基于表观遗传调控的中药防治类风湿关节炎作用机制研究进展
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摘要
表观遗传修饰(epigenetic modifications)代表了调节基因表达的重要机制,使人体能够适应不断变化的环境。应用表观遗传学修饰研究方法是自身免疫疾病机制研究的前沿领域,类风湿关节炎(rheumatoid arthritis,RA)是自身免疫性疾病研究领域的难点之一,其病因不明,发病机制复杂,至今仍然缺乏理想的治疗药物与方法。中医药治疗RA具有独特优势,新近研究发现中药单体成分和复方通过作用于表观遗传修饰而治疗RA。该文拟对表观遗传学在RA发生、发展中的机制,以及中药通过调控表观遗传防治RA的作用进行综述,以期为中药治疗RA临床疗效及其作用机制研究提供新的思路。
Epigenetic modifications represent an important mechanism underlying regulation of gene expression that enables human body to adapt to the changing environment. Research methods of epigenetic modifications are a frontier area for the study of molecular mechanisms underlying the pathogenesis of autoimmune diseases. Rheumatoid arthritis( RA) has been one of the difficulties in both clinical and basic-research fields of autoimmune diseases. The etiology of RA remains elusive,and its pathogenesis involves complex immune and inflammatory pathways. Clinically ideal therapeutic approaches are still lacking for treatment of RA. Recent studies have shown that Chinese herbalmedicine and bioactive components there of potentially target epigenetic modifications in the treatment of RA. In order to provide new research ideas for therapeutic interventions and mechanistic studies of RA,we here reviewed and summarized literature on the epigenetic mechanism underlying the generation and development of RA and therapeutic effects of Chinese herbal medicine in RA that involve targeting epigenetic modifications.
Epigenetic modifications represent an important mechanism underlying regulation of gene expression that enables human body to adapt to the changing environment. Research methods of epigenetic modifications are a frontier area for the study of molecular mechanisms underlying the pathogenesis of autoimmune diseases. Rheumatoid arthritis( RA) has been one of the difficulties in both clinical and basic-research fields of autoimmune diseases. The etiology of RA remains elusive,and its pathogenesis involves complex immune and inflammatory pathways. Clinically ideal therapeutic approaches are still lacking for treatment of RA. Recent studies have shown that Chinese herbalmedicine and bioactive components there of potentially target epigenetic modifications in the treatment of RA. In order to provide new research ideas for therapeutic interventions and mechanistic studies of RA,we here reviewed and summarized literature on the epigenetic mechanism underlying the generation and development of RA and therapeutic effects of Chinese herbal medicine in RA that involve targeting epigenetic modifications.
引文
[1] Smolen J S,Aletaha D,Barton A,et al. Rheumatoid arthritis[J].Nat Rev Dis Primers,2018,4:18001.
[2] Mc Innes I B,Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis[J]. Lancet,2017,389(10086):2328-37.
[3]余黄合,曾嵘,李鑫,等.土家族药物血筒抗佐剂性关节炎药效作用研究[J].中国药理学通报,2016,32(10):1427-32.[3] Yu H H,Zeng R,Li X,et al. Tujia ethnomedicine Xuetong suppresses onset and progression of adjuvantinduced arthritis in rats[J]. Chin Pharmacol Bull,2016,32(10):1427-32.
[4] Ospelt C,Gay S,Klein K. Epigenetics in the pathogenesis of RA[J]. Semin Immunopathol,2017,39(4):409-19.
[5] Takami N,Osawa K,Miura Y,et al. Hypermethylated promoter region of DR3,the death receptor 3 gene,in rheumatoid arthritis synovial cells[J]. Arthritis Rheum,2006,54(3):779-87.
[6]缪成贵,黄成,黄艳,等. Wnt调控类风湿性关节炎研究进展[J].中国药理学通报,2013,29(2):149-53.[6] Miao C G,Huang C,Huang Y,et al. Research progress of the Wnt in rheumatoid arthritis[J]. Chin Pharmacol Bull,2013,29(2):149-53.
[7] Sun Z H,Liu Y H,Liu J D,et al. Me CP2 regulates PTCH1 expression through DNA methylation in rheumatoid arthritis[J]. Inflammation,2017,40(5):1497-508.
