Mechanisms and synergistic effects of the active components of Xanthocerais lignum in inhibiting rheumatoid arthritis through the modulation of the biological behavior of synovial cells.

IF 4.8 2区 医学 Q1 CHEMISTRY, MEDICINAL
Hao Qian, Cuilan Bai, Xin Jia, Yaqiong Yang, Xiangyang Tian, Xiaoqin Wang
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引用次数: 0

Abstract

Ethnopharmacological relevance: Xanthocerais lignum, a classic medicinal herb in Mongolian medicine for the treatment of rheumatoid arthritis (RA), is documented in traditional Mongolian texts such as the "Wu Wu Meng Yao Jian" and "Meng Yao Zhi" for its efficacy in clearing heat, reducing swelling, and modulating "Xie Ri Wu Su" (the pathogenesis related to rheumatism). However, the active compounds and molecular mechanisms of action remain inadequately elucidated, hindering its modernization and development.

Aim of the study: This study aims to systematically elucidate the molecular mechanisms by which the active components of Xanthocerais lignum inhibit RA through the modulation of the biological behavior of synovial cells, while also revealing the patterns of synergistic interactions among its multiple components.

Materials and methods: Initially, serum network pharmacology was utilized to predict the potential active components and mechanisms of Xanthocerais lignum against RA, followed by quantitative analysis of 6 primary active ingredients via high performance liquid chromatography (HPLC). Subsequently, a collagen-induced arthritis (CIA) rat model was established, and the expression of relevant proteins and mRNA in synovial tissues was assessed using western blot and quantitative real-time polymerase chain reaction (qPCR). Primary fibroblast-like synoviocytes (FLS) were isolated and cultured using the tissue block adherence culture method. Cell proliferation, invasion, apoptosis, and other assays were conducted to evaluate the biological effects of the active components and explore their mechanisms. Finally, the median drug-effect analysis (Chou-Talalay method) and molecular simulation were employed to investigate the synergistic effects and mechanisms among the active components.

Results: Serum network pharmacology predictions indicated that Xanthocerais lignum may exert its anti-RA effects by regulating biological processes such as cell proliferation, apoptosis, and inflammation via the PI3K-Akt signaling pathway. Animal experiments confirmed that the ethanol extract and ethyl acetate fraction of Xanthocerais lignum significantly reduced the abnormal overexpression of key proteins like phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) in the synovial tissues of CIA rats. Further in vitro experiments revealed that the content of the 6 active components in Xanthocerais lignum exceeded 1.4 mg/g, and they were found to modulate various biological processes in primary RA-FLS cells, including proliferation, invasion, migration, apoptosis, cycle, and inflammation, alongside the expression of the PI3K-Akt signaling pathway. It is noteworthy that quantitative analysis using the median drug-effect method revealed that the combined administration of epicatechin and procyanidin A2 exerted a markedly synergistic inhibitory effect on RA-FLS cell proliferation (combination index < 0.1), with the underlying mechanism potentially closely linked to their cooperative interaction with the PI3K protein through distinct active binding sites.

Conclusions: The active components of Xanthocerais lignum can modulate multiple biological processes of FLS cells via the PI3K-Akt signaling pathway, thereby alleviating joint damage, with epicatechin and procyanidin A2 demonstrating significant synergistic effects.

黄原木有效成分通过调节滑膜细胞的生物学行为抑制类风湿关节炎的机制和协同作用。
民族药理学相关性:黄蜡是治疗类风湿性关节炎(RA)的蒙医药经典草药,被记载在蒙古传统文献中,如“五五b孟尧建”和“b孟尧治”,以其清热,消肿,调节“泻日五素”(与风湿病有关的发病机制)。然而,对其活性成分和作用分子机制的研究仍不充分,阻碍了其现代化和发展。研究目的:本研究旨在系统阐明黄蜡木有效成分通过调节滑膜细胞的生物学行为来抑制RA的分子机制,同时揭示其多组分之间的协同作用模式。材料与方法:首先利用血清网络药理学方法预测黄蜡木抗RA的潜在有效成分及其作用机制,然后通过高效液相色谱(HPLC)对6种主要有效成分进行定量分析。随后,建立胶原诱导关节炎(CIA)大鼠模型,采用western blot和定量实时聚合酶链反应(qPCR)检测滑膜组织中相关蛋白和mRNA的表达。采用组织块粘附培养法分离培养原代成纤维细胞样滑膜细胞(FLS)。通过细胞增殖、侵袭、凋亡等实验,评价活性成分的生物学作用,探讨其作用机制。最后,采用药物效应中值分析(Chou-Talalay法)和分子模拟的方法研究了活性成分之间的协同作用及其机制。结果:血清网络药理学预测提示木原可能通过PI3K-Akt信号通路调节细胞增殖、凋亡、炎症等生物学过程,发挥其抗ra作用。动物实验证实,黄原木犀草乙醇提取物和乙酸乙酯部位可显著降低CIA大鼠滑膜组织中磷酸肌肽3激酶(PI3K)和蛋白激酶B (AKT)等关键蛋白的异常过表达。进一步的体外实验发现,黄原木质素中6种活性成分含量均超过1.4 mg/g,并可调节原代RA-FLS细胞的增殖、侵袭、迁移、凋亡、周期和炎症等多种生物学过程,同时还可表达PI3K-Akt信号通路。值得注意的是,采用药物效应中位数法进行的定量分析显示,表儿茶素与原花青素A2联合给药对RA-FLS细胞增殖具有明显的协同抑制作用(联合指数< 0.1),其潜在机制可能与它们通过不同的活性结合位点与PI3K蛋白协同作用密切相关。结论:黄蜡木有效成分可通过PI3K-Akt信号通路调节FLS细胞的多个生物学过程,从而减轻关节损伤,其中表儿茶素和原花青素A2具有显著的协同作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of ethnopharmacology
Journal of ethnopharmacology 医学-全科医学与补充医学
CiteScore
10.30
自引率
5.60%
发文量
967
审稿时长
77 days
期刊介绍: The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.
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