中药活性成分在炎症性肠病治疗中的应用研究
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摘要
炎症性肠病是一种慢性反复发作累及胃肠道的非特异性自身免疫性疾病,肠道出血、腹泻、体质量减轻等临床症状严重威胁人类身体健康,同时可诱发结直肠癌。主要病因及发病机制涉及生活环境改变、多基因遗传因素、炎症性免疫细胞浸润及持续免疫应激状态、黏膜屏障防御作用减弱及肠道内菌群紊乱等因素。目前临床治疗用药主要包括氨基水杨酸类、皮质类固醇类、免疫抑制剂、生物制剂等,鉴于其治疗效果不佳及价格昂贵等缺点。中药活性成分具有抗炎、抗菌、抗肿瘤、免疫调节等多种生物活性及药理作用,其多靶点的作用特点在炎症性肠病的治疗防治中独具优势。该文主要从保护肠上皮屏障及维持肠道微生物稳态、抑制致炎因子、调节Th1/Th17/Treg平衡等方面总结了中药活性成分在治疗炎症性肠病方面的应用与研究进展,为基于中药活性成分治疗炎症性肠病的新药研发及相关机制提供新的思路。
Inflammatory bowel disease(IBD) is a non-specific and chronic recurrent autoimmune disease that involves the gastrointestinal tract. Clinical symptoms of intestinal bleeding, diarrhea, and weight loss threat to human health and induce colorectal cancer. The pathogenesis included living environment, genetic factors, immune cell infiltration and immune stress, weakened mucosal barrier defense and intestinal flora imbalance. At present, clinical treatment drugs mainly include aminosalicylic acid, corticosteroids, immunosuppressants, biological agents, etc., in view of the disadvantages of poor therapeutic effect and expensive price. The active ingredients of traditional Chinese medicine(TCM) in the treatment IBD have various biological activities and multiple targets such as anti-inflammatory, antibacterial, anti-tumor and immune regulation. This article summarized the application and the research progress in protecting intestinal epithelial barrier, maintaining intestinal microbial homeostasis, inhibiting causative factors, and regulating Th1/Th17/Treg balance about TCM in the treatment of IBD. The review provided new ideas for further development of the new drugs on the mechanism based on active ingredients of TCM in IBD treatment.
Inflammatory bowel disease(IBD) is a non-specific and chronic recurrent autoimmune disease that involves the gastrointestinal tract. Clinical symptoms of intestinal bleeding, diarrhea, and weight loss threat to human health and induce colorectal cancer. The pathogenesis included living environment, genetic factors, immune cell infiltration and immune stress, weakened mucosal barrier defense and intestinal flora imbalance. At present, clinical treatment drugs mainly include aminosalicylic acid, corticosteroids, immunosuppressants, biological agents, etc., in view of the disadvantages of poor therapeutic effect and expensive price. The active ingredients of traditional Chinese medicine(TCM) in the treatment IBD have various biological activities and multiple targets such as anti-inflammatory, antibacterial, anti-tumor and immune regulation. This article summarized the application and the research progress in protecting intestinal epithelial barrier, maintaining intestinal microbial homeostasis, inhibiting causative factors, and regulating Th1/Th17/Treg balance about TCM in the treatment of IBD. The review provided new ideas for further development of the new drugs on the mechanism based on active ingredients of TCM in IBD treatment.
引文
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[25] 王青,苏聪平,张惠敏,等.从炎性反应角度探讨清热解毒药的作用机制[J].中国中药杂志, 2018,43(18):3787.
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[34] Zou Y, Lin J T, Li W Y, et al. Huangqin-tang ameliorates dextran sodium sulphate-induced colitis by regulatingintestinal epithelial cell homeostasis, inflammation and immune response[J]. Sci Rep, 2016, 6(13):2045.
[35] Yan Y X, Shao M J, Qi Q, et al. Artemisinin analogue SM934 ameliorates DSS-induced mouse ulcerativecolitis via suppressing neutrophils and macrophages[J]. Acta Pharmacol Sin, 2018, doi: 10.1038/aps.2017.185.
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[41] Liang J, Liang J W, Hao H R, et al. The extracts of Morinda officinalis and its hairy roots attenuate dextran sodium sulfate-induced chronic ulcerative colitis in mice by regulating inflammation and lymphocyte apoptosis[J]. Front Immunol, 2017, 8(17):1664.
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[43] Hu S R, Chen M M, Wang Y L, et al. mTOR inhibition attenuates dextran sulfate sodium-induced colitis by suppressing T cell proliferation and balancing TH1/TH17/Treg profile[J]. PLoS ONE, 2016, 11(4):19.
[44] Wu X, Dou Y N, Yang Y, et al. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway[J]. Biochem Pharmacol, 2015, 96(4):323.
[45] Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine[J]. Phytother Res, 2008, 22(8):999.
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[47] Li Y H, Xiao H T, Hu D D, et al. Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses[J]. Pharmacol Res, 2016, 110(227):1043.
[48] 岑彦艳,赵祎博,李攀,等.青蒿琥酯的药代动力学以及相关药理作用研究进展[J].中国中药杂志, 2018,43(19):3970.
