model of acute experimental autoimmune encephalolmyelitis.[J].Biol Pharm Bull,30(8):1438-1444.
[12]Gu B,Zeng Y,Yin C,et al.Sinomenine reduces i NOSexpression via inhibiting the T-bet IFN-γpathway in experimental autoimmune encephalomyelitis in rats[J].JBiomed Res,2012,26(6):448-455.
[13]Namkwon K,Jimin D,Jae-Sung B,et al.Piperlongumine inhibits neuroinflammation via regulating NF-κBsignaling pathways in lipopolysaccharide-stimulated BV2microglia cells[J].J Pharmacol Sci,2018,137(2):195-201.
[14]Gu S M,Yun J,Son D J,et al.Piperlongumine attenuates experimental autoimmune encephalomyelitis through inhibition of NF-kappaB activity[J].Free Rad Biol Med,2017,doi:10.1016/j.freeradbiomed.2016.12.027.
[15]Wang J,Chen F,Chen Y,et al.Huperzine A ameliorates experimental autoimmune encephalomyelitis via the suppression of T cell-mediated neuronal inflammation in mice[J].Exp Neurol,2012,236(1):79-87.
[16]Tian G X,Zhu X Q,Chen Y,et al.Huperzine A inhibits CCL2 production in experimental autoimmune encephalomyelitis mice and in cultured astrocyte[J].Int JImmunopathol Pharmacol,2013,26(3):757-764.
[17]Daniel P,David B A,Myles M,et al.Amelioration of experimental autoimmune encephalomyelitis by anatabine[J].PLoS One,2013,8(1):e55392.
[18]Paris D,Beaulieu-Abdelahad D,Abdullah L,et al.Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation[J].Eur J Pharmacol,2013,698(1/3):145-153.
[19]Zhang Y,Li X,Ciric B,et al.Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway[J].Sci Rep,2015,doi:10.1038/srep17407.
[20]Xu J,Zhang Y,Xiao Y,et al.Inhibition of12/15-lipoxygenase by baicalein induces microglia PPARβ/δ:A potential therapeutic role for CNSautoimmune disease[J].Cell Death Dis,2013,doi:10.1038/cddis.2013.86.
[21]Dias A T,Castro S B R D,Alves C C D S,et al.Genistein modulates the expression of Toll-like receptors in experimental autoimmune encephalomyelitis[J].Inflamm Res,2018,doi:10.1007/s00011-018-1146-7.
[22]De Paula M L,Rodrigues D H,Teixeira H C,et al.Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis[J].Inter Immunopharmacol,2008,8(9):1291-1297.
[23]Min K,Yoon W K,Sang K K,et al.Immunosuppressive effect of silibinin in experimental autoimmune encephalomyelitis[J].Arch Pharm Res,2007,30(10):1265-1272.
[24]Navabi F,Shaygannejad V,Abbasirad F,et al.Immunoregulatory effects of silymarin on proliferation and activation of Th1 cells isolated from newly diagnosed and IFN-β1b-treated MS patients[J].Inflammation,2018,doi:10.1007/s10753-018-0872-x.
[25]Lee B K,Lee W G,Jung Y S.Chrysin attenuates VCAM-1 expression and monocyte adhesion in lipopolysaccharide-stimulated brain endothelial cells by preventing NF-κB signaling[J].Inter J Mol Sci,2017,doi:10.3390/ijms18071424.
[26]Zhang K,Ge Z,Xue Z,et al.Chrysin suppresses human CD14(+)monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis[J].J Neuroimmunol,2015,doi:10.1016/j.jneuroim.2015.08.017.
[27]Haghmorad D,Mahmoudi M B,Salehipour Z,et al.Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis[J].J Neuroimmunol,2016,doi:10.1016/j.jneuroim.2016.11.009.
[28]Ciftci O,Ozcan C,Kamisli O,et al.Hesperidin,a citrus flavonoid,has the ameliorative effects against experimental autoimmune encephalomyelitis(EAE)in a C57BL/J6 mouse model[J].Neurochem Res,2015,40(6):1111-1120.
[29]Ginwala R,Mctish E,Raman C,et al.Apigenin,a natural flavonoid,attenuates EAE severity through the modulation of dendritic cell and other immune cell functions[J].J Neuroim Pharm,2016,11(1):1-12.
[30]Alge C S,Priglinger S G,Neubauer A S,et al.Retinal pigment epithelium is protected against apoptosis by alphaB-crystallin[J].Invest Ophthalmol Vis Sci,2002,43(11):3575-3582.
[31]Verbeek R,Plomp A C,Tol E A F V,et al.The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells[J].Biochem Pharmacol,2004,68(4):621-629.
