Abstract
BackgroundSho-saiko-to (SST) (also known as so-shi-ho-tang or xiao-chai-hu-tang) has been widely prescribed for chronic liver diseases in traditional Oriental medicine. Despite the substantial amount of clinical evidence for SST, its molecular mechanism has not been clearly identified at a genome-wide level.MethodsBy using a microarray, we analyzed the temporal changes of messenger RNA (mRNA) and microRNA expression in primary mouse hepatocytes after SST treatment. The pattern of genes regulated by SST was identified by using time-series microarray analysis. The biological function of genes was measured by pathway analysis. For the identification of the exact targets of the microRNAs, a permutation-based correlation method was implemented in which the temporal expression of mRNAs and microRNAs were integrated. The similarity of the promoter structure between temporally regulated genes was measured by analyzing the transcription factor binding sites in the promoter region.ResultsThe SST-regulated gene expression had two major patterns: (1) a temporally up-regulated pattern (463 genes) and (2) a temporally down-regulated pattern (177 genes). The integration of the genes and microRNA demonstrated that 155 genes could be the targets of microRNAs from the temporally up-regulated pattern and 19 genes could be the targets of microRNAs from the temporally down-regulated pattern. The temporally up-regulated pattern by SST was associated with signaling pathways such as the cell cycle pathway, whereas the temporally down-regulated pattern included drug metabolism-related pathways and immune-related pathways. All these pathways could be possibly associated with liver regenerative activity of SST. Genes targeted by microRNA were moreover associated with different biological pathways from the genes not targeted by microRNA. An analysis of promoter similarity indicated that co-expressed genes after SST treatment were clustered into subgroups, depending on the temporal expression patterns.ConclusionsWe are the first to identify that SST regulates temporal gene expression by way of microRNA. MicroRNA targets and non-microRNA targets moreover have different biological roles. This functional segregation by microRNA would be critical for the elucidation of the molecular activities of SST.
Highlights
IntroductionSho-saiko-to (SST) ( known as so-shi-ho-tang or xiao-chai-hu-tang) has been widely prescribed for chronic liver diseases in traditional Oriental medicine
Sho-saiko-to (SST) has been widely prescribed for chronic liver diseases in traditional Oriental medicine
Among these patterns of gene expression, Sub-cluster 1 was composed of genes that temporally increased expression, whereas Sub-cluster 2 was composed of genes with temporally decreased expression
Summary
Sho-saiko-to (SST) ( known as so-shi-ho-tang or xiao-chai-hu-tang) has been widely prescribed for chronic liver diseases in traditional Oriental medicine. SST and its major components (e.g., baicalin, baicalein, glycyrrhizin, and saikosaponinD) have marked antiproliferative activity on hepatocellular carcinoma [2,3,4], prevent liver injury [5], and promote liver regeneration in animal models [6,7]. These pharmacologic effects of SST involve the immunomodulation of diverse immune cells and immune molecules [8,9]. We previously reported the usefulness of a genome-wide approach in elucidating the molecular effects of herbal extracts [20,21]
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