Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice

Guo, Yongze; Ding, Qian; Chen, Lei; Ji, Chenguang; Hao, Huiyao; Wang, Jia; Qi, Wei; Xie, Xing; Ma, Junwei; Li, Aidi; Jiang, Xiaoyu; Li, Xiaotian; Jiang, Huiqing

doi:10.1016/j.amjms.2017.04.011

Cited by 9 publications

(8 citation statements)

References 30 publications

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“…Heparin-binding epidermal growth factor, which was identified by network pharmacology and not of network analysis, has also been reported to serve as a fibrosis inducer ( Guo et al, 2017 ). Also, other studies indicated that HBEGF inhibitor could cure liver fibrosis by efficiently inhibiting HSCs activation ( Zhang D. et al, 2014 ).…”

Section: Resultsmentioning

confidence: 99%

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

Xing

Chen

et al. 2018

Front. Pharmacol.

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Purpose: This study aimed to identify the active components of Fuzheng Huayu (FZHY) formula and the mechanism by which they inhibit the viability of hepatic stellate cells (HSCs) by a combination of network pharmacology and transcriptomics.Methods: The active components of FZHY formula were screened out by text mining. Similarity match and molecular docking were used to predict the target proteins of these compounds. We then searched the STRING database to analyze the key enriched processes, pathways and related diseases of these target proteins. The relevant networks were constructed by Cytoscape. A network analysis method was established by integrating data from above network pharmacology with known transcriptomics analysis of quiescent HSCs-activated HSCs to identify the most possible targets of the active components in FZHY formula. A cell-based assay (LX-2 and T6 cells) and surface plasmon resonance (SPR) analysis were used to validate the most possible active component-target protein interactions (CTPIs).Results: 40 active ingredients in FZHY formula and their 79 potential target proteins were identified by network pharmacology approach. Further network analysis reduced the 79 potential target proteins to 31, which were considered more likely to be the target proteins of the active components in FZHY formula. In addition, further enrichment analysis of 31 target proteins indicated that the HIF-1, PI3K-Akt, FoxO, and chemokine signaling pathways may be the primary pathways regulated by FZHY formula in inhibiting the HSCs viability for the treatment of liver fibrosis. Of the 31 target proteins, peroxisome proliferator activator receptor gamma (PPARG) was selected for validation by experiments at the cellular and molecular level. The results demonstrated that schisandrin B, salvianolic acid A and kaempferol could directly bind to PPARG, decreasing the viability of HSCs (T6 cells and LX-2 cells) and exerting anti-fibrosis effects.Conclusion: The active ingredients of FZHY formula were successfully identified and the mechanisms by which they inhibit HSC viability determined, using network pharmacology and transcriptomics. This work is expected to benefit the clinical application of this formula.

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Section: Resultsmentioning

confidence: 99%

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

Xing

Chen

et al. 2018

Front. Pharmacol.

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“…Then, the sections were stained with H&E for the morphological evaluation and Masson stain or Sirius-red stain for the assessment of collagen. The collagen I (1:50, Affinity) and α-SMA (1:200, Abcam) immunohistochemical staining was performed following heat-induced epitope retrieval as previously described 18 .…”

Section: Methodsmentioning

confidence: 99%

The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis

et al. 2019

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The clearance of activated hepatic stellate cells (HSCs) by apoptosis is critical for the reversibility of hepatic fibrosis. Mitochondrial homeostasis is regulated by mitophagy, which is an efficient way of clearing injured mitochondria that plays an important role in apoptosis. However, the role of mitophagy in apoptosis in HSCs and hepatic fibrosis is still unclear. Here, we show that mitophagy is enhanced in parallel with increased apoptosis in hepatic stellate cells during the reversal of hepatic fibrosis. The inhibition of mitophagy suppressed apoptosis in HSCs and aggravated hepatic fibrosis in mice. In contrast, the activation of mitophagy induced apoptosis in HSCs. Furthermore, we confirmed that BCL-B, which is a member of the BCL-2 family, is a regulator mediating mitophagy-related apoptosis. The knockdown of BCL-B resulted in increased apoptosis and mitophagy in HSCs, while the overexpression of BCL-B caused the opposite effects. BCL-B inhibited the phosphorylation of Parkin (a key regulator of mitophagy) and directly bound phospho-Parkin. Altogether, enhanced mitophagy promotes apoptosis in HSCs during the reversal of hepatic fibrosis. BCL-B suppresses mitophagy in HSCs by binding and suppressing phospho-Parkin, thereby inhibiting apoptosis. BCL-B-dependent mitophagy is a new pathway for the regulation of apoptosis in HSCs during the regression of hepatic fibrosis.

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“…While this may be due to the use of different promoters in these experiments (cytomegalovirus [CMV] for sHB-EGF and MCK for GALGT2), HB-EGF has additional well-described functions not reported with GALGT2. For example, Hbegf-deficient mice have extensive phenotypes related to cardiac development (61,65,66), cardiac hypertrophy (66,67), tumor cell growth and angiogenesis (57,68), embryo implantation and placental development (69)(70)(71), cognitive function and synaptic plasticity (72,73), tissue fibrosis (74)(75)(76)(77), and intestinal health and regeneration after injury (78)(79)(80)(81)(82). Some of these phenotypes have been not reported in Galgt2 Ϫ/Ϫ mice, although Galgt2 deletion can give rise to blood, cardiac, pregnancy, and tumor-related phenotypes (14,31,(83)(84)(85).…”

Section: Discussionmentioning

confidence: 99%

Soluble Heparin Binding Epidermal Growth Factor-Like Growth Factor Is a Regulator of GALGT2 Expression and GALGT2-Dependent Muscle and Neuromuscular Phenotypes

Cramer

Martin

2019

Molecular and Cellular Biology

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GALGT2 (also B4GALNT2) encodes a glycosyltransferase that is normally confined to the neuromuscular and myotendinous junction in adult skeletal muscle. GALGT2 overexpression in muscle can inhibit muscular dystrophy in mouse models of the disease by inducing the overexpression of surrogate muscle proteins, including utrophin, agrin, laminins, and integrins. Despite its well-documented biological properties, little is known about the endogenous regulation of muscle GALGT2 expression. Here, we demonstrate that epidermal growth factor receptor (EGFR) ligands can activate the human GALGT2 promoter. Overexpression of one such ligand, soluble heparin-binding EGF-like growth factor (sHB-EGF), also stimulated mouse muscle Galgt2 gene expression and expression of GALGT2-inducible surrogate muscle genes. Deletion analysis of the GALGT2 promoter identified a 45-bp region containing a TFAP4-binding site that was required for sHB-EGF activation. sHB-EGF increased TFAP4 binding to this site in muscle cells and increased endogenous Tfap4 gene expression. sHB-EGF also increased muscle EGFR protein expression and activated EGFR-Akt signaling. sHB-EGF expression was concentrated at the neuromuscular junction, and Hbegf deletion reduced Galgt2-dependent synaptic glycosylation. Hbegf deletion also mimicked Galgt2-dependent neuromuscular and muscular dystrophy phenotypes. These data demonstrate that sHB-EGF is an endogenous regulator of muscle Galgt2 gene expression and can mimic Galgt2-dependent muscle phenotypes.

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Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice

Cited by 9 publications

References 30 publications

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis

Soluble Heparin Binding Epidermal Growth Factor-Like Growth Factor Is a Regulator of GALGT2 Expression and GALGT2-Dependent Muscle and Neuromuscular Phenotypes

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