[32]Huang B X,Liu J X,Ju C,et al.Licochalcone a prevents the loss of dopaminergic neurons by inhibiting microglial activation in lipopolysaccharide(LPS)-induced Parkinson’s disease models[J].Inter J Mol Sci,2017,doi:10.3390/ijms18102043.
[33]Fontes L B,Dos Santos D D,de Carvalho L S,et al.Immunomodulatory effects of licochalcone A on experimental autoimmune encephalomyelitis[J].J Pharm Pharmacol,2014,66(6):886-894.
[34]Wang Y,Mei Y,Feng D,et al.Triptolide modulates T-cell inflammatory responses and ameliorates experimental autoimmune encephalomyelitis[J].J Neur Res,2008,86(11):2441-2449.
[35]Kizelsztein P,Komarnytsky S,Raskin I.Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis(EAE)by induction of HSP70 and stabilization of NF-κB/IκBαtranscriptional complex[J].J Neuroimmunol,2009,doi:10.1016/j.jneuroim.2009.08.017.
[36]Iruretagoyena M I,Tobar J A,González P A,et al.Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse[J].J Pharmacol Exper Ther,2005,312(1):366-372.
[37]Iruretagoyena M I,Sepúlveda S E,Lezana J P,et al.Inhibition of nuclear factor-kappa B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis[J].J Pharm Exper Ther,2006,doi:10.1124/jpet.106.103259.
[38]Wang L,Zhao W L,Yan J S,et al.Eriocalyxin B induces apoptosis of t(8;21)leukemia cells through NF-kappaBand MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner[J].Cell Death Differ,2007,14(2):306-317.
[39]Lu Y,Chen B,Song J H,et al.Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells[J].PNAS,2013,110(6):2258-2263.
[40]Yin Q Q,Liu C X,Wu Y L,et al.Preventive and therapeutic effects of adenanthin on experimental autoimmune encephalomyelitis by inhibiting NF-kBsignaling[J].J Immunol,2013,191(5):2115-2125.
[41]Crume K P,O'Sullivan D,Miller J H,et al.Delaying the onset of experimental autoimmune encephalomyelitis with the microtubule-stabilizing compounds,paclitaxel and peloruside A[J].J Leukoc Biol,2009,86(4):949-958.
[42]O'Sullivan D,Miller J H,Northcote P T,et al.Microtubule-stabilizing agents delay the onset of EAEthrough inhibition of migration[J].Immunol Cell Biol,2013,91(9):583-592.
[43]Lsa D C,Lba F,Gazolla M C,et al.Parthenolide modulates immune response in cells from C57BL/6 mice induced with experimental autoimmune encephalomyelitis[J].Planta Med,2016,83(8):693-700.
[44]Fiebich B L,Lieb K,Engels S,et al.Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells[J].J Neuroimmunol,2002,132(1/2):18-24.
[45]He Y X,Du M,Gao Y,et al.Astragaloside IV attenuates experimental autoimmune encephalomyelitis of mice by counteracting oxidative stress at multiple levels[J].PLoSOn E,2013,8(10):e76495.
[46]Liu H S,Shi H L,Huang F,et al.Astragaloside IVinhibits microglia activation via glucocorticoid receptor mediated signaling pathway[J].Sci Rep,2016,doi:10.1038/srep19137.
[47]Yang L,Xing F,Han X,et al.Astragaloside IV regulates differentiation and induces apoptosis of activated CD4+Tcells in the pathogenesis of experimental autoimmune encephalomyelitis[J].Toxicol Appl Pharmacol,2019,doi:10.1016/j.taap.2018.10.024.
[48]Singh N P,Hegde V L,Hofseth L J,et al.Resveratrol(trans-3,5,4′-trihydroxystilbene)ameliorates experimental allergic encephalomyelitis,primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor[J].Mol Pharmacol,2007,72(6):1508-1521.
[49]Shindler K S,Ventura E,Dutt M,et al.Oral resveratrol reduces neuronal damage in a model of multiple sclerosis[J].J Neuro-Ophthalmol,2010,30(4):328-339.
[50]Natarajan C,Bright J J.Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes[J].J Immunol,2002,168(12):6506-6513.
[51]Fahey A J,Adrian R R,Constantinescu C S.Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells[J].J Cell Mol Med,2007,11(5):1129-1137.
[52]Zhang K,Ge Z,Da Y,et al.Plumbagin suppresses dendritic cell functions and alleviates experimental autoimmune encephalomyelitis[J].J Neuroimmunol,2014,273(1/2):42-52.
