Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/β-catenin and TGF-β/smads pathways.
Mai A ZaafanAmr M AbdelhamidPublished in: Journal of enzyme inhibition and medicinal chemistry (2022)
Hepatic stellate cells activation (HSCs) plays a crucial role in the pathogenesis of liver fibrosis. Specific microRNAs have been suggested to affect the activation of HSCs via various signalling pathways including TGF-β/smads and Wnt/β-catenin pathways. Dasatinib is a multitarget inhibitor of many tyrosine kinases has recently studied for its anti-fibrotic effects in a variety of fibrous diseases. This study investigated the role of modulation of miRNA-378 and miRNA-17 in the pathogenesis of liver fibrosis through altering Wnt/β-catenin and TGF-β/smads pathways and evaluated the beneficial effect of the tyrosine kinase inhibitor, dasatinib, in thioacetamide-induced liver fibrosis model in mice. Treatment with dasatinib down-regulated miRNA-17 expression, leading to the restoration of WiF-1 and smad-7 which cause the inhibition of both Wnt/β-catenin and TGF-β/smads signalling. In addition, it upregulated miRNA-378 leading to the decrease of Wnt-10 which contributes to the suppression of activated HSCs.
Keyphrases
- liver fibrosis
- cell proliferation
- transforming growth factor
- epithelial mesenchymal transition
- stem cells
- pi k akt
- high glucose
- long non coding rna
- signaling pathway
- chronic myeloid leukemia
- diabetic rats
- induced apoptosis
- poor prognosis
- type diabetes
- mass spectrometry
- long noncoding rna
- cell cycle arrest
- drug induced
- metabolic syndrome
- idiopathic pulmonary fibrosis
- skeletal muscle
- insulin resistance
- replacement therapy
- binding protein
- high fat diet induced