Genome Analysis Reveals a Synergistic Mechanism of Ursodeoxycholic Acid and Jasminoidin in Mice Brain Repair After Ischemia/Reperfusion: Crosstalk Among Muti-Pathways.

Yingying Zhang,Zhong Wang,Ping Wu,Pengqian Wang,Xiaoxu Zhang,Zide Zhao,Haixia Li,Jie Wang,Huan Guo,Jun Liu,Hongli Wu,Yinying Chen,Bing Li

doi:10.3389/fphar.2019.01383

Abstract

Studies have shown that combination drug therapy which corresponding treatment involves multiple genes and targets is more effective against cerebral ischemia. To identify the synergistic mechanism of ursodeoxycholic acid and jasminoidin based on differential pathway network, which protect against brain ischemia-reperfusion injury. Totally 115 mice with focal cerebral ischemia-reperfusion injury were allocated into five groups: sham, vehicle, ursodeoxycholic acid (UA), jasminoidin (JA), and JA and UA combination group (JU). The differentially expressed genes identified by microarray which consisted of 11,644 complementary DNAs were loaded to the GeneGo MetaCore™ software to analyze the enriched pathways and processes among different groups. Of the top 10 pathways and process networks, 5, 6, and 3 overlapping pathways as well as 5, 3, and 4 overlapping process networks were observed between UA and JA, UA and JU, and JA and JU, respectively. Of these, three pathways and three process networks overlapped across the three groups. Interestingly, four representative pathways and six process networks were only noted in the JU group. Gene Ontology process analysis showed 2 processes were shared by all three treatment groups in the top 10 processes. The UA and JA combination resulted in synergistic effects through affecting multi-signal transduction pathways, different locations in the same pathway, and the new signaling pathway emerged in drug combination group, those together may enhance the treatment of cerebral ischemia-reperfusion injury through promoting neural cell apoptosis, decreasing calcium levels, inhibiting inflammation, and protecting neurons.

Highlights

Cerebral ischemia is one of the leading lethal disorders worldwide (Go et al, 2014)
It has been shown that the JA-ursodeoxycholic acid (UA) combination had a pharmacodynamic synergistic effect in treating cerebral ischemia (Koo et al, 2006; Guo et al, 2014)
There were specific pathways in each treatment group, for example, there were four specific pathways in JU groups, including Mucin expression in CF via interleukin 6 (IL-6), IL-17 signaling pathways, transcription-role of vitamin D receptor (VDR) in regulation of genes involved in osteoporosis, regulation of cystic fibrosis transmembrane conductance regulator (CFTR) activity 9, developmentgranulocyte-macrophage colony-stimulating factor (GM-CSF) signaling (Figure 2)

Summary

Introduction

Cerebral ischemia is one of the leading lethal disorders worldwide (Go et al, 2014). Its pathological process involves a series of biochemical and molecular changes (Mehta et al, 2007). The Chinese medicine Qingkailing injection, which includes baicalin (BA), ursodeoxycholic acid (UA), jasminoidin (JA), and Concha margaritifera (CM) has been shown to display protective effects against focal cerebral ischemia and reperfusion injury (Zhang et al, 2006). It has diverse components with pharmacodynamic characteristics (Zhou et al, 2010), of which synergistic effect noted with the JU (JA-UA combination) treatment, such as decreased infarction volumes, recovery of the neurological deficit score and MRI findings in ischemic mice (Koo et al, 2006; Zhang et al, 2006; Zhou et al, 2010). This study aimed to further investigate the mechanisms by which UA and JA combination protects against brain ischemia with GeneGo MetaCoreTM software

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