Fusion of core pathways reveals a horizontal synergistic mechanism underlying combination therapy.

Combination therapies have recently been shown to be more effective than monotherapies that may provide synergistic effects in the treatment of stroke, but its selective mechanism still remains unclear. Based on the median-effect method, the combination therapy of jasminoidin and ursodeoxycholic acid had a synergic effect on reducing the infarct volume. The numbers of up- or down-regulated genes by at least 1.5-fold in the vehicle, jasminoidin, ursodeoxycholic acid, and the combination of jasminoidin and ursodeoxycholic acid treatment groups were 228, 95, 136, and 101, respectively. According to clustering and principal component analysis, the pattern of gene expression in the combination group was similar to that of jasminoidin group rather than ursodeoxycholic acid group. Based on these nine top sequences in the combination group excluding four overlapping pathways (MAPK-ERK, Kitlg, Icam1-Ap1, and prolactin), the jasminoidin group had four (PRLR-STAT1, AcvR2-AcvR1B, ACVR1/2A-SMAD1, GHR-NF-κB) contributing pathways, and the ursodeoxycholic acid group had one (IL-6) contributing pathway. Based on the multiple-pathway-dependent comparison analysis (MPDCA), it may lead to the conclusion that jasminoidin possibly contributes more important pharmacological effect in the combined treatment as jasminoidin regulated 80% of the pathways that the combination group mediated. The study reveals a horizontal synergistic effect by optimizing the fusion of more pathways from the compounds with more contribution to the combination therapy. Rather than selecting compounds only based on experience in the past, this study would give a new insight into the systematic strategies for designing synergistic combination therapies.