A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation.
A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation.
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基于网络药理学和实验验证的金合欢素抗脓毒症机制的系统研究
DOI：
10.3389/fphar.2021.683645
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发表时间：
2021
影响因子：
5.6
通讯作者：
Ma K
中科院分区：
文献类型：
--
作者：
Ouyang Y;Rong Y;Wang Y;Guo Y;Shan L;Yu X;Li L;Si J;Li X;Ma K
脓毒症是对感染的失调的全身反应，并且没有有效的治疗选择。金合欢素是一种天然黄酮类化合物，存在于多种植物中，包括三棱、大蓟和糙叶败酱。研究表明，金合欢素可能对脓毒症发挥抗炎和抗氧化作用。在这项研究中，我们研究了金合欢素对脓毒症的潜在保护作用，并使用网络药理学方法结合实验验证和分子对接揭示了潜在的机制。首先，我们发现金合欢素显著抑制LPS诱导的暴发性肝衰竭和急性肺损伤小鼠的病理损伤和促炎细胞因子表达，体外实验进一步证实金合欢素减弱LPS诱导的M1极化。然后，网络药理学筛选显示EGFR、PTGS 2、SRC和ESR 1是PPI网络中的前四个重叠靶点，GO和KEGG分析显示了与金合欢素对脓毒症的治疗作用相关的前20个丰富的生物过程和信号传导途径。进一步的网络药理学分析表明，缝隙连接可能高度参与了金合欢素对脓毒症的保护作用。最后，分子对接证实了金合欢素与网络药理学预测的4个靶点的活性位点结合，体外实验进一步证实金合欢素显著抑制LPS诱导的p-src上调，并通过缝隙连接减弱LPS诱导的M1极化。综上所述，我们的研究结果表明，金合欢素可能通过涉及多个靶点和途径的机制来预防脓毒症，并且间隙连接可能高度参与这一过程。
Sepsis is a dysregulated systemic response to infection, and no effective treatment options are available. Acacetin is a natural flavonoid found in various plants, including Sparganii rhizoma, Sargentodoxa cuneata and Patrinia scabiosifolia. Studies have revealed that acacetin potentially exerts anti-inflammatory and antioxidative effects on sepsis. In this study, we investigated the potential protective effect of acacetin on sepsis and revealed the underlying mechanisms using a network pharmacology approach coupled with experimental validation and molecular docking. First, we found that acacetin significantly suppressed pathological damage and pro-inflammatory cytokine expression in mice with LPS-induced fulminant hepatic failure and acute lung injury, and in vitro experiments further confirmed that acacetin attenuated LPS-induced M1 polarization. Then, network pharmacology screening revealed EGFR, PTGS2, SRC and ESR1 as the top four overlapping targets in a PPI network, and GO and KEGG analyses revealed the top 20 enriched biological processes and signalling pathways associated with the therapeutic effects of acacetin on sepsis. Further network pharmacological analysis indicated that gap junctions may be highly involved in the protective effects of acacetin on sepsis. Finally, molecular docking verified that acacetin bound to the active sites of the four targets predicted by network pharmacology, and in vitro experiments further confirmed that acacetin significantly inhibited the upregulation of p-src induced by LPS and attenuated LPS-induced M1 polarization through gap junctions. Taken together, our results indicate that acacetin may protect against sepsis via a mechanism involving multiple targets and pathways and that gap junctions may be highly involved in this process.
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