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[54] 李晓冰, 崔利宏, 陈玉龙,等. 参苓白术散对溃疡性结肠炎小鼠肠道调节性T细胞免疫调节作用[J]. 中成药, 2014,36(6):1295.
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[2] Molodecky N A, Soon I S, Rabi D M, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review[J]. Gastroenterology, 2012, 142(1):46.
[3] Neurath M F. Current and emerging therapeutic targets for IBD[J]. Nat Rev Gastroenterol Hepatol, 2017,14(5):269.
[4] Peteroson L W, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis[J]. Nat Rev Immunol, 2014, 14(3):141.
[5] 赵美华,龚陈,楼江明,等.黏蛋白与炎症性肠病关系的研究进展[J].世界华人消化杂志,2014,22(27):4100.
[6] Safdari B K, Sia T C, Wattchow D A, et al. Effects of pro-inflammatory cytokines, lipopolysaccharide and COX-2 mediators on human colonic neuromuscular function and epithelial permeability[J]. Cytokine, 2016, 83:231.
[7] 余秀婷. 广藿香和黄连主要活性成分抗炎症性肠病的作用和机制探讨[D]. 广州:广州中医药大学, 2016.
[8] Fries W, Belvedere A, Vetrano S. Sealing the broken barrier in IBD: intestinal permeability, epithelial cells and junctions[J]. Curr Drug Targets, 2013, 14(12):1460.
[9] Wang Y L, Liu L J, Guo Y, et al. Effects of indigo naturalis on colonic mucosal injuries and inflammation in rats with dextran sodium sulphate-induced ulcerative colitis[J]. Exp Ther Med, 2017, 14(2):1327.
[10] 方静,陈江,彭君伟,等. 薏苡附子败酱散对小鼠急性期溃疡性结肠炎肠黏膜的修复作用[J]. 上海中医药大学学报, 2018, 32(3):1008.
[11] 刘玉晖,胡婕,易文凤,等.参苓白术散治疗炎症性肠病与肠上皮细胞紧密连接的关系探讨[J].中国实验方剂学杂志,2015,21(3):130.
[12] Ogata M, Ogita T, Tari H, et al. Supplemental psyllium fibre regulates the intestinal barrier and inflammation in normal and colitic mice[J]. Br J Nutr, 2017, 118(9):661.
[13] Li M, Gao J L, Tang G Y, et al. Traditional herbal medicine-derived sulforaphene LFS-01 reverses colitis in mice by selectively altering the gut microbiota and promoting intestinal gamma-delta T cells[J]. Front Pharmacol, 2018, 8(16):1663.
[14] 杨文静,刘占举.肠道菌群失衡在炎症性肠病中的作用[J].胃肠病学,2015,20(11):691.
[15] De Souza H S P, Fiocchi C. Immunopathogenesis of IBD: current state of the art[J]. Nat Rev Gastroenterol Hepatol, 2016, 13(1):13.
[16] 王珊珊,王佳堃,刘建新. 肠道微生物对宿主免疫系统的调节及其可能机制[J]. 动物营养学报,2017, 15(9):1574.
[17] Emge J R, Huynh K, Miler E N, et al. Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease[J]. Am J Physiol Gastrointest Liver Physiol, 2016, 310(11):G989.
[18] Feng T, Wang L F, Schoeb T R, et al. Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis[J]. J Exp Med, 2010, 207(6):1321.
[19] 陈珠. 砂仁对炎症性肠病大鼠的治疗作用及其初步机理研究[D]. 昆明:云南中医学院, 2017.
[20] Clemente J C, Ursell L K, Parfrey L W, et al. The impact of the gut microbiota on human health: an integrative view[J]. Cell, 2012, 148(6):1258.
[21] Tao J H, Duan J A, Jiang S, et al. Polysaccharides from Chrysanthemum morifolium Ramat ameliorate colitis rats by modulating the intestinal microbiota community[J]. Oncotarget, 2017, 8(46):80790.
[22] Neurath M F. Cytokines in inflammatory bowel disease[J]. Nat Rev Immunol, 2014, 14:329.
[23] Ishiguro Y. Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis[J]. J Gastroenterol, 1999, 34(1): 66.
[24] 孟晓弘,季明昉,方一,等. 炎症性肠病患者血清巨噬细胞极化相关细胞因子水平及其意义[J]. 胃肠病学, 2015, 20(9):538.
[25] 王青,苏聪平,张惠敏,等.从炎性反应角度探讨清热解毒药的作用机制[J].中国中药杂志, 2018,43(18):3787.
[26] Ge Y, Wang Y Z, Chen P P, et al. Polyhydroxytriterpenoids and phenolic constituents from Forsythia suspensa (Thunb.) Vahl leaves[J]. J Agric Food Chem, 2016, 64(1):125.
[27] Hwang Y H, Kim D G, Li W, et al. Anti-inflammatory effects of Forsythia suspensa in dextran sulfate sodium-induced colitis[J]. J Ethnopharmacol, 2017, 206(73/77):0378.
[28] Fasseu M, Treton X, Guichard C, et al. Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease[J]. PLoS ONE, 2010, 5(10):12.
