Suppression of Amphiregulin/Epidermal Growth Factor Receptor Signals Contributes to the Protective Effects of Quercetin in Cirrhotic Rats ,

Abstract

The hepatic wound-healing response to chronic noxious stimuli may lead to liver fibrosis, a key feature of the preneoplastic cirrhotic liver. Fibrogenic cells activate in response to a variety of cytokines, growth factors, and inflammatory mediators. The involvement of members of the epidermal growth factor family in this process has been suggested. Amphiregulin is an epidermal growth factor receptor (EGFR) ligand specifically induced upon liver injury. We investigated the effects of quercetin on the amphiregulin/EGFR signal and on the activation of downstream pathways leading to cell growth. Rats were divided into 4 groups (8 rats/group): rats subjected to common bile duct ligation (CBDL), Sham (rats subjected to simulated CBDL), quercetin-treated sham, and quercetin-treated CBDL (CBDL-Q). Quercetin (50 mg/kg i.p. injection) was administered daily for 2 wk starting on d 14 after surgery. Overexpression of amphiregulin, EGFR, TNFα, IL-6, TGFβ, platelet-derived growth factor (PDGF), extracellular regulated kinase, protein kinase B (Akt), cycloxygenase (COX)-2, and glioma-associated oncogenes (GLI)-1 and-2 were observed in liver of CBDL rats after 4 wk of bile duct ligation. CBDL-Q rats had a significantly diminished expression of amphiregulin and EGFR compared with untreated CBDL rats. Furthermore, mRNA levels of TNFα, IL-6, TGFβ, and PDGF and the protein content of COX-2, GLI-1, and GLI-2 were significantly lower in CBDL-Q rats than in untreated CBDL rats. The findings indicate that quercetin ameliorated activation of survival pathways and downregulated the expression of genes related to inflammation and precancerous conditions. Suppression of amphiregulin/EGFR signals may contribute to this effect.

Impact of epidermal growth factor receptor and transforming growth factor–α on hepatitis C virus‐induced hepatocarcinogenesis

“…Increasing in the number of EGFR positive cases as well as in the extent of its expression with raising grades of hepatitis activity matched findings of Cuevas et al (30) and Berasain et al (31). 1 Significant difference compared to control cases (p < 0.01).…”

Lung and Liver Changes Due to the Induction of Cirrhosis in Two Experimental Models

“…The BDL model is used as an animal model for secondary biliary cirrhosis and cirrhosis caused by progressive and fatal damage to the liver. This model simulates the effects of the disease present in humans, causing changes in the inflammatory reaction by leaking bile and the subsequent disorganization of parenchymal inflammation, collagen deposition and formation of fibrosis (7,13,20) . Studies by Kontouras et al (14) showed that 15 days after bile duct ligation (BDL), the metabolic and biochemical changes were not fully established.…”

“…Physiological defense mechanisms are effective in preventing or counteracting the damage caused by free radicals, which can include a set of endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The two models used in this study showed an increase in lipid peroxidation in lung tissue and are likely to increase in response to an increase of ROS in the SOD, which plays an important role in the balance of the redox cell, as the catalyst free radicals are generated in an attempt to protect the tissue against lesions (1,2,7) . Arterial blood gas analysis is an indicator used to facilitate the evaluation of trade gasosas (20) .…”

“…Patients who have secondary biliary cirrhosis exhibit hyperbilirubinemia due to biliary obstruction resulting from liver damage and present results of liver function tests in higher ranges for FA and aminotransferases. High levels of these enzymes are largely caused by the necrosis of tissues that are rich in aminotransferases (1,7) . In the presence of liver cirrhosis, there is an increase in lipid peroxidation due to the formation of reactive oxygen species and lipid peroxidation.…”

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…Oxidative stress aggravates liver fibrosis. 5 Thus, inhibiting oxidative stress has been considered a potential useful strategy to prevent the development of hepatic fibrogenesis, and it has been reported that antioxidants such as epigallocatechin-3-gallate, 6 polyprenols, 7 quercetin, 8 or proanthocyanidin, 9 among others, may prevent liver injury in different animal models of fibrosis.…”