Effect of <italic style="font-style: italic">Fangji Huangqi Decoction</italic>（防己黄芪汤）on Notch2 /DLL1 Pathway in Joint Tissues of Collagen-induced Arthritis Model Rats

Yuting GAO; Zhen LI; Yuwei ZHAO; Caihong ZHAO; Jin LIU; Huiqin HAO

doi:10.13288/j.11-2166/r.2021.20.013

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Effect of Fangji Huangqi Decoction（防己黄芪汤）on Notch2 /DLL1 Pathway in Joint Tissues of Collagen-induced Arthritis Model Rats

更新时间：2021-10-15

- Effect of Fangji Huangqi Decoction（防己黄芪汤）on Notch2 /DLL1 Pathway in Joint Tissues of Collagen-induced Arthritis Model Rats
- Journal of Traditional Chinese Medicine Vol. 62, Issue 20, Pages: 1820-1826(2021)
- 作者机构：
  
  山西中医药大学基础医学院，山西省晋中市高校园区大学街121号，030619
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2021.20.013
  CLC：
- Received：18 May 2021，
  
  Revised：2021-07-23，
  
  Published：17 October 2021
- 稿件说明：
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高玉亭,李振,赵雨薇等.防己黄芪汤对胶原诱导性关节炎模型大鼠关节组织Notch2/DLL1通路的影响[J].中医杂志,2021,62(20):1820-1826.

GAO Yuting,LI Zhen,ZHAO Yuwei,et al.Effect of Fangji Huangqi Decoction（防己黄芪汤）on Notch2 /DLL1 Pathway in Joint Tissues of Collagen-induced Arthritis Model Rats[J].Journal of Traditional Chinese Medicine,2021,62(20):1820-1826.
高玉亭,李振,赵雨薇等.防己黄芪汤对胶原诱导性关节炎模型大鼠关节组织Notch2/DLL1通路的影响[J].中医杂志,2021,62(20):1820-1826. DOI： 10.13288/j.11-2166/r.2021.20.013.

GAO Yuting,LI Zhen,ZHAO Yuwei,et al.Effect of Fangji Huangqi Decoction（防己黄芪汤）on Notch2 /DLL1 Pathway in Joint Tissues of Collagen-induced Arthritis Model Rats[J].Journal of Traditional Chinese Medicine,2021,62(20):1820-1826. DOI： 10.13288/j.11-2166/r.2021.20.013.

摘要

目的

探讨防己黄芪汤治疗类风湿关节炎（RA）的可能作用机制。

方法

72只Wistar雌性大鼠随机分为正常组12只及造模组60只。造模组大鼠给予注射牛Ⅱ型胶原溶液和完全弗氏佐剂/不完全弗氏佐剂建立胶原诱导性关节炎（CIA）模型，造模成功的48只大鼠随机分为模型组及防己黄芪汤低、中、高剂量组，每组12只。防己黄芪汤低、中、高剂量组分别给予2.2、4.4、8.8 g/（kg·d）防己黄芪汤灌胃，正常组和模型组给予4 ml/（kg·d）生理盐水灌胃，均连续灌胃6周。每周记录大鼠体质量并进行关节炎评分，观察大鼠关节组织病理形态，检测血清中肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）和干扰素γ（IFN-γ）水平，关节组织Notch2、DLL1 mRNA和蛋白表达水平。

结果

与模型组比较，防己黄芪汤中、高剂量组大鼠体质量升高，关节炎评分降低，血清细胞因子TNF-α、IL-6和IFN-γ水平显著降低，关节组织Notch2、DLL1蛋白及mRNA表达显著降低（

＜0.05或

＜0.01）。病理结果显示，滑膜增生、炎性细胞浸润、关节翳形成和关节间隙变窄显著缓解。与防己黄芪汤低剂量组比较，防己黄芪汤中、高剂量组关节组织病理改善情况良好，关节炎评分降低，血清细胞因子TNF-α、IL-6和IFN-γ水平显著降低，关节组织DLL1 mRNA和Notch2蛋白表达显著降低（

＜0.05或

＜0.01）。与防己黄芪汤中剂量组比较，防己黄芪汤高剂量组血清中细胞因子TNF-α和IL-6水平升高，关节组织Notch2

mRNA表达升高，DLL1 mRNA表达降低（

＜0.01）。

结论

防己黄芪汤可显著改善CIA模型大鼠关节炎症状，中剂量效果最佳，其作用机制可能与抑制关节组织Notch2/DLL1信号通路、调节自身免疫功能、降低促炎细胞因子的表达有关。

Abstract

Objective

To explore the possible mechanism of

Fangji Huangqi Decoction

（防己黄芪汤， FHD） in the treatment of rheumatoid arthritis （RA）.

