scholarly journals Plumbagin Ameliorates CCl4-Induced Hepatic Fibrosis in Rats via the Epidermal Growth Factor Receptor Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Si Chen ◽  
Yi Chen ◽  
Bi Chen ◽  
Yi-jing Cai ◽  
Zhuo-lin Zou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Epidermal Growth Factor ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Growth Factor Receptor ◽  
Stellate Cells ◽  
Heparin Binding ◽  
Fibrotic Liver ◽  
Epidermal Growth

Epidermal growth factor (EGF) and its signaling molecules, EGFreceptor (EGFR) and signal transducer and activator of transcription factor 3 (STAT3), have been considered to play a role in liver fibrosis and cirrhosis. Plumbagin (PL) is an extracted component from the plant and has been used to treat different kinds of cancer. However, its role in regulation of EGFR and STAT3 during liver fibrosis has not been investigated. In this study, the effects of PL on the regulation of EGFR and STAT3 were investigated in carbon tetrachloride (CCl4) induced liver fibrosis and hepatic stellate cells (HSC-T6). PL significantly attenuated liver injury and fibrosis in CCl4treated rats. At concentrations of 2 to 6 μM, PL did not induce significant cytotoxicity of HSC-T6 cells. Moreover, PL reduced phosphorylation of EGFR and STAT3 in both fibrotic liver and heparin-binding EGF-like growth factor (HB-EGF) treated HSC-T6 cells. Furthermore, PL reduced the expression ofα-SMA, EGFR, and STAT3 in both fibrotic liver and HB-EGF treated HSC-T6 cells. In conclusion, plumbagin could ameliorate the development of hepatic fibrosis through its downregulation of EGFR and STAT3 in the liver, especially in hepatic stellate cells.

scholarly journals Non-Invasively Distinguishing Progress of Liver Fibrosis by Visualizing Hepatic Platelet Derived Growth Factor Receptor-Beta Expression with an MRI Modality in Mice

2020 ◽  
Author(s):  
Ling Wu ◽  
Xiao-quan Huang ◽  
Na Li ◽  
Cao Xie ◽  
Sheng-xiang Rao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Cyclic Peptides ◽  
Growth Factor Receptor ◽  
Stellate Cells ◽  
Platelet Derived Growth Factor ◽  
Dependent Manner ◽  
Activated Hepatic Stellate Cells

Abstract Background: Activated hepatic stellate cells are the most critical cell responsible for liver fibrosis. In liver fibrogenesis, platelet-derived growth factor is the most prominent mitogen for hepatic stellate cells. This study aims to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeted to platelet-derived growth factor receptor-β (PDGFR-β) as a magnetic resonance imaging (MRI) radiotracer to identify the progress of liver fibrosis by imaging hepatic PDGFR-β expression. Results: Hepatic PDGFR-β expression level was found to be paralleled with the severity of liver fibrosis, which was increased with the progression of fibrosis and reduced with the regression. Majority of cells expressing PDGFR-β was determined to be activated hepatic stellate cells in fibrotic livers. Culture-activated human hepatic stellate cells expressed abundant PDGFR-β, and FITC-labeled pPB could bind to human hepatic stellate cells in a concentration and time dependent manner. With Gd-labeled pPB as a tracer, an MRI modality demonstrated that the relative hepatic T1-weighed MR signal value was increased progressively along with severity of hepatic fibrosis and reduced with the remission. Conclusion: Hepatic PDGFR-β expression reflects the progress of hepatic fibrosis, and MR imaging using Gd-labeled pPB as a tracer may distinguish different stages of liver fibrosis in mice.

scholarly journals The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis

Hepatology ◽  
2008 ◽  
Vol 48 (4) ◽  
pp. 1251-1261 ◽  
Author(s):  
Maria J. Perugorria ◽  
M. Ujue Latasa ◽  
Alexandra Nicou ◽  
Hugo Cartagena-Lirola ◽  
Josefa Castillo ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Epidermal Growth Factor ◽  
Mouse Liver ◽  
Growth Factor Receptor ◽  
Receptor Ligand ◽  
Epidermal Growth

scholarly journals The Membrane-anchoring Domain of Epidermal Growth Factor Receptor Ligands Dictates Their Ability to Operate in Juxtacrine Mode

2005 ◽  
Vol 16 (6) ◽  
pp. 2984-2998 ◽  
Author(s):  
Jianying Dong ◽  
Lee K. Opresko ◽  
William Chrisler ◽  
Galya Orr ◽  
Ryan D. Quesenberry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Resonance Energy ◽  
Structural Basis ◽  
Cell Contact ◽  
Heparin Binding ◽  
Epidermal Growth ◽  
Membrane Anchoring

