Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies
Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies
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网络药理学结合分子机制和代谢组学研究揭示枳实和枳壳的抗炎作用。
DOI：
10.1016/j.phymed.2018.09.184
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发表时间：
2018-11-15
期刊：
影响因子：
7.9
通讯作者：
Lu Aiping
中科院分区：
文献类型：
--
作者：
Zhao Siyu;Liu Zhenli;Lu Aiping
工作背景：炎症反应具有复杂的发病机制;因此，它是许多疾病的发展和并发症的关键因素。枳实、枳樵是著名的柑橘类中草药，富含具有多种抗炎活性的酚类活性成分。目的：建立枳实、枳樵抗炎作用的多组分靶点网络策略，为研究枳实、枳樵的抗炎作用机制提供参考。本研究将多组分测定、网络药理学、细胞内分子机制和动物体内代谢组学相结合，构建了一个多组分-靶点-通路的网络策略，以阐明枳实和栀翘的多种降血脂作用。基于定量测定的枳实和连翘的全局和特征化学图谱，采用网络药理学结合文本挖掘和对接的方法，对枳实和连翘的成分-靶点-途径网络进行预测。通过脂多糖诱导的RAW 264.7细胞炎症反应，验证了枳实和枳壳各成分的潜在抗炎机制。结果：枳实主要通过抑制MAPK信号通路发挥作用，而栀翘则同时通过抑制PPAR-AKT信号通路发挥作用。同时，枳实和栀翘均通过抑制NF-κ B B信号通路，减少炎症介质的产生，发挥抗炎作用。在代谢组学研究中，枳实和栀翘分别通过氨基酸代谢、糖代谢和脂代谢对紊乱的代谢途径进行了不同程度的纠正。结论：枳实和栀翘的抗炎作用是通过多种途径发挥的。这些发现有助于开发枳实和栀翘在炎症性疾病中的应用。
Background: The inflammatory response has a complex pathogenesis; thus, it is a critical contributor to the development and complication of many diseases. Zhishi and Zhiqiao are famous Citrus herbal medicines that are rich in bioactive phenolic constituents with multiple anti-inflammatory activities.Purpose: Establishment of a multi-component-target-pathway network strategy to investigate the usage of Zhishi and Zhiqiao on inflammatory diseases can provide a reference for mechanisms of traditional Chinese medicine (TCM).Study Design: A multi-component-target-pathway network strategy was constructed to elucidate the various antiinflammatory effects of Zhishi and Zhiqiao by integrating multi-constituent determination, network pharmacology, molecular mechanisms in cells and integrated metabolomics in animals.Methods: Based on the quantitatively determined global and characteristic chemical profiles of Zhishi and Zhiqiao, the component-target-pathway network was predicted by network pharmacology coupled with text mining and docking. The potential antiinflammatory mechanism of the various components in Zhishi and Zhiqiao were verified using LPS-induced inflammatory responses in RAW 264.7 cells. The different metabolic regulating effects of Zhishi and Zhiqiao against an LPS-induced inflammation model were investigated using a plasma metabolomics strategy.Results: The molecular mechanism of Zhishi mainly suppressed the MAPK signaling pathway, whereas Zhiqiao emphasized the PPAR-AKT signaling pathways simultaneously to block the inflammatory process. Meanwhile, Zhishi and Zhiqiao both exhibited an anti-inflammatory effect by inhibiting the NF-kappa B signaling pathway to reduce the production of inflammatory mediators. In the metabolomics study, Zhishi and Zhiqiao exhibited variant corrections of the disordered metabolic pathways through amino acid metabolism, glycometabolism and lipid metabolism.Conclusion: All of these results indicate that Zhishi and Zhiqiao, in a diversified mixture, exert their anti-inflammatory effect through variant pathways. These findings can assist in developing the use of Zhishi and Zhiqiao for inflammatory diseases.