[53]Jia Y,Jing J,Bai Y,et al.Amelioration of experimental autoimmune encephalomyelitis by plumbagin through down-regulation of JAK-STAT and NF-κB signaling pathways[J].PLoS One,2011,6(10):e27006.
[54]Wang D,Lu Z,Zhang H,et al.Daphnetin alleviates experimental autoimmune encephalomyelitis via regulating dendritic cell activity[J].CNS Neur Ther,2016,doi:10.1111/cns.12537.
[55]Song B,Wang Z,Liu Y,et al.Immunosuppressive activity of daphnetin,one of coumarin derivatives,is mediated through suppression of NF-κB and NFATsignaling pathways in mouse T cells[J].PLoS One,2014,9(5):e96502.
[56]Chen X,Pi R,Zou Y,et al.Attenuation of experimental autoimmune encephalomyelitis in C57 BL/6 mice by osthole,a natural coumarin[J].Eur J Pharmacol,2010,629(1/3):40-46.
[57]Gao Z,Wen Q,Xia Y,et al.Osthole augments therapeutic efficiency of neural stem cells-based therapy in experimental autoimmune encephalomyelitis[J].JPharmacol Sci,2014,124(1):54-65.
[58]Zamvil S S,Steinman L.How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis[J].Annal Neurol,2010,60(1):12-21.
[2]Constantinescu C S,Farooqi N,O'Brien K.et al.Experimental autoimmune encephalomyelitis(EAE)as a model for multiple sclerosis(MS)[J].Brit J Pharmacol,2011,164(4):1079-1106.
[3]Ziemssen T,Ziemssen F.The role of the humoral immune system in multiple sclerosis(MS)and its animal model experimental autoimmune encephalomyelitis(EAE)[J].Autoimmu Rev,2005,4(7):460-467.
[4]Liu N,Kan Q C,Zhang X J,et al.Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis[J].Exper Mol Pathol,2014,97(3):470-476.
[5]Zhang M L,Zhang X J,Kang J,et al.Matrine promotes NT3 expression in CNS cells inexperimental autoimmune encephalomyelitis[J].Neurosci Lett,2017,doi:10.1016/j.neulet.2017.04.005.
[6]Zhao X,Zhang X,Lv Y,et al.Matrine downregulates IL-33/ST2 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis[J].Immunol Lett,2016,doi:10.1016/j.imlet.2016.08.007.
[7]Zhu L,Pan Q X,Zhang X J,et al.Protective effects of matrine on experimental autoimmune encephalomyelitis via regulation of ProNGF and NGF signaling[J].Exper Mol Pathol,2016,doi:10.1016/j.yexmp.2015.12.006.
[8]Zhang S,Kan Q C,Xu Y,et al.Inhibitory effect of matrine on blood-brain barrier disruption for the treatment of experimental autoimmune encephalomyelitis[J].Med Inflamm,2013,doi:10.1155/2013/736085.
[9]Ma X,Jiang Y,Wu A,et al.Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6mice[J].PLoS One,2010,5(10):e13489.
[10]Jiang Y,Wu A,Zhu C,et al.The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis[J].Neurol Res,2013,35(4):360-368.
[11]Zeng Y,Gu B,Ji X,et al.Sinomenine,an antirheumatic alkaloid,ameliorates clinical signs of disease in the Lewis rat model of acute experimental autoimmune encephalolmyelitis.[J].Biol Pharm Bull,30(8):1438-1444.
[12]Gu B,Zeng Y,Yin C,et al.Sinomenine reduces i NOSexpression via inhibiting the T-bet IFN-γpathway in experimental autoimmune encephalomyelitis in rats[J].JBiomed Res,2012,26(6):448-455.
[13]Namkwon K,Jimin D,Jae-Sung B,et al.Piperlongumine inhibits neuroinflammation via regulating NF-κBsignaling pathways in lipopolysaccharide-stimulated BV2microglia cells[J].J Pharmacol Sci,2018,137(2):195-201.
[14]Gu S M,Yun J,Son D J,et al.Piperlongumine attenuates experimental autoimmune encephalomyelitis through inhibition of NF-kappaB activity[J].Free Rad Biol Med,2017,doi:10.1016/j.freeradbiomed.2016.12.027.
[15]Wang J,Chen F,Chen Y,et al.Huperzine A ameliorates experimental autoimmune encephalomyelitis via the suppression of T cell-mediated neuronal inflammation in mice[J].Exp Neurol,2012,236(1):79-87.
[16]Tian G X,Zhu X Q,Chen Y,et al.Huperzine A inhibits CCL2 production in experimental autoimmune encephalomyelitis mice and in cultured astrocyte[J].Int JImmunopathol Pharmacol,2013,26(3):757-764.
