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Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting PDGFRβ/PI3K/AKT pathway

ABSTRACT: Yinchenzhufu decoction (YCZFD) is a traditional Chinese medicine formula with hepatoprotective effects. In this study, the protective effects of YCZFD against cholestatic liver fibrosis and its mechanisms of action were evaluated in a mouse model of 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC)-induced cholestasis. YCZFD significantly decreased levels of serum biochemical, liver injury, and fibrosis indicators. Data-independent acquisition-based mass spectrometry (MS) was used to investigate proteomic changes in the livers of mice in three groups: control, model, and model treated by high-dose YCZFD. In total, 460 differentially expressed proteins (DEPs) were identified. Enrichment analyses of these DEPs uncovered that YCZFD influences multiple pathways, including PI3K-Akt, focal adhesion, ECM-receptor interaction, glutathione metabolism, and steroid biosynthesis pathways. PDGFRβ, a receptor associated with the PI3K/AKT and focal adhesion pathways, was significantly upregulated in the livers of cholestatic mice but downregulated by YCZFD. The effects of YCZFD on the expression levels of key proteins in the PDGFRβ/PI3K/AKT pathway were further confirmed in TGFβ-induced hepatic stellate cells. Finally, we uncovered six components (i.e., chlorogenic acid, scoparone, isoliquiritigenin, glycyrrhetinic acid, formononetin, atractylenolide I, and benzoylaconitine) of YCZFD that may regulate PDGFRβ expression. Overall, YCZFD exerts a substantial protective effect against DDC-induced cholestatic liver fibrosis mainly through regulating the PDGFRβ/PI3K/AKT signaling pathway.

ORGANISM(S): Mus Musculus

SUBMITTER: Yueming Ma

PROVIDER: PXD046101 | iProX | Fri Oct 13 00:00:00 BST 2023

REPOSITORIES: iProX

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Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting the PDGFRβ/PI3K/AKT pathway.

Meng Qian Q Zhu Hongwen H Li Yuanyuan Y Peng Xiaotian X Wang Tianming T Huang Hui H Zhou Hu H Liu Yuejia Y Ru Sujie S Wu Jiasheng J Ma Yueming Y

Frontiers in pharmacology 20240226

<b>Introduction:</b> Yinchenzhufu decoction (YCZFD) is a traditional Chinese medicine formula with hepatoprotective effects. In this study, the protective effects of YCZFD against cholestatic liver fibrosis (CLF) and its underlying mechanisms were evaluated. <b>Methods:</b> A 3, 5-diethoxycarbonyl-1, 4-dihydro-collidine (DDC)-induced cholestatic mouse model was used to investigate the amelioration of YCZFD on CLF. Data-independent acquisition-based mass spectrometry was performed to investigate ...[more]

PMID: 38469403

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Project description:Aim: Inflammation and fibrosis have been shown to be critical factors in heart failure (HF) progression. Calycosin (Cal) is the major active component of Radix astragali and has been widely used to treat inflammation in clinical practice. However, whether Cal could ameliorate myocardial infarction (MI)-induced inflammation and fibrosis and precise mechanisms remain uncertain. The aim of this study is to explore the role of Cal in HF and to clarify the underlying mechanisms. Methods: For in vivo experiments, rats underwent left anterior descending (LAD) artery ligation for HF model, and the cardioprotective effects of Cal were measured by echocardiographic assessment and histological examination. RNA-seq approach was applied to explore potential differential genes and pathways. For further mechanistic study, pro-inflammatory conditioned media (CM)-induced H9C2 cells injury model and TGFβ-stimulated cardiac fibroblasts model were applied to determine the regulatory mechanisms of Cal. Results: In vivo experiment, echocardiography results showed that Cal significantly improved heart function. GO and Reactome enrichment revealed that inflammation and fibrosis pathway are involved in Cal-treated group. KEGG enrichment indicated that PI3K-AKT pathway is enriched in the Cal-treated group. Further experiments proved that Cal alleviated cardiomyocyte inflammatory responses evidenced by down-regulating the expressions of phosphorylated IκB kinase α/β (p-IKKα/β), phosphorylated nuclear factor kapa B (p-NFκB) and tumor necrosis factor α (TNFα). Besides, Cal effectively attenuated cardiac fibrosis through the inhibitions of expressions and depositions of collagen I and collagen III. In vitro experiments, the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 could abrogate the anti-inflammation and anti-fibrosis therapeutic effects of Cal, demonstrating that the cardio-protective effects of Cal were mediated through upregulations of PI3K and serine/threonine kinase (AKT). Conclusion: Cal improves cardiac function against HF by inhibiting cardiomyocytes inflammation and fibroblasts fibrosis via activation of the PI3K-AKT pathway.

Dataset Information

Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting PDGFRβ/PI3K/AKT pathway

Publications

Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting the PDGFRβ/PI3K/AKT pathway.

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