Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
J Ethnopharmacol. 2021 Oct 5;278:114214. doi: 10.1016/j.jep.2021.114214. Epub 2021 May 24.
Fangji is an ancient combinatorial formula. The compatibility mechanisms that how component herbs of Fangji work cooperatively to achieve the executive framework remain unexplored.
Toexplore 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.
Here, 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.
As 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.
This 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.
防己是一种古老的组合配方。成分草药如何协同工作以实现执行框架的配伍机制仍未得到探索。
以温心颗粒（WXKL）为例，探讨防己的配伍机制和系统作用，WXKL 由党参、麦冬、三七、菖蒲和木香组成。
在这里，我们采用了生物信息学方法，包括聚类分析、协同模块对分析、主要模块识别以及草药靶标谱之间的邻近性检查，以研究 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，我们在 WXKL 靶标网络（W 网络）中鉴定了 695 个潜在靶标蛋白和 27 个簇（W 模块），其中 W 模块 1、2、4、8、10 为主要模块。协同模块对为 W 模块 2 和 4、W 模块 2 和 8 以及 W 模块 2 和 1，它们都存在于党参或三七的条件下。而木香只产生了 W 模块 1 和 2 之间的协同作用。党参和三七的草药靶标谱的邻近性相似，木香和菖蒲的邻近性相似。对于配伍框架，党参一般调节 70.67%的靶标和大多数 W 模块（81.48%）作为君药，主要涉及神经激素调节、血管运动、炎症和氧化应激。其他草药通过共同模块协助党参增强主要结果，并通过包括有丝分裂细胞周期、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%枢纽蛋白，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、肾脏和神经系统为重点的调节网络，逆转心律失常的病理过程。体内实验表明，WXKL 通过抑制钙调蛋白（CaM）和兰尼碱受体 2（RYR2）磷酸化来抑制儿茶酚胺激活引起的交感性心房颤动，从而抑制神经激素作用。
该策略提供了 WXKL 抗心律失常机制及其内在配伍的整体观点，并可能从现代生物学的角度促进对防己配伍的理解。