[8] Zhang Y,Zhang B. Trichostatin A,an inhibitor of histone deacetylase,inhibits the viability and invasiveness of hypoxic rheumatoid arthritis fibroblast-like synoviocytes via PI3K/Akt signaling[J]. J Biochem Mol Toxicol,2016,30(4):163-9.
[9] Chung Y L,Lee M Y,Wang A J,et al. A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis[J]. Mol Ther,2003,8(5):707-17.
[10]李会丹,孙悦,火蓉芬,等.组蛋白去乙酰化酶1通过NF-κB调控炎症性滑膜细胞表达Cyr61[J].现代免疫学,2014,34(1):1-6.[10] Li H D,Sun Y,Huo R F,et al. HDAC1 regulates expression of cyr61 in inflammatory synovial cells through NF-κB[J]. Current Immunol,2014,34(1):1-6.
[11] Tarcic O,Pateras I S,Cooks T,et al. RNF20 links histone H2B ubiquitylation with inflammation and inflammation-associated cancer[J]. Cell Rep,2016,14(6):1462-76.
[12] Li X,Tian F,Wang F. Rheumatoid arthritis-associated microRNA-155 targets SOCS1 and upregulates TNF-αand IL-1βin PBMCs[J]. Int J Mol Sci,2013,14(12):23910-21.
[13] Hong B K,You S,Yoo S A,et al. MicroRNA-143 and-145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis[J]. Exp Mol Med,2017,49(8):e363.
[14] Li H,Guan S B,Lu Y,et al. MiR-140-5p inhibits synovial fibroblasts proliferation and inflammatory cytokines secretion through targeting TLR4[J]. Biomed Pharmacother,2017,96:208-14.
[15] Shu K,Kuang N,Zhang Z,et al. Therapeutic effect of daphnetin on the autoimmune arthritis through demethylation of proapoptotic genes in synovial cells[J]. J Transl Med,2014,12:287.
[16] Liu Y F,Wen C Y,Chen Z,et al. Effects of Wutou decoction on DNA methylation and histone modifications in rats with collagen-induced arthritis[J]. Evid Based Complement Alternat Med,2016,2016:5836879.
[17]陈欢,巨少华,魏江平,等.白虎加桂枝汤对热痹模型大鼠特征性甲基化基因表达的影响[J].中国中药杂志,2017,42(2):332-40.[17] Chen H,Ju S H,Wei J P,et al. Effect of Baihu Guizhi decoction on characteristic methylation genes expression of pyretic arthralgia rat model[J]. China J Chin Mater Med,2017,42(2):332-40.
[18] Wada T T,Araki Y,Sato K,et al. Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts[J]. Biochem Biophys Res Commun,2014,444(4):682-6.
[19]王妍.雷公藤与甲氨蝶呤、黄芪与当归联用治疗RA机制的生物信息学分析[D].北京:中国中医科学院,2012.[19] Wang Y. Bioinformatics analysis on the mechanisms of rheumatoid arthritis treatment by tripterygium wilfordii in combination with methotrexate,astragalus arid angelica[D]. Beijing:China Academy Chinese medical Science,2012.
[20] Chen Z Z,Zhang X D,Chen Y,et al. The role of circulating miR-146a in patients with rheumatoid arthritis treated by Tripterygium wilfordii Hook F[J]. Medicine(Baltimore),2017,96(20):e6775.
[21]朴雪梅,薛鸾,胡建东.益气清络方对类风湿关节炎患者外周血单个核细胞中miR-146a表达的影响[J].上海中医药大学学报,2015,29(1):37-40.[21] Piao X M,Xue L,Hu J D. Effect of Yiqi Qingluo Formula on expression of miR-146a in peripheral blood mononuclear cells in patients with rheumatoid arthritis[J]. Acta Univ Tradit Med Sin Pharmacol Shanghai,2015,29(1):37-40.
[22]彭桉平,黄宪章,刘瑞萍,等.雷公藤内酯醇调控miR-155抑制类风湿性关节炎患者单核细胞促炎反应[J].细胞与分子免疫学杂志,2014,30(6):635-8.[22] Peng A P,Huang X Z,Liu R P,et al. Triptolide inhibits the inflammatory response of monocytes from rheumatoid arthritis patients by regulating miR-155[J]. Chin J Cell Mol Immunol,2014,30(6):635-8.
