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  • Title: Effects of Carvedilol on the Expression of TLR4 and its Downstream Signaling Pathway in the Liver Tissues of Rats with Cholestatic Liver Fibrosis.
    Author: Tian X, Zhao H, Guo Z.
    Journal: Curr Mol Med; 2020; 20(9):708-716. PubMed ID: 32077825.
    Abstract:
    OBJECTIVES: This study was designed to investigate the effects of carvedilol on the expression of TLR4 and its downstream signaling pathway in the liver tissues of rats with cholestatic liver fibrosis and provide experimental evidence for clinical treatment of liver fibrosis with carvedilol. METHODS: A total of fifty male Sprague Dawley rats were randomly divided into five groups (10 rats per group): sham operation (SHAM) control group, bile duct ligation (BDL) model group, low-dose carvedilol treatment group (0.1mg·kg-1·d-1), medium-dose carvedilol treatment group (1mg·kg-1·d-1), and high-dose carvedilol treatment group (10mg·kg-1·d-1). Rat hepatic fibrosis model was established by applying BDL. Forty-eight hours after the operation, carvedilol was administered twice a day. The blood and liver were simultaneously collected under the aseptic condition for further detection in two weeks after the operation. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (Alb) in serum were measured. HE and Masson staining were used to determine hepatic fibrosis degree. Hydroxyproline assay was employed to detect liver collagen synthesis. Western Blot was used to measure the expression of TLR4, NF-κB p65 and β-arrestin2 protein. Quantitative analysis of TLR4, MyD88, TNF-α and IL-6 mRNA was performed by Realtime-PCR. RESULTS: Compared with the SHAM group, the BDL group showed obvious liver injury, increased levels of inflammatory factors, and continued progression of liver fibrosis. The above changes in the BDL group were alleviated in the carvedilol treatment groups. The improvement effects augmented as dosages increased. In addition, compared with the BDL group, the reduction of the expressions of TLR4, MyD88 and NF-κB p65 in liver tissues and the increase of the expression of β -arrestin2 in the high-dose carvedilol group were more significant. CONCLUSION: Carvedilol can reduce the release of inflammatory mediators by downregulating TLR4 expression and inhibiting its downstream signaling pathway, thus playing a potential therapeutic role in cholestatic liver fibrosis.
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