[17]Daniel P,David B A,Myles M,et al.Amelioration of experimental autoimmune encephalomyelitis by anatabine[J].PLoS One,2013,8(1):e55392.
[18]Paris D,Beaulieu-Abdelahad D,Abdullah L,et al.Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation[J].Eur J Pharmacol,2013,698(1/3):145-153.
[19]Zhang Y,Li X,Ciric B,et al.Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway[J].Sci Rep,2015,doi:10.1038/srep17407.
[20]Xu J,Zhang Y,Xiao Y,et al.Inhibition of12/15-lipoxygenase by baicalein induces microglia PPARβ/δ:A potential therapeutic role for CNSautoimmune disease[J].Cell Death Dis,2013,doi:10.1038/cddis.2013.86.
[21]Dias A T,Castro S B R D,Alves C C D S,et al.Genistein modulates the expression of Toll-like receptors in experimental autoimmune encephalomyelitis[J].Inflamm Res,2018,doi:10.1007/s00011-018-1146-7.
[22]De Paula M L,Rodrigues D H,Teixeira H C,et al.Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis[J].Inter Immunopharmacol,2008,8(9):1291-1297.
[23]Min K,Yoon W K,Sang K K,et al.Immunosuppressive effect of silibinin in experimental autoimmune encephalomyelitis[J].Arch Pharm Res,2007,30(10):1265-1272.
[24]Navabi F,Shaygannejad V,Abbasirad F,et al.Immunoregulatory effects of silymarin on proliferation and activation of Th1 cells isolated from newly diagnosed and IFN-β1b-treated MS patients[J].Inflammation,2018,doi:10.1007/s10753-018-0872-x.
[25]Lee B K,Lee W G,Jung Y S.Chrysin attenuates VCAM-1 expression and monocyte adhesion in lipopolysaccharide-stimulated brain endothelial cells by preventing NF-κB signaling[J].Inter J Mol Sci,2017,doi:10.3390/ijms18071424.
[26]Zhang K,Ge Z,Xue Z,et al.Chrysin suppresses human CD14(+)monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis[J].J Neuroimmunol,2015,doi:10.1016/j.jneuroim.2015.08.017.
[27]Haghmorad D,Mahmoudi M B,Salehipour Z,et al.Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis[J].J Neuroimmunol,2016,doi:10.1016/j.jneuroim.2016.11.009.
[28]Ciftci O,Ozcan C,Kamisli O,et al.Hesperidin,a citrus flavonoid,has the ameliorative effects against experimental autoimmune encephalomyelitis(EAE)in a C57BL/J6 mouse model[J].Neurochem Res,2015,40(6):1111-1120.
[29]Ginwala R,Mctish E,Raman C,et al.Apigenin,a natural flavonoid,attenuates EAE severity through the modulation of dendritic cell and other immune cell functions[J].J Neuroim Pharm,2016,11(1):1-12.
[30]Alge C S,Priglinger S G,Neubauer A S,et al.Retinal pigment epithelium is protected against apoptosis by alphaB-crystallin[J].Invest Ophthalmol Vis Sci,2002,43(11):3575-3582.
[31]Verbeek R,Plomp A C,Tol E A F V,et al.The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells[J].Biochem Pharmacol,2004,68(4):621-629.
[32]Huang B X,Liu J X,Ju C,et al.Licochalcone a prevents the loss of dopaminergic neurons by inhibiting microglial activation in lipopolysaccharide(LPS)-induced Parkinson’s disease models[J].Inter J Mol Sci,2017,doi:10.3390/ijms18102043.
[33]Fontes L B,Dos Santos D D,de Carvalho L S,et al.Immunomodulatory effects of licochalcone A on experimental autoimmune encephalomyelitis[J].J Pharm Pharmacol,2014,66(6):886-894.
[34]Wang Y,Mei Y,Feng D,et al.Triptolide modulates T-cell inflammatory responses and ameliorates experimental autoimmune encephalomyelitis[J].J Neur Res,2008,86(11):2441-2449.
[35]Kizelsztein P,Komarnytsky S,Raskin I.Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis(EAE)by induction of HSP70 and stabilization of NF-κB/IκBαtranscriptional complex[J].J Neuroimmunol,2009,doi:10.1016/j.jneuroim.2009.08.017.
[36]Iruretagoyena M I,Tobar J A,González P A,et al.Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse[J].J Pharmacol Exper Ther,2005,312(1):366-372.
