Deciphering the pharmacological mechanism of the Chinese formula Huanglian-Jie-Du decoction in the treatment of ischemic stroke using a systems biology-based strategy

Abstract

Aim: Huanglian-Jie-Du decoction (HLJDD) is an important multiherb remedy in TCM, which is recently demonstrated to be effective to treat ischemic stroke. Here, we aimed to investigate the pharmacological mechanisms of HLJDD in the treatment of ischemic stroke using systems biology approaches. Methods: Putative targets of HLJDD were predicted using MetaDrug. An interaction network of putative HLJDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HLJDD targets were identified by calculating topological features, including 'Degree', 'Node-betweenness', 'Closeness', and 'K-coreness'. The binding efficiencies of the candidate HLJDD targets with the corresponding compositive compounds were further validated by a molecular docking simulation. Results: A total of 809 putative targets were obtained for 168 compositive compounds in HLJDD. Additionally, 39 putative targets were common to all four herbs of HLJDD. Next, 49 major nodes were identified as candidate HLJDD targets due to their network topological importance. The enrichment analysis based on the Gene Ontology (GO) annotation system and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway demonstrated that candidate HLJDD targets were more frequently involved in G-protein-coupled receptor signaling pathways, neuroactive ligand-receptor interactions and gap junctions, which all played important roles in the progression of ischemic stroke. Finally, the molecular docking simulation showed that 170 pairs of chemical components and candidate HLJDD targets had strong binding efficiencies. Conclusion: This study has developed for the first time a comprehensive systems approach integrating drug target prediction, network analysis and molecular docking simulation to reveal the relationships between the herbs contained in HLJDD and their putative targets and ischemic stroke-related pathways.

Optimization of Huang-Lian-Jie-Du-Decoction for Ischemic Stroke Treatment and Mechanistic Study by Metabolomic Profiling and Network Analysis

“…HLJDD acted as a potential neuroprotective agent and offered protection on ischemic injury (Hwang et al, 2002; Wang et al, 2014; Zhang et al, 2015). However, the optimal proportions and combinational mechanisms of HLJDD on the treatment of ischemic stroke remain unidentified.…”

Network pharmacology-based identification of key pharmacological pathways of Yin–Huang–Qing–Fei capsule acting on chronic bronchitis

“…The neuroactive ligand–receptor pathway includes many G-protein-coupled receptors, which are often located on the cell surface and involved in the transduction of an endogenous signal into an intracellular response 49. G-protein-coupled receptors regulate vital processes by controlling the expression and function of seven transmembrane receptors, which play a particularly important role in some widespread neurological disorders 19. For example, the activation of the A1 adenosine receptor in allergic rabbit airway smooth muscle causes the production of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] via a pertussis toxin-sensitive G protein-coupled phospholipase C. This signaling mechanism may be involved in the generation of contractile responses.…”

“…(Gan Cao [GC]) – were collected from the Chinese Academy of Sciences chemistry database (http://www.organchem.csdb.cn/scdb/main/slogin.asp, updated on July 20, 2015). This database displays chemical information, including chemical and crystal structures, spectra, reactions, syntheses, and thermo-physical properties 19. The available structural information for YHQFC included 29 compounds in MMH, 12 compounds in BTLZ, 7 compounds in KXR, 34 compounds in ZBM, 24 compounds in PPY, 1 compound in SSG (as CaSO 4 ⋅2H 2 O), 18 compounds in SCP, 14 compounds in DQY, 35 compounds in XJYZH, 7 compounds in CSL, 89 compounds in WWZ, 55 compounds in YXY, 78 compounds in ZS, and 190 compounds in GC.…”

Fangjiomics: revealing adaptive omics pharmacological mechanisms of the myriad combination therapies to achieve personalized medicine

“…Wang et al demonstrated that Chang'an II protected the intestinal mucosa against post-inflammation irritable bowel syndrome (PI-IBS) through integrated effects of immunomodulation, anti-inflammation, and anti-anxiety [13] . In two articles by Zhao et al [14] and Zhang et al [15] , the contributions of different parties in Fangjis to the total action of Fangjis were demonstrated. Though each single herb (Ramulus Cinnamomi, Guizhi; Paeonia lactiflora, Shaoyao; Rhizoma Anemarrhenae, Zhimu) could affect some diabetic peripheral neuropathy (DPN)-related functions and pathways, GuizhiShaoyao-Zhimu decoction showed more effects on those DPNrelated functions and pathways, such as aryl hydrocarbon receptor signaling and apoptosis signaling [14] .…”

“…Though each single herb (Ramulus Cinnamomi, Guizhi; Paeonia lactiflora, Shaoyao; Rhizoma Anemarrhenae, Zhimu) could affect some diabetic peripheral neuropathy (DPN)-related functions and pathways, GuizhiShaoyao-Zhimu decoction showed more effects on those DPNrelated functions and pathways, such as aryl hydrocarbon receptor signaling and apoptosis signaling [14] . A network analysis of the ingredients in Huanglian-Jie-du Decoction revealed their putative targets in ischemic stroke-related pathway systems [15] . With a rational combination of compounds diverse functions with different combined modes may emerge for the therapeutic purpose.…”