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Strategy and exploration of identifying drug combinations for antithrombosis from Xijiao Dihuang Tang formulae as p38MAPK inhibitor
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  • Lian Yin,
  • Yang Dai,
  • Gui Zhou,
  • Cui Chen,
  • Jiang Ping,
  • Jie Xia,
  • Guo Li
Lian Yin
Nanjing University of Chinese Medicine
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Yang Dai
Nanjing University of Chinese Medicine
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Gui Zhou
Nanjing University of Chinese Medicine
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Cui Chen
Nanjing University of Chinese Medicine
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Jiang Ping
Nanjing University of Chinese Medicine
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Jie Xia
Nanjing University of Chinese Medicine
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Guo Li
Nanjing University of Chinese Medicine

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Abstract

Background and Purpose: Combination therapy has been widely recognized internationally, however, identifying drug combinations with synergism is very challenging. We first proposed a strategy for identifying drug combinations from herbs with mutual reinforcement or assistance in traditional Chinese medicine (TCM) formulae, and verified it using the example of Xijiao Dihuang Tang (XDT) , a classical TCM formula. Experimental Approach: In vitro the smallest half maximal inhibitory concentration (IC50) values of the candidate ingredients in XDT and synergistic neuroprotective effect of the drug combinationsin were studied in injured PC12 and BV2 cell by CCK8 and flow cytometry assay. The p38MAPK pathway affected by the drug combinations were predicted and validated using molecular docking method, biolayer interferometry, western blot and immunoprecipitation assessment. Antithrombotic of the drug combinations were evaluated in zebrafish thrombosis model in vivo. Results Two drug combinations with a combination index value of 0.1- 0.5 were obtained, indicating strong synergy. Our results suggested that, compared to the individual ingredients, the two drug combinations can strengthen the synergistic neuroprotective effects and have a significant antithrombotic effect, and not only enhanced the interaction with on MKK3, MKK6 and p38 in the p38MAPK pathway, but also interrupted the MKK3-p38 axis to inhibit MKK3-induced activation of p38 MAPK. Conclusions Our study identified two synergistic drug combinations as p38MAPK pathway inhibitors to develop antithrombotics and suggests that provide approaches and effective means for identifying drug combinations with synergism from the combination of herb-herb with mutual reinforcement or assistance in TCM formulae for drug combination development.