强心补肾汤通过AMPK/ fox01介导的铁凋亡途径减轻II型心肾综合征：多组学和实验研究

IF 8.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-09-09 DOI:10.1016/j.phymed.2025.157247

Shuo Han , Hui Zhang , Junfeng Qian , Sijie Yao , Yali Sun , Xuan Zhao , Xinyue Ding , Lina Xing , Zongjun Liu

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引用次数: 0

摘要

背景：我们前期研究表明强心补肾汤对心力衰竭合并肾功能不全患者有一定的治疗作用。然而，QBD改善II型心肾综合征（CRS2）进展的确切分子途径和病理生理机制尚不清楚。目的：探讨QBD治疗CRS2的作用机制。方法：采用UPLC-Q-TOF-MS对QBD样品进行综合代谢物谱分析。利用网络药理学、RNA-seq和代谢组学预测QBD对CRS2作用的生物活性成分、潜在治疗靶点和干预途径。采用超声心动图及血清、尿液生化指标评价小鼠的心功能和肾功能。收集心脏和肾脏组织样本进行组织学、蛋白质和遗传学检查，并使用免疫组织化学（IHC）染色、western blotting（WB）分析和qPCR分析对靶基因进行验证。结果：QBD样品中共检出74种化合物，含QBD血清中检出118种化合物。超声心动图显示CRS2小鼠有明显的心室重构，QBD治疗后明显改善。血清和尿液生化分析进一步证实QBD能有效减轻心肾损伤。组织病理学检查显示，qbd治疗小鼠心脏和肾脏组织的病理性损伤明显减轻。包括免疫组化染色、WB和qPCR分析在内的多模式验证表明，QBD通过调节amp激活的蛋白激酶(AMPK)/Forkhead box蛋白O1 （FOXO1）通路，减轻了CRS2小鼠的组织铁凋亡。利用AMPK抑制剂Dorsomorphin和铁下垂激活剂Erastin进行的体外实验证实，QBD是通过这一途径发挥其治疗作用的。综合转录组学和代谢组学分析显示，QBD治疗调节了与能量代谢、氧化应激和生物合成功能相关的代谢途径。结论：本研究通过当代多组学研究工具揭示了QBQ通过AMPK/ fox01依赖性铁下沉抑制CRS2发挥其心肾保护作用。

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Qiangxin bushen decoction attenuates cardiorenal syndrome type II via AMPK/FOXO1-mediated ferroptosis pathway: A multi-omics and experimental study

Background

Our previous studies have demonstrated that Qiangxin Bushen Decoction (QBD) exhibits therapeutic effects in heart failure patients complicated with renal insufficiency. However, the precise molecular pathways and pathophysiological mechanisms through which QBD ameliorates cardiorenal syndrome type II (CRS2) progression remain unclear.

Purpose

To explore the mechanism of QBD for the treatment of CRS2.

Methods

UPLC-Q-TOF-MS was employed to explore comprehensive metabolite profiling from QBD samples. Network pharmacology, RNA-seq, and metabolomics were utilized to predict the bioactive constituents, potential therapeutic targets, and intervention pathways through which QBD exerts its effects on CRS2. Cardiac and renal function in mice were assessed by echocardiography along with serum and urinary biochemical markers. Cardiac and renal tissue samples were collected for histological, protein, and genetic examinations, and targeted genes werevalidated using immunohistochemistry (IHC) staining, western blotting(WB) analysis, and qPCR analysis.

Results

A total of 74 compounds were identified in QBD samples, and 118 compounds were detected in QBD-containing serum. Echocardiography revealed significant ventricular remodeling in CRS2 mice, which was markedly ameliorated following QBD treatment. Serum and urine biochemical assays further confirmed that QBD effectively alleviated cardiorenal injury. Histopathological examination demonstrated significantly reduced pathological damage in the heart and kidney tissues of QBD-treated mice. Multimodal validation, including IHC staining, WB, and qPCR analyses, indicated that QBD attenuated tissue ferroptosis by modulating the AMP-activated protein kinase (AMPK)/Forkhead box protein O1 (FOXO1) pathway in CRS2 mice. In vitro experiments using AMPK inhibitor Dorsomorphin and ferroptosis activator Erastin confirmed that QBD exerted its therapeutic effects via this pathway. Integrated transcriptomic and metabolomic analyses revealed that QBD treatment modulated metabolic pathways associated with energy metabolism, oxidative stress, and biosynthetic functions.

Conclusion

This study reveals that QBQ exerts its cardiorenal protection for CRS2 through AMPK/FOXO1-dependent ferroptosis inhibition with contemporary multi-omics research tools.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.