Modular Screening Reveals Driver Induced Additive Mechanisms of Baicalin and Jasminoidin on Cerebral Ischemia Therapy

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 integra...

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Published inFrontiers in cardiovascular medicine Vol. 9; p. 813983
Main Authors Li, Bing, Wang, Ying, Gu, Hao, Yu, Yanan, Wang, Pengqian, Liu, Jun, Zhang, Yingying, Chen, Yinying, Niu, Qikai, Wang, Bo, Liu, Qiong, Guan, Shuang, Li, Yanda, Zhang, Huamin, Wang, Zhong
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 21.02.2022
Subjects
Cardiovascular Medicine
cerebral ischemia
combination therapy
modular pharmacology
network driver
synergistic effect
combination therapy
network driver
cerebral ischemia
modular pharmacology
synergistic effect
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Summary: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 of BA, JA, and BJ by modular similarity analysis. Compared with the monotherapy groups, four additive modules ( , 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.
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This article was submitted to Cardiovascular Therapeutics, a section of the journal Frontiers in Cardiovascular Medicine
These authors have contributed equally to this work
Edited by: Xiaofeng Yang, Temple University, United States
Reviewed by: Howard Prentice, Florida Atlantic University, United States; Yanming Li, Baylor College of Medicine, United States
ISSN:2297-055X
2297-055X
DOI:10.3389/fcvm.2022.813983