[29] Yu Q, Zhu S Y, Zhou R, et al. Effects of sinomenine on the expression of microRNA-155 in 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice[J]. PLoS ONE, 2013, 8(9):8.
[30] Bryant C, Fitzgerald K A. Molecular mechanisms involved in inflammasome activation[J]. Trends Cell Biol, 2009, 19(9):455.
[31] Wu X F, Ouyang Z J, Feng L L, et al. Suppression of NF-kappa B signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone[J]. Toxicol Appl Pharmacol, 2014, 281(1):146.
[32] Mcdaniel D K, Eden K, Ringel V M, et al. Emerging roles for noncanonical NF-kappa B signaling in the modulation of inflammatory bowel disease pathobiology[J]. Inflamm Bowel Dis, 2016, 22(9):2265.
[33] Sakthivel K M, Guruvayoorappan C. Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-κB signal transduction pathways in rats with ulcerative colitis[J]. Int Immunopharmacol, 2013, 17(3):907.
[34] Zou Y, Lin J T, Li W Y, et al. Huangqin-tang ameliorates dextran sodium sulphate-induced colitis by regulatingintestinal epithelial cell homeostasis, inflammation and immune response[J]. Sci Rep, 2016, 6(13):2045.
[35] Yan Y X, Shao M J, Qi Q, et al. Artemisinin analogue SM934 ameliorates DSS-induced mouse ulcerativecolitis via suppressing neutrophils and macrophages[J]. Acta Pharmacol Sin, 2018, doi: 10.1038/aps.2017.185.
[36] Cua D J, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain[J]. Nature, 2003, 421(6924):744.
[37] Chen M L, Sundrud M S. Cytokine networks and T-cell subsets in inflammatory bowel diseases[J]. Inflamm Bowel Dis, 2016, 22(5):1157.
[38] Li J, Ueno A, Iacucci M, et al. Crossover subsets of CD4+ T lymphocytes in the intestinal lamina propria of patients with Crohn′s disease and ulcerative colitis[J]. Dig Dis Sci, 2017, 62(9):2357.
[39] Bu P, Keshavarzizn A, Stone D D, et al. Apoptosis: one of the mechanisms that maintains unresponsiveness of the intestinal mucosal immune system[J]. J Immunol, 2001, 166(10):6399.
[40] Zhang W F, Yang Y, Su X, et al. Deoxyschizandrin suppresses DSS-induced ulcerative colitis in mice[J]. Saudi J Gastroenterol, 2016, 22(6):448.
[41] Liang J, Liang J W, Hao H R, et al. The extracts of Morinda officinalis and its hairy roots attenuate dextran sodium sulfate-induced chronic ulcerative colitis in mice by regulating inflammation and lymphocyte apoptosis[J]. Front Immunol, 2017, 8(17):1664.
[42] Martelli A M, Buontempo F, Mccubrey J A. Drug discovery targeting the mTOR pathway[J]. Clin Sci, 2018, 132(5):543.
[43] Hu S R, Chen M M, Wang Y L, et al. mTOR inhibition attenuates dextran sulfate sodium-induced colitis by suppressing T cell proliferation and balancing TH1/TH17/Treg profile[J]. PLoS ONE, 2016, 11(4):19.
[44] Wu X, Dou Y N, Yang Y, et al. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway[J]. Biochem Pharmacol, 2015, 96(4):323.
[45] Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine[J]. Phytother Res, 2008, 22(8):999.
[46] 沈雁,钟继红,徐磊,等.盐酸小檗碱对溃疡性结肠炎小鼠结肠组织TNF-α、IL-1β和IL-10表达的影响[J].中国现代应用药学,2017,34(8):1094
[47] Li Y H, Xiao H T, Hu D D, et al. Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses[J]. Pharmacol Res, 2016, 110(227):1043.
[48] 岑彦艳,赵祎博,李攀,等.青蒿琥酯的药代动力学以及相关药理作用研究进展[J].中国中药杂志, 2018,43(19):3970.
[49] Yang Z, Ding J, Yang C, et al. Immunomodulatory and anti-inflammatory properties of artesunate in experimental colitis[J]. Curr Med Chem, 2012, 19(26):4541.
[50] Luo A N, Leach S T, Barres R, et al. The microbiota and epigenetic regulation of T helper 17/regulatory T cells: in search of a balanced immune system[J]. Front Immunol, 2017, 8(14):1664.
[51] Takhashi M, Nakmura K, Hond K, et al. An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis[J]. Dig Dis Sci, 2006, 51(4):677.
[52] 曹霞. 中药溃克灵对TNBS结肠炎模型大鼠TGF-β1表达的影响[D]. 南京:南京中医药大学, 2011.
[53] 孙艺凡,张霞,王晓艳,等.长期服用人参提取物对大鼠肠道菌群结构的影响[J]. 中国中药杂志,2018,43(19):3927.
[54] 李晓冰, 崔利宏, 陈玉龙,等. 参苓白术散对溃疡性结肠炎小鼠肠道调节性T细胞免疫调节作用[J]. 中成药, 2014,36(6):1295.
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