Integrated Network Pharmacology and Lipidomics to Reveal the Inhibitory Effect of Qingfei Oral Liquid on Excessive Autophagy in RSV-Induced Lung Inflammation.
Integrated Network Pharmacology and Lipidomics to Reveal the Inhibitory Effect of Qingfei Oral Liquid on Excessive Autophagy in RSV-Induced Lung Inflammation.
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综合网络药理学和脂质组学揭示清肺口服液对 RSV 所致肺部炎症过度自噬的抑制作用
DOI：
10.3389/fphar.2021.777689
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发表时间：
2021
影响因子：
5.6
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Lin L;An L;Chen H;Feng L;Lu M;Liu Y;Chu C;Shan J;Xie T;Wang X;Wang S
背景：呼吸道合胞病毒（RSV）可引起儿童不同程度的肺部炎症。清肺口服液治疗小儿呼吸道合胞病毒性肺炎（RSV-LI）临床疗效显著，但其药理作用及机制尚不清楚。方法：本研究结合网络药理学、脂质体组学、药效学、途径验证等方法，对QF的治疗作用机制进行评价。使用Cytoscape（v3.8.2）和来自京都基因和基因组百科全书（KEGG）和基因本体论（GO）的富集分析，创建了推定的化合物-靶标-途径网络的全局视图。然后使用相应的脂质组学图谱检测不同活化的脂质，使用与混合四极杆-Exactive Orbitrap质谱法（UHPLC-Q-Exactive Orbitrap MS）连接的超高效液相色谱法揭示代谢途径。同时，在RSV感染小鼠模型中验证了QF的体内效率、富集途径和过度自噬抑制机制。结果：网络药理学结果表明，117个活性化合物直接作用于QF抗RSV-LI的101个核心靶点。最显著富集的途径是PI 3 K/Akt/mTOR信号传导途径（p < 0.05）。此外，进行非靶向脂质组学，并且显示在QF施用后，RSV-LI组中较高的DAG 30：0、DAG 30：5、DAG 32：0、DAG 16：0_18：0、DAG 17：0_17：0、DAG 34：1、DAG 36：0、DAG 36：1的肺水平降低（FDR < 0.05，FC > 1.2）。在RSV-LI小鼠模型中，DAG合成中的关键酶Lipin-1增加。动物实验进一步证实，QF可抑制PI 3 K/Akt/mTOR信号通路，降低肺组织磷酸化PI 3 K、AKT和mTOR及其相关蛋白lipin-1和VPS 34的水平（p < 0.01）。最后，药效学研究表明，QF通过降低RSV F和G蛋白、Beclin-1、Atg 5和LC 3B II、IL-1和TNF-α的肺水平来减少由过度自噬引起的气道炎症（p < 0.05）。结论：基于脂质组学的网络药理学，沿着实验验证，可能是阐明QF治疗RSV-LI的治疗机制的有效方法。
Background: Respiratory syncytial virus (RSV) can cause varying degrees of lung inflammation in children. Qingfei Oral Liquid (QF) is effective in treating childhood RSV-induced lung inflammation (RSV-LI) in clinics, but its pharmacological profiles and mechanisms remain unclear. Methods: This study combined network Pharmacology, lipidomics, pharmacodynamics, and pathway validation to evaluate the therapeutic mechanisms of QF. Using Cytoscape (v3.8.2) and enrichment analyses from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), a global view of the putative compound-target-pathway network was created. The corresponding lipidomic profiles were then used to detect differently activated lipids, revealing the metabolic pathway, using ultra-high-performance liquid chromatography linked to hybrid Quadrupole-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS). Meanwhile, the in vivo efficiency of QF, the enrichment pathway, and the excessive autophagy inhibition mechanisms were validated in RSV-infected mice models. Results: The network pharmacology results demonstrated 117 active compounds acted directly upon 101 core targets of QF against RSV-LI. The most significantly enriched pathway was the PI3K/Akt/mTOR signaling pathway (p < 0.05). In addition, untargeted lipidomics were performed, and it was revealed that higher lung levels of DAG 30:0, DAG 30:5, DAG 32:0, DAG 16:0_18:0, DAG 17:0_17:0, DAG 34:1, DAG 36:0, DAG 36:1 in the RSV-LI group were decreased after QF administration (FDR < 0.05, FC > 1.2). Lipin-1, a key enzyme in DAG synthesis, was increased in the RSV-LI mouse model. Animal experiments further validated that QF inhibited the PI3K/Akt/mTOR signaling pathway, with lower lung levels of phosphorylated PI3K, AKT and mTOR, as well as its related proteins of lipin-1 and VPS34 (p < 0.01). Finally, pharmacodynamic investigations indicated that QF reduced airway inflammation caused by excessive autophagy by decreasing lung levels of RSV F and G proteins, Beclin-1, Atg5, and LC3B II, IL-1 and TNF-α (p < 0.05). Conclusion: Lipidomic-based network pharmacology, along with experimental validation, may be effective approaches for illustrating the therapeutic mechanism of QF in the treatment of RSV-LI.
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