A Network Pharmacology Approach to Decipher the Total Flavonoid Extract of Dracocephalum Moldavica L. In the Treatment of Cerebral Ischemia- Reperfusion Injury
Xu Hu, Yideresi Mola, Wen-ling Su, Yue Wang, Rui-fang Zheng, Jian-guo Xing
Abstract
Background and objective
Cerebral ischemia-reperfusion injury (CIRI) is a major injury that seriously endangers human health and is characterized by high mortality and high disability. The total flavonoid extract of Dracocephalum moldavica L.(TFDM) in the treatment of CIRI has been proved by clinical practice. But the mechanism for the treatment of CIRI by TFDM has not been systematically revealed.
Study design and methods
The active compounds contained in TFDM were screened by literature mining and pharmacokinetic parameters, and the targets related to CIRI were collected by searching Drugbank, Genecards and OMIM databases. Cytoscape software was used to construct the protein interaction network of TFDM for the prevention and treatment of CIRI. Geneontology and signal pathway enrichment were analyzed. The key target pathway network of TFDM compounds was constructed and verified by pharmacological experiment in vitro.
Introduction
Stroke is one of the three major diseases affecting human health. At present, the domestic and foreign guidelines recommend the use of intravenous recombinant tissue plasminogen activator (rtPA) thrombolysis for recanalization in the acute phase. Thrombolytic therapy has a strict treatment time window. Thrombolytic therapy beyond the time window can achieve certain therapeutic effects, but reperfusion will cause further damage to the brain tissue and expand the degree of brain injury caused by cerebral ischemia, which becomes cerebral ischemia-reperfusion injury (CIRI) [1]. Therefore, how to protect the ischemic penumbra, prevent or reduce CIRI, and improve the prognosis of stroke has become a hot topic and focus of many studies. CIRI is a dynamically changing process involving multiple links, including oxidative stress, inflammatory response, energy metabolism disorder, excitatory amino acids toxicity, apoptosis, and mitochondrial dysfunction. However, a single compound cannot exert the therapeutic effect on multiple links, and Chinese medicine with multi-component and multi-target treatment characteristics can achieve this goal.
Materials and methods
Collection and screening of active components of total flavonoids
Using "Dracocephalum moldavica L." as the key word, the chemical components of dracocephalum moldavica were collected through literature retrieval, BATMAN-TCM database and ChemSrc database (https://www.chemsrc.com/). Potential active ingredients were screened in the SwissADME (http://www.swissadme.ch/) database based on pharmacokinetic parameters. Filter by [9, 10]: (1) defining gastrointestinal absorption (gastrointestinal absorption / GI absorption) in pharmacokinetics as "high" as a condition for chemical composition; (2) bioavailability score ≥ 0.5; (3) at least two of the pharmaceutical (druglikeness) rules as "yes"; (4) screening flavonoids active components.
Results
Preparation of active compounds of TFDM
The active components of TFDM were identified using the SwissADME ™ analysis platform and literature collection. To ensure the accuracy and completeness of the data, a small number of bioactive molecules were added as candidate active molecules according to the literature reports, although they did not meet the screening criteria. Finally, 21 compounds were selected as candidate active molecules, and the results are shown in Table 1.
Discussion
Cerebral ischemia-reperfusion injury(CIRI) is a common and frequently-occurring disease in the clinic. The mortality and disability rate are extremely high. It seriously threatens human health and life, and the burden on society and families is immeasurable. Therefore, scientists and clinicians need to make great efforts to find potential pathogenic mechanisms, so as to take appropriate preventive measures and successful treatment methods. CIRI involves a variety of mechanisms [14], including free radical action, excitatory amino acids, cellular Ca2+ overload. To understand the mechanism of CIRI and deepen the understanding of the process of cerebral ischemic injury is conducive to the research and selection of medication. so as to achieve the purpose of treatment. Natural medicines have a long history of treatment for cerebral ischemia and have accumulated rich theoretical knowledge. Screening active ingredients from natural medicines is also the current trend of research and development. The whole world is promoting the separation of chemical components of natural medicines and their application in the treatment of brain diseases. Our research group has continuously conducted a series of studies on this issue, and have made great progress.
Acknowledgments
We sincerely thank the team of aid experts in Xinjiang for their help and technical support for this study.
Citation: Hu X, Mola Y, Su W-l, Wang Y, Zheng R-f, Xing J-g (2023) A network pharmacology approach to decipher the total flavonoid extract of Dracocephalum Moldavica L. in the treatment of cerebral ischemia- reperfusion injury. PLoS ONE 18(7): e0289118. https://doi.org/10.1371/journal.pone.0289118
Editor: Yong Sze Ong, Monash University Malaysia, MALAYSIA
Received: December 29, 2022; Accepted: July 6, 2023; Published: July 26, 2023
Copyright: © 2023 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: Funding: 1)Xu Hu, this work was funded by the Scientific Research Business Expenses of Xinjiang Uygur Autonomous Region (ky2022143). 2)Rui-fang Zheng, this work was funded by the Scientific Research Business Expenses of Xinjiang Uygur Autonomous Region (ky2022140) and National Natural Science Foundation of China (82204767). 3)Jian-guo Xing, this work was funded by the Xinjiang Uygur Autonomous Region Key Laboratory Open Project (2020D04020),National Natural Science Foundation of China (82260845,U1803281), Special project of the central government to guide local science and technology development (ZYYD2022A02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CIRI, cerebral ischemia-reperfusion injury; TFDM, total flavonoid extract of Dracocephalum moldavica L.; rtPA, recombinant tissue plasminogen activator; TCM, Traditional Chinese Medicine; DML, Dracocephalum Moldavica L.; EPDM, effective parts of dracocephalum moldavica; PPI, protein-protein interaction; GO, Gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; MF, molecular function; BP, biological process; CC, cellular components; HRP, horseradish peroxidase; ANOVA, analysis of variance; SD, standard deviation; RIPA, radio immuno precipitation assay; PMSF, phenyl methyl sulfonyl fluoride; LDH, lactate dehydrogenase; MDA, malondialdehyde; NO, nitric oxide
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0289118#abstract0
