4.7 Article

Detecting Key Functional Components Group and Speculating the Potential Mechanism of Xiao-Xu-Ming Decoction in Treating Stroke

Journal

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.753425

Keywords

XXMD; KFCG; network pharmacology; functional response space; effective proteins; PC12 cells; HT22 cells

Funding

  1. Startup fund from Southern Medical University [G820282016]
  2. Natural Science Foundation Council of China [31501080, 32070676]
  3. Hong Kong Baptist University Strategic Development Fund [SDF13-1209-P01, SDF15-0324-P02, SDF19-0402-P02]
  4. Hong Kong Baptist University Interdisciplinary Research Matching Scheme [RC/IRCs/17-18/04]
  5. General Program of National Natural Science Foundation of China [81774260]
  6. Guangdong Basic and Applied Basic Research Foundation [2020A1515010172]
  7. Key Area R&D Program of Guangdong Province [2019B020227003]

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This study constructs a functional response space by combining the pathogenetic genes of stroke and the targets of Xiao-Xu-Ming decoction (XXMD), and selects key functional components group (KFCG) using a novel node importance calculation method and dynamic programming strategy. The results improve the understanding of the action mechanism of XXMD.
Stroke is a cerebrovascular event with cerebral blood flow interruption which is caused by occlusion or bursting of cerebral vessels. At present, the main methods in treating stroke are surgical treatment, statins, and recombinant tissue-type plasminogen activator (rt-PA). Relatively, traditional Chinese medicine (TCM) has widely been used at clinical level in China and some countries in Asia. Xiao-Xu-Ming decoction (XXMD) is a classical and widely used prescription in treating stroke in China. However, the material basis of effect and the action principle of XXMD are still not clear. To solve this issue, we designed a new system pharmacology strategy that combined targets of XXMD and the pathogenetic genes of stroke to construct a functional response space (FRS). The effective proteins from this space were determined by using a novel node importance calculation method, and then the key functional components group (KFCG) that could mediate the effective proteins was selected based on the dynamic programming strategy. The results showed that enriched pathways of effective proteins selected from FRS could cover 99.10% of enriched pathways of reference targets, which were defined by overlapping of component targets and pathogenetic genes. Targets of optimized KFCG with 56 components can be enriched into 166 pathways that covered 80.43% of 138 pathways of 1,012 pathogenetic genes. A component potential effect score (PES) calculation model was constructed to calculate the comprehensive effective score of components in the components-targets-pathways (C-T-P) network of KFCGs, and showed that ferulic acid, zingerone, and vanillic acid had the highest PESs. Prediction and docking simulations show that these components can affect stroke synergistically through genes such as MEK, NF kappa B, and PI3K in PI3K-Akt, cAMP, and MAPK cascade signals. Finally, ferulic acid, zingerone, and vanillic acid were tested to be protective for PC12 cells and HT22 cells in increasing cell viabilities after oxygen and glucose deprivation (OGD). Our proposed strategy could improve the accuracy on decoding KFCGs of XXMD and provide a methodologic reference for the optimization, mechanism analysis, and secondary development of the formula in TCM.

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