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

Yu-Peng Chen; Ke-Xin Wang; Jie-Qi Cai; Yi Li; Hai-Lang Yu; Qi Wu; Wei Meng; Han-Duo Wang; Chuan-Hui Yin; Jie Wu; Mian-Bo Huang; Rong Li; Dao-Gang Guan

doi:10.3389/fcell.2022.753425

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

Front Cell Dev Biol. 2022 May 12:10:753425. doi: 10.3389/fcell.2022.753425. eCollection 2022.

Authors

Yu-Peng Chen^{1

2}, Ke-Xin Wang³, Jie-Qi Cai^{1

2}, Yi Li⁴, Hai-Lang Yu^{1

2}, Qi Wu⁵, Wei Meng^{1

2}, Han-Duo Wang^{1

2}, Chuan-Hui Yin^{1

2}, Jie Wu^{1

2}, Mian-Bo Huang⁶, Rong Li⁷, Dao-Gang Guan^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China.
³ Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, National Key Clinical Specialty/Engineering Technology Research Center of Education Ministry of China, Neurosurgery Institute, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁴ Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁵ Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁶ Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
⁷ Department of Cardiovascular Disease, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.

Abstract

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, NFκB, 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.

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

Grants and funding

This study is financially supported by the Startup fund from Southern Medical University (Grant No. G820282016), the Natural Science Foundation Council of China (Grant Nos 31501080, 32070676), Hong Kong Baptist University Strategic Development Fund (Grant Nos SDF13-1209-P01, SDF15-0324-P02(b), and SDF19-0402-P02), Hong Kong Baptist University Interdisciplinary Research Matching Scheme (Grant No. RC/IRCs/17-18/04) and General Program of National Natural Science Foundation of China (Grant No. 81774260), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2020A1515010172). Key Area R&D Program of Guangdong Province (2019B020227003).