Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-κB bioluminescent imaging-guided transcriptomic analysis

In this study, we applied bioluminescent imaging-guided transcriptomic analysis to evaluate and identify the therapeutic potentials and novel mechanisms of silymarin on carbon tetrachloride (CCl4)-induced liver fibrosis. Transgenic mice, carrying the luciferase genes driven by nuclear factor-kappa B (NF-kappa B), were given with CCl4 and/or silymarin. In vivo NF-kappa B activity was evaluated by bioluminescent imaging, liver fibrosis was judged by Sirius red staining and immunohistochemistry, and gene expression profiles of silymarin-treated livers were analyzed by DNA microarray. CCl4 enhanced the NF-kappa B-dependent hepatic luminescence and induced hepatic fibrosis, while silymarin reduced the CCl4-induced hepatic luminescence and improved CCl4-induced liver fibrosis. Microarray analysis showed that silymarin altered the transforming growth factor-beta-mediated pathways, which play pivotal roles in the progression of liver fibrosis. Moreover, we newly identified that silymarin downregulated the expression levels of cytoskeleton organization genes and mitochondrion electron-transfer chain genes, such as cytochrome c oxidase Cox6a2, Cox7a1, and Cox8b genes. In conclusion, the correlation of NF-kappa B-dependent luminescence and liver fibrosis suggested the feasibility of NF-kappa B bioluminescent imaging for the evaluation of liver fibrosis progression and therapeutic potentials. Moreover, our findings suggested that silymarin might exhibit anti-fibrotic effects in vivo via altering the expression of genes involved in cytoskeleton organization and mitochondrion electron-transfer chain. (C) 2012 Elsevier Ltd. All rights reserved.