Combination therapy with increased efficacy and reduced toxicity plays a crucial role in treating complex diseases, such as stroke, but it remains an insurmountable barrier to elucidate the mechanisms of synergistic effects. Here, we present a Driver-induced Modular Screening (DiMS) strategy integrated synergistic module and driver gene identification to elucidate the additive mechanisms of Baicalin (BA) and Jasminoidin (JA) on cerebral ischemia (CI) therapy. Based on anti-ischemia genomic networks BA, JA, and their combination (BJ), we obtained 4, 3, and 9 On-modules of BA, JA, and BJ by modular similarity analysis. Compared with the monotherapy groups, four additive modules (Add-module, BJ_Mod-4, 7, 9, and 13), 15 driver genes of BJ were identified by modular similarity and network control methods, and seven driver proteins (PAQR8, RhoA, EMC10, GGA2, VIPR1, FAM120A, and SEMA3F) were validated by animal experiments. The functional analysis found neuroprotective roles of the Add-modules and driver genes, such as the Neurotrophin signaling pathway and FoxO signaling pathway, which may reflect the additive mechanisms of BJ. Moreover, such a DiMS paradigm provides a new angle to explore the synergistic mechanisms of combination therapy and screen multi-targeted drugs for complex diseases.
Keywords: cerebral ischemia; combination therapy; modular pharmacology; network driver; synergistic effect.
Copyright © 2022 Li, Wang, Gu, Yu, Wang, Liu, Zhang, Chen, Niu, Wang, Liu, Guan, Li, Zhang and Wang.