Methods

Seventy-two female Wistar rats were randomly divided into normal group （n=12） and modeling group （n=60）. Rats in the modeling group were given bovine typeⅡcollagen solution and complete/incomplete Freund's adjuvant to establish the rat model of collagen-induced arthritis （CIA）. Forty-eight successfully modeled rats were randomly divided into a model group， and FHD low， medium and high dose groups， with 12 rats in each group. FDH at the concentration of 2.2， 4.4， 8.8 g/（kg·d） by gavage was given to FDH low， medium and high dose groups， respectively， while 4 mL/（kg·d） normal saline by gavage was given to the the normal group and model group； the interventions were administered for six weeks in all the groups. The weight of rats and the score of arthritis were assessed every week； the pathological morphology of joint tissues were observed； the levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6） and interferon-γ （IFN-γ） in serum， as well as the Notch2 and DLL1 mRNA and protein expression in the joint tissues were detected.

Results

Compared to those in the model group， the weight of rats in the FHD medium and high dose groups increased； the score of arthritis was reduced； the expression of cytokines TNF-α， IL-6 and IFN-γ in serum significantly decreased； the expression of Notch2， DLL1 mRNA and protein in joints were significantly reduced （

＜0.05 or

＜0.01）. The pathological results showed that synovial hyperplasia， inflammatory cell infiltration， pannus formation and narrowing of joint space were significantly alleviated. Compared to the FHD low dose group， the medium and high dose groups improved the pathological damage of joint tissues； the arthritis score decreased； the expression of cytokines TNF-α， IL-6 and IFN-γ in serum were significantly reduced； the expression of DLL1 mRNA and Notch2 protein in the joint tissues decreased significantly （

＜0.05 or

＜0.01）. Compared to those in the FHD medium dose group， the expression of serum cytokines TNF-α and IL-6 in the high dose group significantly increased； the expression of Notch2 mRNA was significantly up-leveled； and the expression of DLL1 mRNA was significantly reduced.

Conclusion

FHD can signi-ficantly improve the arthritis symptoms of CIA model rats， and the medium dose works best. The mechanism may be related to its function of inhibiting Notch2/DLL1 signaling pathway， regulating autoimmune function and reducing the expression of proinflammatory cytokines.

关键词

Keywords

references

SMOLEN JS ， ALETAHA D ， MCINNES IB . Rheumatoid arthritis ［J］. Lancet ， 2016 ， 388 （ 10055 ）： 2023 - 2038 .

LIN YJ ， ANZAGHE M ， SCHÜLKE S . Update on the pathomechanism， diagnosis， and treatment options for rheumatoid arthritis ［J］. Cells ， 2020 ， 9 （ 4 ）： 880 .

TAHERI M ， EGHTEDARIAN R ， DINGER ME ， et al . Dysregulation of non-coding RNAs in rheumatoid arthritis ［J］. Biomed Pharmacother ， 2020 ， 130 ： 110617 . doi： 10. 1016/j.biopha.2020.110617 http://dx.doi.org/10.1016/j.biopha.2020.110617 .

张仲景 . 金匮要略［M］. 陈纪藩，主编. 北京：人民卫生出版社， 2000 ： 1022 .

王绪辉，周重建，闵熙敬，等 . 防己黄芪汤提取物治疗活动期类风湿性关节炎的临床药效评估［J］. 中医杂志， 1993 ， 34 （ 3 ）： 156 - 158 .

华英 . 防己黄芪汤合四物汤治疗老年性类风湿性关节炎的体会［J］. 浙江中医杂志， 2015 ， 50 （ 4 ）： 300 .

万里伟，王燕君，兰凌凌，等 . 防己黄芪汤合独活寄生汤治疗类风湿性关节炎临床观察［J］. 中国中医药现代远程教育， 2020 ， 18 （ 3 ）： 71 - 72 .

贾庆运，王拥军，梁倩倩，等 . 防己黄芪汤对胶原诱导性关节炎小鼠的影响［J］. 中国中医骨伤科杂志， 2018 ， 26 （ 5 ）： 6 - 9 .

RIDGLEY LA ， ANDERSON AE ， PRATT AG . What are the dominant cytokines in early rheumatoid arthritis？［J］ . Curr Opin Rheumatol ， 2018 ， 30 （ 2 ）： 207 - 214 .

YANG G ， ZHOU R ， ZHOU Q ， et al . Structural basis of Notch recognition by human γ-secretase ［J］. Nature ， 2019 ， 565 （ 7738 ）： 192 - 197 .

高玉亭，李振，赵彩虹，等 . Notch信号通路调控风湿免疫性疾病研究进展［J］. 中华风湿病学杂志， 2020 ， 24 （ 8 ）： 553 - 557 .

KEEWAN E ， NASER SA . The role of Notch signaling in macrophages during inflammation and infection： implication in rheumatoid arthritis？［J］ . Cells ， 2020 ， 9 （ 1 ）： 111 .