[23]朱亚梅,周玲玲,彭孝武,等.清络通痹方调控miRNA网络干预类风湿关节炎的研究[J].中国免疫学杂志,2016,32(4):495-9.[23] Zhu Y M,Zhou L L,Peng X W,et al. Study of Qingluo Tongbi compound treating rheumatoid arthritis based on miRNA network[J]. Chin J Immunol,2016,32(4):495-9.
[24]彭孝武,周玲玲,朱亚梅,周孝平.清络通痹方对佐剂性关节炎大鼠破骨细胞分化相关miRNA表达的影响[J].中国中西医结合杂志,2016,36(10):1213-8.[24] Peng X W,Zhou L L,Zhu Y M,Zhou X P. Effect of Qingluo Tongbi Compound on osteoclast differentiation related miRNA expressions in adjuvant induced arthritis rats[J]. Chin J Integr Tradit West Med,2016,36(10):1213-8.
[25]冯知涛. RA患者外周血miR-146a、miR-16表达与疾病活动、中医证型相关性及青藤碱制剂对其干预的研究[D].广州:南方医科大学,2011.[25] Feng Z T. Intervention of sinomenine preparation miR-145a and miR-16 expressions in peripheral blood of rheumatoid arthritis patients and correlation with the expression levels and both disease activity and TCM syndrome type[D]. Guangzhou:Southern Medical University,2011.
[2] Mc Innes I B,Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis[J]. Lancet,2017,389(10086):2328-37.
[3]余黄合,曾嵘,李鑫,等.土家族药物血筒抗佐剂性关节炎药效作用研究[J].中国药理学通报,2016,32(10):1427-32.[3] Yu H H,Zeng R,Li X,et al. Tujia ethnomedicine Xuetong suppresses onset and progression of adjuvantinduced arthritis in rats[J]. Chin Pharmacol Bull,2016,32(10):1427-32.
[4] Ospelt C,Gay S,Klein K. Epigenetics in the pathogenesis of RA[J]. Semin Immunopathol,2017,39(4):409-19.
[5] Takami N,Osawa K,Miura Y,et al. Hypermethylated promoter region of DR3,the death receptor 3 gene,in rheumatoid arthritis synovial cells[J]. Arthritis Rheum,2006,54(3):779-87.
[6]缪成贵,黄成,黄艳,等. Wnt调控类风湿性关节炎研究进展[J].中国药理学通报,2013,29(2):149-53.[6] Miao C G,Huang C,Huang Y,et al. Research progress of the Wnt in rheumatoid arthritis[J]. Chin Pharmacol Bull,2013,29(2):149-53.
[7] Sun Z H,Liu Y H,Liu J D,et al. Me CP2 regulates PTCH1 expression through DNA methylation in rheumatoid arthritis[J]. Inflammation,2017,40(5):1497-508.
[8] Zhang Y,Zhang B. Trichostatin A,an inhibitor of histone deacetylase,inhibits the viability and invasiveness of hypoxic rheumatoid arthritis fibroblast-like synoviocytes via PI3K/Akt signaling[J]. J Biochem Mol Toxicol,2016,30(4):163-9.
[9] Chung Y L,Lee M Y,Wang A J,et al. A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis[J]. Mol Ther,2003,8(5):707-17.
[10]李会丹,孙悦,火蓉芬,等.组蛋白去乙酰化酶1通过NF-κB调控炎症性滑膜细胞表达Cyr61[J].现代免疫学,2014,34(1):1-6.[10] Li H D,Sun Y,Huo R F,et al. HDAC1 regulates expression of cyr61 in inflammatory synovial cells through NF-κB[J]. Current Immunol,2014,34(1):1-6.
[11] Tarcic O,Pateras I S,Cooks T,et al. RNF20 links histone H2B ubiquitylation with inflammation and inflammation-associated cancer[J]. Cell Rep,2016,14(6):1462-76.
[12] Li X,Tian F,Wang F. Rheumatoid arthritis-associated microRNA-155 targets SOCS1 and upregulates TNF-αand IL-1βin PBMCs[J]. Int J Mol Sci,2013,14(12):23910-21.
[13] Hong B K,You S,Yoo S A,et al. MicroRNA-143 and-145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis[J]. Exp Mol Med,2017,49(8):e363.