All ligands of the epidermal growth factor (EGF) receptor (EGFR) are synthesized as membrane-anchored precursors. Previous work has suggested that some ligands, such as EGF, must be proteolytically released to be active, whereas others, such as heparin-binding EGF-like growth factor (HB-EGF) can function while still anchored to the membrane (i.e., juxtacrine signaling). To explore the structural basis for these differences in ligand activity, we engineered a series of membrane-anchored ligands in which the core, receptor-binding domain of EGF was combined with different domains of both EGF and HB-EGF. We found that ligands having the N-terminal extension of EGF could not bind to the EGFR, even when released from the membrane. Ligands lacking an N-terminal extension, but possessing the membrane-anchoring domain of EGF, still required proteolytic release for activity, whereas ligands with the membrane-anchoring domain of HB-EGF could elicit full biological activity while still membrane anchored. Ligands containing the HB-EGF membrane anchor, but lacking an N-terminal extension, activated EGFR during their transit through the Golgi apparatus. However, cell-mixing experiments and fluorescence resonance energy transfer studies showed that juxtacrine signaling typically occurred in trans at the cell surface, at points of cell-cell contact. Our data suggest that the membrane-anchoring domain of ligands selectively controls their ability to participate in juxtacrine signaling and thus, only a subclass of EGFR ligands can act in a juxtacrine mode.

scholarly journals Inhibition of Mastermind-like 1 alleviates liver fibrosis induced by carbon tetrachloride in rats

2018 ◽  
Vol 243 (14) ◽  
pp. 1099-1108
Author(s):  
Shaoping Zheng ◽  
Yixiong Chen ◽  
Shaojiang Zheng ◽  
Zhihui He ◽  
Zhihong Weng
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Underlying Mechanism ◽  
Signal Pathways ◽  
Fibrotic Liver ◽  
Hepatic Fibrogenesis ◽  
Signal Transductions

Mastermind-like 1 (MAML1) functions in critical transcriptional coactivation in Notch and Wnt/β-catenin signal pathways, which participate in hepatic fibrosis. This study is aimed to reveal the potential role of MAML1 in liver fibrosis and identify its underlying mechanism. In present research, the enhanced expression of MAML1 was found in the fibrotic liver tissues in carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats, and MAML1 expression increased gradually during the activation of hepatic stellate cells (HSCs) isolated from the normal rat. Further studies showed that blocking MAML1 expression efficiently decreased the expression of α-SMA and collagen I (Col1a1) in HSCs. Interestingly, MAML1 may modulate HSCs activation via interrupting both Notch and Wnt/β-catenin signal transductions, and the inhibition of MAML1 by a recombinant adeno-associated virus type 1 vector carrying shRNA targeting MAML1 alleviated CCl4-induced hepatic fibrosis in rats. These findings suggest that the selective regulation of MAML1 expression may be a feasible therapeutic approach to reverse liver fibrosis. Impact statement Liver fibrosis is a common wound-healing response to all kinds of liver injuries. Hepatic stellate cells (HSCs) activation is the key event during liver fibrogenesis. Thus, the elucidation of mechanisms for regulating HSCs activation is helpful for identifying novel anti-fibrotic targets and strategies. MAML1, an important component of Notch signal, functions in critical transcriptional coactivation in the Notch and Wnt/β-catenin signal pathways. In the present study, we investigated the potential function of MAML1 during hepatic fibrogenesis in rats. Our results demonstrated that MAML1 participates in liver fibrosis through modulating HSCs activation via interrupting both the Notch and Wnt/β-catenin signal transductions. Additionally, the inhibition of MAML1 markedly attenuated CCl4-induced hepatic fibrogenesis in rats. Our results shed a light for the exploitation of a new therapeutic strategy for hepatic fibrosis via targeting MAML1.

scholarly journals Epidermal growth factor receptor regulates pancreatic fibrosis

2009 ◽  
Vol 297 (3) ◽  
pp. G434-G441 ◽  
Author(s):  
Stacy A. Blaine ◽  
Kevin C. Ray ◽  
Kevin M. Branch ◽  
Pamela S. Robinson ◽  
Robert H. Whitehead ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Heparin Binding ◽  
Epidermal Growth

The development of pancreatic fibrosis has been shown to be a major component in several diseases of the pancreas including pancreatic cancer, chronic pancreatitis, and type 2 diabetes mellitus, but its actual role in the progression of these disorders is still unknown. This fibrosis is characterized by stromal expansion and the excessive deposition of extracellular matrix (ECM) that replaces pancreatic tissue. This eventually leads to dysregulation of ECM turnover, production of cytokines, restriction of blood flow, and often exocrine and endocrine insufficiencies. Activated pancreatic stellate cells (PSCs) have been identified as key mediators in the progression of pancreatic fibrosis, serving as the predominant source of excess ECM proteins. Previously, we found that overexpression of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF) in pancreatic islets led to intraislet fibrosis. HB-EGF binds to and activates two receptors, epidermal growth factor receptor (EGFR) and ErbB4, as well as heparin moieties and CD9/DRAP27. To understand the mechanism underlying the induction of fibrogenesis by HB-EGF, we utilized a hypomorphic allele of Egfr, the Waved-2 allele, to demonstrate that EGFR signaling regulates fibrogenesis in vivo. Using an in vitro cell migration assay, we show that HB-EGF regulates both chemoattraction and stimulation of proliferation of PSCs via EGFR activation.

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