于坤，徐枝芳，余楠楠，等 . 佐剂性和胶原诱导性关节炎模型比较分析［J］. 辽宁中医药大学学报， 2018 ， 20 （ 1 ）： 106 - 109 .

XU N ， WANG Y ， ZHAO S ， et al . Naltrexone （NTX） relieves inflammation in the collagen-induced-arthritis （CIA） rat models through regulating TLR4/NFκB signaling pathway ［J］. Int Immunopharmacol ， 2020 ， 79 ： 106056 . doi： 10.1016/j.intimp.2019.106056 http://dx.doi.org/10.1016/j.intimp.2019.106056 .

WANG X ， YAN X ， WANG F ， et al . Role of methotrexate chronotherapy in collagen-induced rheumatoid arthritis in rats ［J］. Z Rheumatol ， 2018 ， 77 （ 3 ）： 249 - 255 .

陈奇 . 中药药理研究方法学［M］. 2版 . 北京：人民卫生出版社， 2006 ： 30 .

李延婷，姜泉，巩勋，等 . 类风湿关节炎患者中医药治疗现状调查分析［J］. 中医杂志， 2020 ， 61 （ 8 ）： 676 - 680 .

赵用，鞠宝兆，唐哲，等 . 从矛盾论之内外因关系视域探析《黄帝内经》营卫之气致痹理论［J］. 中华中医药学刊， 2020 ， 38 （ 6 ）： 62 - 65 .

MATEEN S ， ZAFAR A ， MOIN S ， et al . Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis ［J］. Clin Chim Acta ， 2016 ， 455 ： 161 - 171 . doi： 10.1016/j.cca.2016.02.010 http://dx.doi.org/10.1016/j.cca.2016.02.010 .

NOACK M ， MIOSSEC P . Selected cytokine pathways in rheumatoid arthritis ［J］. Semin Immunopathol ， 2017 ， 39 （ 4 ）： 365 - 383 .

KATO M . New insights into IFN-γ in rheumatoid arthritis： role in the era of JAK inhibitors ［J］. Immunol Med ， 2020 ， 43 （ 2 ）： 72 - 78 .

CATRINA AI ， JOSHUA V ， KLARESKOG L ， et al . Mechanisms involved in triggering rheumatoid arthritis ［J］. Immunol Rev ， 2016 ， 269 （ 1 ）： 162 - 174 .

RADTKE F ， FASNACHT N ， MACDONALD HR . Notch signaling in the immune system ［J］. Immunity ， 2010 ， 32 （ 1 ）： 14 - 27 .

KEEWAN E ， NASER SA . Notch-1 signaling modulates macrophage polarization and immune defense against mycobacterium avium paratuberculosis infection in inflammatory diseases ［J］. Microorganisms ， 2020 ， 8 （ 7 ）： 1006 .

GAO W ， SWEENEY C ， CONNOLLY M ， et al . Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis ［J］. Arthritis Rheum ， 2012 ， 64 （ 7 ）： 2104 - 2113 .

CHRISTOPOULOS PF ， GJØLBERG TT ， KRÜGER S ， et al . Targeting the notch signaling pathway in chronic inflammatory diseases ［J］. Front Immunol ， 2021 ， 12 ： 668207 . doi： 10.3389/fimmu.2021.668207 http://dx.doi.org/10.3389/fimmu.2021.668207 .

PARK JS ， KIM SH ， KIM K ， et al . Inhibition of notch signalling ameliorates experimental inflammatory arthritis ［J］. Ann Rheum Dis ， 2015 ， 74 （ 1 ）： 267 - 274 .

CHEN J ， LI J ， CHEN J ， et al . Treatment of collagen-induced arthritis rat model by using Notch signalling inhibitor ［J］. J Orthop Translat ， 2021 ， 28 ： 100 - 107 . doi： 10.1016/j.jot.2021.01.003 http://dx.doi.org/10.1016/j.jot.2021.01.003 .

WEI K ， KORSUNSKY I ， MARSHALL JL ， et al . Notch signalling drives synovial fibroblast identity and arthritis pathology ［J］. Nature ， 2020 ， 582 （ 7811 ）： 259 - 264 .

Sekine C ， Koyanagi A ， Koyama N ， et al . Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes ［J］. Arthritis Res Ther ， 2012 ， 14 （ 2 ）： R45 .

Sekine C ， Nanki T ， Yagita H . Macrophage-derived delta-like protein 1 enhances interleukin-6 and matrix metalloproteinase 3 production by fibroblast-like synoviocytes in mice with collagen-induced arthritis ［J］. Arthritis Rheumatol ， 2014 ， 66 （ 10 ）： 2751 - 2761 .

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Effect of Fangji Huangqi Decoction（防己黄芪汤）on Notch2 /DLL1 Pathway in Joint Tissues of Collagen-induced Arthritis Model Rats

DOI：10.13288/j.11-2166/r.2021.20.013

摘要

Abstract

关键词

Keywords

references