[37]Iruretagoyena M I,Sepúlveda S E,Lezana J P,et al.Inhibition of nuclear factor-kappa B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis[J].J Pharm Exper Ther,2006,doi:10.1124/jpet.106.103259.
[38]Wang L,Zhao W L,Yan J S,et al.Eriocalyxin B induces apoptosis of t(8;21)leukemia cells through NF-kappaBand MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner[J].Cell Death Differ,2007,14(2):306-317.
[39]Lu Y,Chen B,Song J H,et al.Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells[J].PNAS,2013,110(6):2258-2263.
[40]Yin Q Q,Liu C X,Wu Y L,et al.Preventive and therapeutic effects of adenanthin on experimental autoimmune encephalomyelitis by inhibiting NF-kBsignaling[J].J Immunol,2013,191(5):2115-2125.
[41]Crume K P,O'Sullivan D,Miller J H,et al.Delaying the onset of experimental autoimmune encephalomyelitis with the microtubule-stabilizing compounds,paclitaxel and peloruside A[J].J Leukoc Biol,2009,86(4):949-958.
[42]O'Sullivan D,Miller J H,Northcote P T,et al.Microtubule-stabilizing agents delay the onset of EAEthrough inhibition of migration[J].Immunol Cell Biol,2013,91(9):583-592.
[43]Lsa D C,Lba F,Gazolla M C,et al.Parthenolide modulates immune response in cells from C57BL/6 mice induced with experimental autoimmune encephalomyelitis[J].Planta Med,2016,83(8):693-700.
[44]Fiebich B L,Lieb K,Engels S,et al.Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells[J].J Neuroimmunol,2002,132(1/2):18-24.
[45]He Y X,Du M,Gao Y,et al.Astragaloside IV attenuates experimental autoimmune encephalomyelitis of mice by counteracting oxidative stress at multiple levels[J].PLoSOn E,2013,8(10):e76495.
[46]Liu H S,Shi H L,Huang F,et al.Astragaloside IVinhibits microglia activation via glucocorticoid receptor mediated signaling pathway[J].Sci Rep,2016,doi:10.1038/srep19137.
[47]Yang L,Xing F,Han X,et al.Astragaloside IV regulates differentiation and induces apoptosis of activated CD4+Tcells in the pathogenesis of experimental autoimmune encephalomyelitis[J].Toxicol Appl Pharmacol,2019,doi:10.1016/j.taap.2018.10.024.
[48]Singh N P,Hegde V L,Hofseth L J,et al.Resveratrol(trans-3,5,4′-trihydroxystilbene)ameliorates experimental allergic encephalomyelitis,primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor[J].Mol Pharmacol,2007,72(6):1508-1521.
[49]Shindler K S,Ventura E,Dutt M,et al.Oral resveratrol reduces neuronal damage in a model of multiple sclerosis[J].J Neuro-Ophthalmol,2010,30(4):328-339.
[50]Natarajan C,Bright J J.Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes[J].J Immunol,2002,168(12):6506-6513.
[51]Fahey A J,Adrian R R,Constantinescu C S.Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells[J].J Cell Mol Med,2007,11(5):1129-1137.
[52]Zhang K,Ge Z,Da Y,et al.Plumbagin suppresses dendritic cell functions and alleviates experimental autoimmune encephalomyelitis[J].J Neuroimmunol,2014,273(1/2):42-52.
[53]Jia Y,Jing J,Bai Y,et al.Amelioration of experimental autoimmune encephalomyelitis by plumbagin through down-regulation of JAK-STAT and NF-κB signaling pathways[J].PLoS One,2011,6(10):e27006.
[54]Wang D,Lu Z,Zhang H,et al.Daphnetin alleviates experimental autoimmune encephalomyelitis via regulating dendritic cell activity[J].CNS Neur Ther,2016,doi:10.1111/cns.12537.
[55]Song B,Wang Z,Liu Y,et al.Immunosuppressive activity of daphnetin,one of coumarin derivatives,is mediated through suppression of NF-κB and NFATsignaling pathways in mouse T cells[J].PLoS One,2014,9(5):e96502.
[56]Chen X,Pi R,Zou Y,et al.Attenuation of experimental autoimmune encephalomyelitis in C57 BL/6 mice by osthole,a natural coumarin[J].Eur J Pharmacol,2010,629(1/3):40-46.
[57]Gao Z,Wen Q,Xia Y,et al.Osthole augments therapeutic efficiency of neural stem cells-based therapy in experimental autoimmune encephalomyelitis[J].JPharmacol Sci,2014,124(1):54-65.
[58]Zamvil S S,Steinman L.How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis[J].Annal Neurol,2010,60(1):12-21.