Applying cooperative module pair analysis to uncover compatibility mechanism of Fangjis: An example of Wenxin Keli decoction
Applying cooperative module pair analysis to uncover compatibility mechanism of Fangjis: An example of Wenxin Keli decoction
复制标题
应用协同模块对分析揭示防己方配伍机制——以稳心颗粒汤为例
DOI：
10.1016/j.jep.2021.114214
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发表时间：
2021-06-09
影响因子：
5.4
通讯作者：
Shang，Hongcai
中科院分区：
文献类型：
--
作者：
Wang，Pengqian;He，Tianmai;Shang，Hongcai
民族药理学相关性 防己是一种古老的组合方剂。防己药方如何协同发挥作用，实现执行框架的配伍机制尚待探索。研究目的以党参、黄精、三七、琥珀、甘松组成的经典防己方稳心颗粒汤（WXKL）为例，探讨防己剂的配伍机制及系统作用。方法本文采用生物信息学方法，包括聚类分析、协同模块对分析、初级模块识别和中药靶标谱之间的邻近性检查，研究WXKL的配伍特征和抗心律失常机制。最后，通过体内实验验证了WXKL的核心机制。结果结果，我们在WXKL靶网络（W-network）中鉴定了695个假定的靶蛋白和27个簇（W-modules），其中W-module 1、2、4、8、10是主要模块。协同模块对为W-模块2和4、W-模块2和8、W-模块2和1，均存在于党参或三七条件下。而甘松仅在W模块1和2之间产生协同作用。党参和三七的药效靶标相似度相似，甘松和琥珀的靶标谱相似。从配伍框架来看，党参作为主药一般调节70.67%的靶点和大部分W模块（81.48%），发挥主要治疗作用，主要涉及神经激素调节、血管舒缩、炎症和氧化应激。其他草药通过共同模块辅助党参增强主要功效，并通过有丝分裂细胞周期、生物合成和分解代谢过程等独特过程发挥补充作用。此外，WXKL调节心律失常网络的66.67％的枢纽蛋白，以及原发性心律失常模块1和2中的68.18％和47.37％的蛋白质，主要涉及离子通道活性，神经激素调节和应激反应过程，构成以心血管、肾脏、神经系统为重点的调节网络，扭转心律失常的病理过程。体内实验证明WXKL可以通过抑制钙调蛋白表达（CaM）和兰尼碱受体2（RYR2）磷酸化来调节神经激素作用，从而减轻肾上腺素激活引起的交感心房颤动。结论该策略为WXKL的抗心律失常机制及其内部配伍性提供了总体视角，并可能有助于从现代生物学的角度理解防己的配伍性。
Ethnopharmacological relevanceFangji is an ancient combinatorial formula. The compatibility mechanisms that how component herbs of Fangji work cooperatively to achieve the executive framework remain unexplored.Aim of the studyToexplore compatibility mechanism and systematical effects of Fangjis by taking Wenxin Keli decoction (WXKL), a classical Fangji constituted by Codonopsis Radix, PolygonatiRhizoma, Notoginseng Radix Et Rhizoma, Ambrum, and Nardostachyos Radix Et Rhizoma., as example.Main methodsHere, we employed bioinformatics approach, including cluster analysis, cooperative module pair analysis, primary module identification, and proximity examination among target profile of herbs, to investigate compatibility characterization and anti-arrhythmia mechanism of WXKL. Finally, core mechanisms of WXKL were validatedby in vivo experiments.ResultsAs a result, we identified 695 putative target proteins and 27 clusters (W-modules) inWXKL target network (W-network), in which W-module 1, 2, 4, 8, 10 were primary modules. The cooperative module pairs were W-module 2 and 4, W-module 2 and 8, and W-module 2 and 1, all of which existed in Codonopsis Radix- or Notoginseng Radix Et Rhizoma.-condition. And Nardostachyos Radix Et Rhizoma only yielded cooperation between W-module 1 and 2. The proximity of herbs’ target profiles of Codonopsis Radix and Notoginseng Radix Et Rhizoma were similar, and Nardostachyos Radix Et Rhizoma and Ambrum were similar. For the compatibility framework, Codonopsis Radix general regulated 70.67% targets and majority W-modules (81.48%) as sovereign herb, contributing to primary therapeutic effect, mainly involving neurohormonal regulation, vasomotor, inflammation and oxidative stress. Other herbs assisted Codonopsis Radix to enhance major outcomes through common modules, and acted as complementary roles through unique process including mitotic cell cycle, biosynthetic and catabolic process, etc. Furthermore, WXKL regulated 66.67% hub proteins of arrhythmia-network, 68.18% and 47.37% proteins in primary arrhythmia-module 1 and 2, mainly involving ion channel activity, neurohormonal regulation, and stress response processes, to constitute regulatory network focusing on cardiovascular, renal, nervous system, to reverse the pathological process of arrhythmia. In vivo experiments demonstrated WXKL can attenuate adrenergic activation induced sympathetic atrial fibrillation by inhibiting calmodulin expression (CaM) and ryanodine receptor 2 (RYR2) phosphorylation to regulate neurohormonal action.ConclusionThis strategy provided an overarching view of anti-arrhythmia mechanism of WXKL and its internal compatibility, and may facilitate the understanding of compatibility in Fangjis from the perspectives of modern biology.