天然木脂素苷类成分eleutheroside E对膝骨性关节炎的治疗作用及其与MMPs相互作用方式的分析

doi:10.16333/j.1001-6880.2021.8.010

天然产物研究与开发 ›› 2021, Vol. 33 ›› Issue (8): 1339-1347.doi: 10.16333/j.1001-6880.2021.8.010

天然木脂素苷类成分eleutheroside E对膝骨性关节炎的治疗作用及其与MMPs相互作用方式的分析

闫兆威1,2 *，张敏1,2，魏明刚1，姚鑫1，刘江云2

1苏州大学附属第一医院，苏州 215006；2苏州大学药学院，苏州 215123

出版日期:2021-08-28 发布日期:2021-08-30
基金资助:
江苏省中医药科技发展计划（YB201989）；江苏省青年医学人才资助项目（QNRC2016715）；苏州市科技发展计划（SYSD2020095）

Therapeutic effect of natural lignan glycoside constituents eleutheroside E on models of knee osteoarthritis and analysis of its interaction modes with MMPs

YAN Zhao-wei1,2*,ZHANG Min1,2,WEI Ming-gang1,YAO Xin1,LIU Jiang-yun2#br#

#br#

1The First Affiliated Hospital of Soochow University,Suzhou 215006,China;2College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China

Online:2021-08-28 Published:2021-08-30

摘要/Abstract

摘要：

本文旨在探讨天然木脂素苷类成分eleutheroside E（EE）对膝骨性关节炎模型的治疗作用并对EE的作用机制进行分析，明确EE与MMPs相互作用的位点及结合方式。实验采用ACLT方法建立兔膝骨关节炎模型，通过关节腔注射方式给予EE进行治疗干预，从动物整体水平对EE在实验性兔膝骨性关节炎的治疗作用进行综合评价。进一步运用分子对接技术和分子动力学方法，对EE与MMPs相互作用位点和结合方式进行分析。结果显示：EE能明显改善骨关节炎部位炎细胞浸润、纤维组织增生及软骨表层破坏等情况，并降低关节液中炎症介质（IL-1β和PGE₂）以及MMP-3和MMP-9的水平。分子对接和分子动力学实验发现，EE配体可结合于MMP-3和MMP-9催化位点的凹槽中，EE糖环上的多个羟基可与MMP-3和MMP-9受体中的多个氨基酸形成氢键，这些氢键对于配体的结合起到了重要作用。本研究为开发木脂素苷类母核结构新型MMPs抑制剂以及天然来源的骨性关节炎候选治疗药物奠定了一定基础。

关键词: 天然木脂素苷, eleutheroside E, 基质金属蛋白酶, 膝骨性关节炎, 治疗作用

Abstract:

The paper aimed to investigate the therapeutic effect of eleutheroside E (EE) on knee osteoarthritis and analyze the mechanisms of EE,to clarify the interaction sites and binding modes of EE and MMPs.The ACLT method was adopt to establish a rabbit model of knee osteoarthritis,and EE was given by injection into the joint cavity for therapeutic intervention.Further using molecular docking technology and molecular dynamics methods to analyze the interaction sites and binding modes of EE with MMPs.These results indicated that EE could significantly improve inflammatory cell infiltration,fibrous tissue hyperplasia and cartilage surface destruction in osteoarthritis,and reduce the content levels of inflammatory factors (IL-1β and PGE₂) and MMP-3 and MMP-9 in joint fluid.In addition,molecular docking and molecular dynamics experiments found that EE ligands could bind to the grooves of the catalytic sites of MMP-3 and MMP-9,and the multiple hydroxyl groups on the sugar ring of EE could form hydrogen bonds with multiple amino acids in the MMP-3 and MMP-9 receptors,which play an important role in the binding of ligands.The study lays a foundation for the development of novel MMPs inhibitors with the mother nucleus of lignan glycosides and candidate therapeutic drugs for osteoarthritis from natural sources.

Key words: natural lignan glycoside, eleutheroside E, matrix metalloproteinases (MMPs), knee osteoarthritis, treatment

中图分类号: R284.2

闫兆威, 张敏, 魏明刚, 姚鑫, 刘江云. 天然木脂素苷类成分eleutheroside E对膝骨性关节炎的治疗作用及其与MMPs相互作用方式的分析[J]. 天然产物研究与开发, 2021, 33(8): 1339-1347.

YAN Zhao-wei, ZHANG Min, WEI Ming-gang, YAO Xin, LIU Jiang-yun. Therapeutic effect of natural lignan glycoside constituents eleutheroside E on models of knee osteoarthritis and analysis of its interaction modes with MMPs[J]. NATURAL PRODUCT RESEARCH AND DEVELOPMENT, 2021, 33(8): 1339-1347.

[1]	王风楼1，邓文娟2，贺改英1*. 黄芪复方对成纤维细胞胶原蛋白和MMP的影响[J]. 天然产物研究与开发, 2019, 31(增刊2): 84-87.
[2]	文彬，陈然，彭佩纯，邓鑫*. 天然牛磺酸对肝硬化大鼠MMP-9、Integrin-β1表达的调控[J]. 天然产物研究与开发, 2014, 26(12): 1939-1943.

天然木脂素苷类成分eleutheroside E对膝骨性关节炎的治疗作用及其与MMPs相互作用方式的分析

Therapeutic effect of natural lignan glycoside constituents eleutheroside E on models of knee osteoarthritis and analysis of its interaction modes with MMPs

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