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 (CCl(4))-induced liver fibrosis. Transgenic mice, carrying the luciferase genes driven by nuclear factor-κB (NF-κB), were given with CCl(4) and/or silymarin. In vivo NF-κB 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. CCl(4) enhanced the NF-κB-dependent hepatic luminescence and induced hepatic fibrosis, while silymarin reduced the CCl(4)-induced hepatic luminescence and improved CCl(4)-induced liver fibrosis. Microarray analysis showed that silymarin altered the transforming growth factor-β-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-κB-dependent luminescence and liver fibrosis suggested the feasibility of NF-κB 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.