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Archive > Volume 16 Issue 4 > 2024,16(4):638-655. DOI:https://doi.org/10.1016/j.chmed.2024.07.007 Prev Next

網(wǎng)絡(luò)藥理學(xué)、分子對(duì)接、非靶向代謝組學(xué)探討清肺通絡(luò)膏藥改善呼吸道合胞病毒肺炎多靶點(diǎn)作用的分子機(jī)制

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Network pharmacology, molecular docking, and untargeted metabolomics reveal molecular mechanisms of multi-targets effects of Qingfei Tongluo Plaster improving respiratory syncytial virus pneumonia

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    摘要:
    目的：清肺通絡(luò)膏（QFP）是一種改良的醫(yī)院制劑，臨床療效好、方便、經(jīng)濟(jì)、患者依從性好，是治療呼吸道合胞病毒（RSV）肺炎的一種有吸引力的治療選擇。本研究旨在從減輕肺部炎癥的角度探討芪fp對(duì)RSV大鼠的作用機(jī)制，并進(jìn)一步探討芪fp對(duì)RSV大鼠血清代謝物及代謝途徑的影響。方法：本研究采用網(wǎng)絡(luò)藥理學(xué)方法和分子對(duì)接，結(jié)合分子生物學(xué)和代謝組學(xué)從多維角度篩選和驗(yàn)證治療靶點(diǎn)。利用開放的在線數(shù)據(jù)庫推測有效成分和疾病的基因靶點(diǎn)。然后，我們使用String數(shù)據(jù)庫來檢查藥物和疾病的共同目標(biāo)的基本相互作用。通過在線富集分析來預(yù)測功能通路。采用分子對(duì)接的方法，發(fā)現(xiàn)了重要成分與關(guān)鍵基因靶點(diǎn)之間的結(jié)合方式。最后，我們?cè)趓sv誘發(fā)的肺炎大鼠模型中證明了QFP的抗炎能力，并結(jié)合代謝組學(xué)結(jié)果解釋了其機(jī)制。 結(jié)果：確定了19個(gè)關(guān)鍵指標(biāo)為核心指標(biāo)：腫瘤壞死因子（TNF）、誘導(dǎo)型一氧化氮合酶2 （NOS2）、絲裂原活化蛋白激酶14 （MAPK14）、g1/ s特異性細(xì)胞周期蛋白d1 （CCND1）、轉(zhuǎn)錄1 α / β信號(hào)轉(zhuǎn)導(dǎo)和激活因子（STAT1）、原癌基因酪氨酸蛋白激酶Src （Src）、細(xì)胞腫瘤抗原p53 （TP53）、白細(xì)胞介素6 （IL6）、低氧誘導(dǎo)因子1- α (HIF1A)、rac - α絲氨酸/蘇氨酸蛋白激酶（AKT1）、轉(zhuǎn)錄3信號(hào)轉(zhuǎn)導(dǎo)和激活因子（STAT3）、熱休克蛋白hsp90 - α (HSP90AA1)、酪氨酸蛋白激酶JAK2 （JAK2）、細(xì)胞周期蛋白依賴性激酶抑制劑1 （CDKN1A）、絲裂原活化蛋白激酶3 （MAPK3）、表皮生長因子受體（EGFR）、myc原癌基因蛋白（myc）、蛋白c-Fos （FOS）和轉(zhuǎn)錄因子p65 （RELA）。QFP主要通過磷脂酰肌醇3-激酶(PI3K)/RAC AKT途徑、HIF-1途徑、IL-17途徑、TNF途徑、MAPK途徑治療RSV肺炎。動(dòng)物實(shí)驗(yàn)證明，QFP能有效改善rsv誘導(dǎo)的肺部炎癥。在QFP治療中，共有28種代謝物發(fā)生了顯著變化，通過網(wǎng)絡(luò)藥理學(xué)分析，有4種代謝途徑與KEGG途徑一致，提示它們可能是與治療相關(guān)的關(guān)鍵過程。結(jié)論：這些結(jié)果為QFP作為一種有前途的治療RSV感染藥物的作用機(jī)制提供了必要的研究基礎(chǔ)。

    Abstract:
    Objective: Qingfei Tongluo Plaster (QFP), an improved Chinese medicine hospital preparation, is an attractive treatment option due to its well clinical efficacy, convenience, economy, and patient compliance in the treatment of respiratory syncytial virus (RSV) pneumonia. The aim of this study was to investigate the efficacy mechanism of QFP on RSV rats from the perspective of alleviating lung inflammation and further explore the changes of serum metabolites and metabolic pathways in RSV rats under the influence of QFP. Methods: This study used network pharmacological methods and molecular docking combined with molecular biology and metabolomics from multi-dimensional perspectives to screen and verify the therapeutic targets. Open online databases were used to speculate the gene targets of efficient ingredients and diseases. Then, we used the String database to examine the fundamental interaction of common targets of drugs and diseases. An online enrichment analysis was performed to predict the functional pathways. Molecular docking was applied to discover the binding modes between essential ingredients and crucial gene targets. Finally, we demonstrated the anti-inflammatory ability of QFP in the RSV-evoked pneumonia rat model and explained the mechanism in combination with the metabolomics results. Results: There were 19 critical targets defined as the core targets: tumor necrosis factor (TNF), inducible nitric oxide synthase 2 (NOS2), mitogen-activated protein kinase 14 (MAPK14), g1/S-specific cyclin-D1 (CCND1), signal transducer and activator of transcription 1 alpha/beta (STAT1), proto-oncogene tyrosine-protein kinase Src (SRC), cellular tumor antigen p53 (TP53), interleukin-6 (IL6), hypoxiainducible factor 1-alpha (HIF1A), RAC-alpha serine/threonine-protein kinase (AKT1), signal transducer and activator of transcription 3 (STAT3), heat shock protein HSP 90-alpha (HSP90AA1), tyrosine-protein kinase JAK2 (JAK2), cyclin-dependent kinase inhibitor 1 (CDKN1A), mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor (EGFR), myc proto-oncogene protein (MYC), protein c-Fos (FOS) and transcription factor p65 (RELA). QFP treated RSV pneumonia mainly through the phosphatidylinositol 3-kinase (PI3K)/RAC AKT pathway, HIF-1 pathway, IL-17 pathway, TNF pathway, and MAPK pathway. Animal experiments proved that QFP could effectively ameliorate RSV-induced pulmonary inflammation. A total of 28 metabolites underwent significant changes in the QFP treatment, and there are four metabolic pathways consistent with the KEGG pathway analyzed by network pharmacology, suggesting that they may be critical processes related to treatment. Conclusion: These results provide essential perspicacity into the mechanisms of action of QFP as a promising anti-RSV drug.

    關(guān)鍵詞:
    兒童;代謝組學(xué);網(wǎng)絡(luò)藥理學(xué);PIK3/AKT通路;清肺通絡(luò)膏;呼吸道合胞病毒肺炎

    Keywords:


    Project Supported:
    This work was supported by the National Natural Science Foundation of China (No. 81973906).

    Clc Number:

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