[14] Li H,Guan S B,Lu Y,et al. MiR-140-5p inhibits synovial fibroblasts proliferation and inflammatory cytokines secretion through targeting TLR4[J]. Biomed Pharmacother,2017,96:208-14.
[15] Shu K,Kuang N,Zhang Z,et al. Therapeutic effect of daphnetin on the autoimmune arthritis through demethylation of proapoptotic genes in synovial cells[J]. J Transl Med,2014,12:287.
[16] Liu Y F,Wen C Y,Chen Z,et al. Effects of Wutou decoction on DNA methylation and histone modifications in rats with collagen-induced arthritis[J]. Evid Based Complement Alternat Med,2016,2016:5836879.
[17]陈欢,巨少华,魏江平,等.白虎加桂枝汤对热痹模型大鼠特征性甲基化基因表达的影响[J].中国中药杂志,2017,42(2):332-40.[17] Chen H,Ju S H,Wei J P,et al. Effect of Baihu Guizhi decoction on characteristic methylation genes expression of pyretic arthralgia rat model[J]. China J Chin Mater Med,2017,42(2):332-40.
[18] Wada T T,Araki Y,Sato K,et al. Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts[J]. Biochem Biophys Res Commun,2014,444(4):682-6.
[19]王妍.雷公藤与甲氨蝶呤、黄芪与当归联用治疗RA机制的生物信息学分析[D].北京:中国中医科学院,2012.[19] Wang Y. Bioinformatics analysis on the mechanisms of rheumatoid arthritis treatment by tripterygium wilfordii in combination with methotrexate,astragalus arid angelica[D]. Beijing:China Academy Chinese medical Science,2012.
[20] Chen Z Z,Zhang X D,Chen Y,et al. The role of circulating miR-146a in patients with rheumatoid arthritis treated by Tripterygium wilfordii Hook F[J]. Medicine(Baltimore),2017,96(20):e6775.
[21]朴雪梅,薛鸾,胡建东.益气清络方对类风湿关节炎患者外周血单个核细胞中miR-146a表达的影响[J].上海中医药大学学报,2015,29(1):37-40.[21] Piao X M,Xue L,Hu J D. Effect of Yiqi Qingluo Formula on expression of miR-146a in peripheral blood mononuclear cells in patients with rheumatoid arthritis[J]. Acta Univ Tradit Med Sin Pharmacol Shanghai,2015,29(1):37-40.
[22]彭桉平,黄宪章,刘瑞萍,等.雷公藤内酯醇调控miR-155抑制类风湿性关节炎患者单核细胞促炎反应[J].细胞与分子免疫学杂志,2014,30(6):635-8.[22] Peng A P,Huang X Z,Liu R P,et al. Triptolide inhibits the inflammatory response of monocytes from rheumatoid arthritis patients by regulating miR-155[J]. Chin J Cell Mol Immunol,2014,30(6):635-8.
[23]朱亚梅,周玲玲,彭孝武,等.清络通痹方调控miRNA网络干预类风湿关节炎的研究[J].中国免疫学杂志,2016,32(4):495-9.[23] Zhu Y M,Zhou L L,Peng X W,et al. Study of Qingluo Tongbi compound treating rheumatoid arthritis based on miRNA network[J]. Chin J Immunol,2016,32(4):495-9.
[24]彭孝武,周玲玲,朱亚梅,周孝平.清络通痹方对佐剂性关节炎大鼠破骨细胞分化相关miRNA表达的影响[J].中国中西医结合杂志,2016,36(10):1213-8.[24] Peng X W,Zhou L L,Zhu Y M,Zhou X P. Effect of Qingluo Tongbi Compound on osteoclast differentiation related miRNA expressions in adjuvant induced arthritis rats[J]. Chin J Integr Tradit West Med,2016,36(10):1213-8.
[25]冯知涛. RA患者外周血miR-146a、miR-16表达与疾病活动、中医证型相关性及青藤碱制剂对其干预的研究[D].广州:南方医科大学,2011.[25] Feng Z T. Intervention of sinomenine preparation miR-145a and miR-16 expressions in peripheral blood of rheumatoid arthritis patients and correlation with the expression levels and both disease activity and TCM syndrome type[D]. Guangzhou:Southern Medical University,2011.
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