目的 研究仲景炮附子Aconiti Lateralis Radix Preparata對慢性心力衰竭（CHF）的治療作用，并采用超高效液相色譜四級桿靜電場軌道阱高分辨質(zhì)譜（UPLC-QE-Orbitrap-MS）測定仲景炮附子水煎液的成分，結(jié)合網(wǎng)絡(luò)藥理學探究其治療CHF的作用機制。方法 采用ip鹽酸阿霉素構(gòu)建大鼠CHF模型，ig給予仲景炮附子水煎液（3.3 g·kg^-1）16d后，試劑盒法檢測血清腦鈉素（BNP）含量、心肌組織Ca²⁺-ATP酶和Na⁺，K⁺-ATP酶活性，蘇木素-伊紅（HE）染色后鏡下觀察左心室組織病理學形態(tài)變化。采用UPLC-QE-Orbitrap-MS測定仲景炮附子水煎液的成分，借助Swiss Target Prediction、DrugBank、Gene Cards、OMIM、TTD等平臺預測仲景炮附子治療CHF的作用靶點，利用Cytoscape軟件構(gòu)建相關(guān)作用網(wǎng)絡(luò)，并對核心基因進行基因本體論（GO）功能富集分析和京都基因與基因組百科全書（KEGG）通路富集分析。結(jié)果 與對照組比較，模型組大鼠出現(xiàn)稀便、腹水、體質(zhì)量減輕等現(xiàn)象；血清BNP水平顯著升高（P<0.01）；Ca²⁺-ATP酶、Na⁺，K⁺-ATP酶活力均有降低趨勢；左心室心肌組織切片出現(xiàn)明顯的心肌纖維斷裂，心肌間隙增寬，出現(xiàn)部分空泡變性等病理變化。與模型組比較，仲景炮附子水煎液組大鼠稀便情況得到一定程度改善，腹水和體型消瘦情況改善不明顯；BNP水平顯著降低（P<0.05）；Ca²⁺-ATP酶、Na⁺，K⁺-ATP酶活力均有升高趨勢；左心室組織病理學形態(tài)有明顯改善。采用UPLC-QE-Orbitrap-MS共鑒定出仲景炮附子水煎液主要成分52個。通過網(wǎng)絡(luò)藥理學預測得到仲景炮附子治療CHF活性成分43個，活性成分靶點472個，CHF疾病靶點1063個，活性成分與疾病交集靶點68個；網(wǎng)絡(luò)分析結(jié)果表明，仲景炮附子可能通過作用于信號轉(zhuǎn)導與轉(zhuǎn)錄激活子3（STAT3）、磷脂酰肌醇-4，5-二磷酸3-激酶催化亞基α（PIK3CA）、MAPK1等關(guān)鍵靶點發(fā)揮抗CHF作用，涉及到RAS相關(guān)蛋白1（Rap1）、磷脂酰肌醇3'-激酶（PI3K）-蛋白激酶B （Akt）、絲裂原活化蛋白激酶（MAPK）等信號通路。結(jié)論 仲景炮附子對阿霉素誘導的慢CHF有一定的治療作用，可通過多成分、多靶點、多途徑發(fā)揮作用。

Objective To study the therapeutic effect of Zhongjing's Paofuzi on chronic heart failure(CHF), and use UPLC-QEOrbitrap-MS to determine the components of Zhongjing's Paofuzi decoction, combined with network pharmacology to explore its mechanism of action in the treatment of CHF.Methods The rat model of CHF was established by the ip of adriamycin hydrochloride.After 16 days of Zhongjing's Paofuzi decoction(3.3 g·kg^-1), the serum brain natriuretic peptide(BNP) level, the activities of Ca²⁺-ATP and Na⁺, K⁺-ATP enzymes in cardiac myocytes, and the cardiac histopathology were measured.UPLC-QEOrbitrap-MS was used to determine the components of Zhongjing's Paofuzi decoction, and the Swiss Target Prediction, DrugBank, Gene Cards, OMIM, and TTD platforms were used to predict the target of Zhongjing's Paofuzi in the treatment of CHF, and Cytoscape software was used to construct the correlation of effect network, and GO analysis and KEGG pathway enrichment for core genes were performed.Results Compared with the control group, the model group showed loose stool, ascites and weight loss, the serum BNP level was significantly increased(P<0.01), and the activities of Ca²⁺-ATPase and Na⁺-K⁺-ATPase decreased.Besides, the myocardial tissue sections of the left ventricle showed obvious myocardial fiber rupture, widened myocardial space, and some pathological changes, such as vacuolar degeneration.Compared with model group, the loose stool of rats in Zhongjing's Paofuzi decoction group was improved to a certain extent, but the ascites and body weight loss were not improved significantly, the serum BNP level was decreased(P<0.05), and the activities of Ca²⁺-ATP and Na⁺, K⁺-ATP enzymes tended to increase.The histopathological morphology of left ventricle was significantly improved.A total of 52 main components of Zhongjing's Paofuzi decoction were identified by UPLC-QE-Orbitrap-MS.According to the network pharmacology prediction, 43 active components, 472 active component targets, 1 063 CHF disease targets and 68 intersection targets of active components and disease were obtained.The results of network analysis showed that Zhongjing's Paofuzi may exert its anti-heart failure effect by acting on key targets such as signal transduction and transcription activator 3(STAT3), Phosphatidylinositol-4, 5-diphosphate 3-kinase catalytic subunit alpha(PIK3 CA), mitogen-activated protein kinase 1(MAPK1), involving signaling pathways such as Ras-associated protein l(Rap1), phosphatidylinositol 3'-kinase(PI3 K)-Protein kinase B(Akt), and MAPK.Conclusion Zhongjing's Paofuzi has a certain therapeutic effect on CHF induced by adriamycin, and can treat CHF through the multi-component, multi-target and multi-way.

R285.5

國家自然科學基金面上項目（81973479）