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  3. Decoding the anti-heart failure effects of Xinbao Pills: AMPKα1 activation and active compound screening

Decoding the anti-heart failure effects of Xinbao Pills: AMPKα1 activation and active compound screening

  • Phytomedicine. 2025 Sep:145:157016. doi: 10.1016/j.phymed.2025.157016.
Zunjiang Li 1,  Yingxin Long 2,  Xing Sun 3,  Aoyin Liu 3,  Zhenzhu Ding 3,  Dongli Li 1,  Yueyao Wang 3,  Ruifeng Zeng 1,  Quanle Liu 1,  Baijian Chen 1,  Hong Nie 4,  Wei Zhu 5,  Banghan Ding 6
Affiliations

Affiliations

  • 1 The Second Affiliated Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine, Guangzhou, 510120, China; The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
  • 2 State Key Laboratory of Bioactive Molecules and Draggability Assessment, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug; Development of Chinese Ministry of Education (MOE), Guangzhou 510632, China; College of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 3 The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
  • 4 State Key Laboratory of Bioactive Molecules and Draggability Assessment, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug; Development of Chinese Ministry of Education (MOE), Guangzhou 510632, China; College of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: hongnie1970@163.com.
  • 5 The Second Affiliated Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine, Guangzhou, 510120, China. Electronic address: 13826260112@163.com.
  • 6 The Second Affiliated Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine, Guangzhou, 510120, China; The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address: 13682238225@139.com.
PMID: 40614586 DOI: 10.1016/j.phymed.2025.157016
Abstract

Background: Previous studies have focused on the protective effect of Xinbao pills (XBP) on heart failure (HF) irrespective of the ejection fraction-based classification, However, there are still no reports on the mechanism and active compounds of XBP in HF with reduced ejection fraction (HFrEF).

Objective: This study aimed to elucidate the anti-HFrEF effects and mechanism of XBP and identify its active compounds.

Methods: Doxorubicin-induced HFrEF rats and H2O2-induced damage to H9c2 cardiomyocytes were established. Transthoracic echocardiography, HE staining, commercial assay kits, and cellular flow cytometry analysis were used to evaluate the cardioprotective effect of XBP. Subsequently, myocardial energy metabolomics and transcriptomics were used to explore the mechanism of XBP, which was verified via western blotting and commercial assay kits. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), high-throughput molecular docking, molecular dynamics simulation analysis and in vitro verification were applied to explore the active ingredients of XBP.

Results: XBP improved cardiac function (ejection fraction: 81.1 vs DOX 55.3 %, p < 0.001, and cardiac output: 71.3 vs DOX 47.3 μl/min, p = 0.002 etc.) in HFrEF rats, and protected against myocardial H9c2 cardiomyocyte damage (cell viability: 0.56 vs DOX 0.35, p < 0.05, and LDH: 3562 vs DOX 7073 ng/ml, p < 0.05 etc.), enhanced myocardial energy metabolism levels(ATP: 2887 vs DOX 809.9 nM, p < 0.05, and Glutamine: 387.4 vs DOX 212.8 μM, p < 0.0001 etc.), and protected mitochondrial respiratory function (maximum respiratory capacity: 219.7 vs DOX 81.4 pmol/min, p < 0.05, and glycolytic function: 11.17 vs DOX 5.62 pmol/min, p < 0.001 etc.), which required the activation of AMPKα1. Inhibition of AMPKα1 blocked the cardioprotective effect of XBP. In contrast, activation of the AMPKα1 pathway can exert a similar protective effect as that of XBP. Additionally, Kaempferol-7-O-glucoside, Luteolin-7-O-glucoside, Grossamide, Isorhamnetin-3,7-O-diglucoside, and Kaempferol-7-O-rhamnoside were identified as key compounds that activating AMPKα1 and protecting against myocardial injury.

Conclusions: Our findings suggest that the AMPKα1 pathway is integral to the XBP's anti-HF effects, with key identified compounds likely contributing to the XBP's pharmacological protection, providing a novel mechanistic understanding and identifying the main active compounds of XBP.

Keywords

AMPKα1 signaling pathway; Active compounds; Heart failure; Myocardial dysfunction; Xinbao pills.

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