Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang, Beijing, China.
Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
CPT Pharmacometrics Syst Pharmacol. 2018 Apr;7(4):269-280. doi: 10.1002/psp4.12281. Epub 2018 Mar 14.
Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We first identified a total of eight core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Second, we redefined a weak allosteric module and a strong allosteric module. Then, we identified 15 pharmacological module drivers (PMDs) by leave-one-out screening with a cutoff of two folds, which were at least, in part, validated by expression and variation of topological contribution. Finally, we revealed the fusional and emergent variation of PMD in core modules contributing to multidimensional synergistic mechanism in ischemic mice and rats. Our findings provide a new set of drivers that might promote the pharmacological modular flexibility and offer a potential avenue for disease treatment.
确定核心模块和枢纽的变化似乎对于基于疾病网络拓扑结构改变来描述可变的药理学机制至关重要。我们首先通过从缺血性小鼠的不同靶向网络中使用多种模块化特征融合（MMCF）方法总共鉴定了八个核心模块。有趣的是，药物组合组中的模块干扰强度（MDI）值增加。其次，我们重新定义了一个弱变构模块和一个强变构模块。然后，我们通过 2 倍的截止值进行了一轮留一法筛选，鉴定了 15 个药理学模块驱动因子（PMD），其中至少部分通过拓扑贡献的表达和变化进行了验证。最后，我们揭示了核心模块中 PMD 的融合和新兴变化，这有助于缺血性小鼠和大鼠的多维协同机制。我们的发现提供了一组新的驱动因子，可能会促进药理学模块的灵活性，并为疾病治疗提供潜在途径。
