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Archive > Volume 16 Issue 4 > 2024,16(4):599-611. DOI:https://doi.org/10.1016/j.chmed.2024.02.001 Prev Next

代謝組學(xué)結(jié)合網(wǎng)絡(luò)藥理學(xué)揭示大苞荊芥對(duì)過(guò)敏性哮喘大鼠的抗哮喘機(jī)制

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Metabolomics combined with network pharmacology reveals anti-asthmatic effects of Nepeta bracteata on allergic asthma rats

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    摘要:
    目的：本研究旨在利用代謝組學(xué)和網(wǎng)絡(luò)藥理學(xué)技術(shù)，探究大苞荊芥（簡(jiǎn)稱DBJJ）對(duì)大鼠的抗哮喘作用及其機(jī)制。 方法：本研究首先通過(guò)卵清蛋白（OVA）誘導(dǎo)建立哮喘大鼠模型，隨后給予大苞荊芥煎劑治療。觀察了肺組織的病理變化，并在支氣管肺泡灌洗液（BALF）中定量檢測(cè)了嗜酸性粒細(xì)胞（EOS）和白細(xì)胞（WBC），同時(shí)測(cè)定了OVA誘導(dǎo)的哮喘相關(guān)血清因子水平。利用核磁共振（1H NMR）光譜技術(shù)，對(duì)血清代謝組學(xué)中的差異化代謝物及其代謝途徑進(jìn)行了鑒定和分析。此外，結(jié)合UPC-QE-MS/MS和網(wǎng)絡(luò)藥理學(xué)方法預(yù)測(cè)了DBJJ在抗哮喘作用中的核心靶點(diǎn)和途徑。通過(guò)整合代謝組學(xué)和網(wǎng)絡(luò)藥理學(xué)的方法，進(jìn)一步研究了DBJJ的抗哮喘特性，并通過(guò)分子對(duì)接及關(guān)鍵靶點(diǎn)的Western blotting分析進(jìn)行了驗(yàn)證。 結(jié)果：本研究發(fā)現(xiàn)DBJJ能有效減輕OVA誘導(dǎo)的肺組織病理變化，并減少BALF中的EOS和WBC數(shù)量。DBJJ還抑制了OVA誘導(dǎo)的TNF-α、IL-18、IgE、EOS、IL-1B、MDA、VEGF-A和TGF-β1的升高。代謝組學(xué)分析共鑒定出21個(gè)生物標(biāo)志物和10條代謝途徑。UPC-QE-MS/MS技術(shù)鑒定出29個(gè)化合物，通過(guò)口服利用度和Caco-2細(xì)胞通透性篩選出13個(gè)有效活性成分，預(yù)測(cè)了120個(gè)靶點(diǎn)和173個(gè)KEGG途徑。代謝組學(xué)和網(wǎng)絡(luò)藥理學(xué)的綜合分析揭示了DBJJ的主要成分，包括阿魏酸和熊果酸，對(duì)DAO、NOS2、MAPK和STAT3等四個(gè)靶點(diǎn)及其相關(guān)代謝物和途徑的影響。分子對(duì)接結(jié)果表明DBJJ的有效活性成分對(duì)DAO和NOS2具有高結(jié)合親和力。此外，觀察到DBJJ能顯著降低NOS2、MAPK和STAT3的蛋白表達(dá)和磷酸化水平。 結(jié)論：本研究表明DBJJ在過(guò)敏性哮喘大鼠模型中顯示出顯著的抗哮喘效果，可能通過(guò)其主要成分阿魏酸和熊果酸對(duì)DAO、NOS2、MAPK和STAT3等多個(gè)靶點(diǎn)的作用發(fā)揮抗哮喘效果。

    Abstract:
    Objective: To investigate the mechanisms that underlie the anti-asthmatic effects of Nepeta bracteata (DBJJ, Dabao Jingjie in Chinese) in rats by integrating metabolomics and network pharmacology. Methods: In this study, the rat model of asthma was induced by ovalbumin (OVA), and the rats were treated with a decoction of N. bracteata. Pathological changes in lung tissue were observed, and the quantification of eosinophils (EOS) and white blood cells (WBC) in bronchoalveolar lavage fluid was performed. Furthermore, the serum levels of asthma-related factors induced by OVA were assessed. 1H NMR spectroscopy serum metabolomics method was utilized to identify differential metabolites and their associated metabolic pathways. UPLC-QE-MS/MS combined with network pharmacology was employed to predict the core targets and pathways of DBJJ in its action against asthma. The anti-asthmatic properties of DBJJ were investigated using an integrated approach of metabolomics and network pharmacology. The findings were validated through molecular docking and Western blotting analysis of the key targets. Results: The administration of DBJJ effectively alleviated OVA-induced lung histopathological changes and decreased the number of EOS and WBC in BALF. Additionally, DBJJ inhibited the OVA-induced elevation of TNF-a, IL-18, Ig-E, EOS, IL-1b, MDA, VEGF-A, and TGF-b1. A total of 21 biomarkers and 10 pathways were found by metabolomics analysis. A total of 29 compounds were identified by UPLC-QE-MS/MS, in which 13 active components were screened by oral availability and Caco-2 cell permeability, the 120 targets and 173 KEGG pathways were predicted. The integration of metabolomics and network pharmacological analysis revealed that DBJJ’s main constituents, including ferulic acid and ursolic acid, exerted their effects on four targets, namely DAO and NOS2, as well as their associated metabolites and pathways. The active constituents of DBJJ demonstrated a high binding affinity towards DAO and NOS2. Furthermore, DBJJ was observed to decrease the protein expression and phosphorylation levels of NOS2, MAPK, and STAT3. Conclusion: The administration of DBJJ demonstrates notable anti-asthma properties in rats with allergic asthma. This effect can be attributed to the modulation of various targets, including NOS2, MAPK, and STAT3, by primary constituents such as ferulic acid and ursolic acid.

    關(guān)鍵詞:
    過(guò)敏性哮喘;MAPK;代謝組學(xué);網(wǎng)絡(luò)藥理學(xué);大苞荊芥;NOS2;STAT3

    Keywords:


    Project Supported:
    This work was financially supported by Xinjiang Uygur Autonomous Region Department of Science and Technology (No. 2016A03005-1).

    Clc Number:

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