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Table of Contents
ORIGINAL ARTICLE
Year : 2023  |  Volume : 9  |  Issue : 1  |  Page : 53-60

Elucidation of the mechanism of Gualou-Xiebai-Banxia decoction for the treatment of unstable angina based on network pharmacology and molecular docking


1 National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
2 National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences; Cardiovascular Department, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China

Date of Submission16-Jul-2021
Date of Acceptance27-Sep-2021
Date of Web Publication21-Dec-2022

Correspondence Address:
Dr. Xiao-Juan Ma
National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, No. 1, Xiyuan Caochang, Haidian District, Beijing City 100091
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2311-8571.364411

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  Abstract 


Objective: The aim of this study was to identify the potential pharmacological mechanisms of Gualou-Xiebai-Banxia decoction (GLXBBX) against unstable angina (UA). Materials and Methods: The active compounds of GLXBBX were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and their targets were predicted using the SwissTargetPrediction database. The targets associated with UA were obtained from the Online Mendelian Inheritance in Man, GeneCards, and Therapeutic Target Database. Individual targets associated with UA and GLXBBX were cross-checked to identify the targets of GLXBBX involved in the treatment of UA. A protein–protein interaction network was built using the STRING online database. Cytoscape 3.7.2 software was used to screen out hub genes. Additional gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the clusterProfiler package in R. Results: A total of 28 bioactive compounds and 320 protein targets of GLXBBX associated with UA were screened out. Enrichment analysis indicated that the therapeutic effect of GLXBBX may be mediated through the PI3K/AKT, MAPK, and HIF-1 signaling pathways. Molecular docking suggested that the active compounds including Vitamin E, cavidine, and baicalein can bind to their protein receptors. Conclusions: This research confirmed the multifactorial effects of GLXBBX in the treatment of UA and laid the foundation for the experimental research on GLXBBX.

Keywords: Gualou Xiebai Banxia decoction, molecular docking, network pharmacology, unstable angina


How to cite this article:
Tan Y, Chen L, Qu H, Shi DZ, Ma XJ. Elucidation of the mechanism of Gualou-Xiebai-Banxia decoction for the treatment of unstable angina based on network pharmacology and molecular docking. World J Tradit Chin Med 2023;9:53-60

How to cite this URL:
Tan Y, Chen L, Qu H, Shi DZ, Ma XJ. Elucidation of the mechanism of Gualou-Xiebai-Banxia decoction for the treatment of unstable angina based on network pharmacology and molecular docking. World J Tradit Chin Med [serial online] 2023 [cited 2023 Feb 3];9:53-60. Available from: https://www.wjtcm.net/text.asp?2023/9/1/53/364411




  Introduction Top


Unstable angina (UA), a severe type of acute coronary syndrome, is the leading cause of death in industrialized western countries.[1] UA results from the rupture of unstable atherosclerotic plaques and the formation of a thrombus, which in turn keeps the ischemic cardiomyocytes in a state of low perfusion.[2] Patients with UA usually experience chest discomfort or pain, occurring frequently or unpredictably, and may develop acute myocardial infarction, which greatly affects their quality of life.[3] Treatments for UA include antiplatelet therapy, antithrombin therapy, nitrate administration, or interventional therapy.[4] However, these therapies are often associated with adverse secondary effects and high costs, imposing a heavy burden on patients.[5],[6] Therefore, a more economical and safer treatment, in combination with standard measures, is required to improve the therapeutic efficacy and quality of life for patients with UA.

Traditional Chinese Medicine (TCM) has been widely used to prevent cardiovascular diseases, including UA.[7],[8] Gualou Xiebai Banxia decoction (GLXBBX) consists of three herbs: Fructus Trichosanthis (dried ripen fruit of Trichosanthes kirilowii Maxim.), Bulbus Allii Macrostemonis (dried bulb of Allium macrostemon Bge), and Pinelliae Rhizoma (dry tuber of Pinellia ternata [Thunb.] Breit.). In TCM, GLXBBX has been confirmed to invigorate qi to relieve depression, dredge yang, and disperse knots, thereby eliminating phlegm and broadening the chest. However, the mechanism of action of GLXBBX against UA remains unknown.

Owing to the complex herbal formulations, it is difficult to investigate the interactions between ingredients and their mechanisms of action. Network pharmacology and molecular docking can reveal the synergistic effects of complex herbal formulations on the human systems. Previous studies suggested that network pharmacology and molecular docking are ideal tools to search for interactions among compounds, genes, proteins, and diseases.[9],[10],[11] These observations led us to analyze the potential mechanism by which GLXBBX attenuates UA.


  Materials and Methods Top


Screening of active ingredients

The active ingredients of GLXBBX were collected from the TCM Systems Pharmacology Database and Analysis Platform[12] (TCMSP, http://lsp.nwu.edu.cn/tcmsp.php).[13] Based on the thresholds of oral bioavailability (≥30%) and drug-likeness (≥0.18), repetitive compounds and compounds that lacked target prediction were eliminated.

Prediction of bioactive compound targets

The SwissTargetPrediction database[14] (http://www.swisstargetprediction.ch) was used to identify the protein targets of the bioactive compounds of GLXBBX.

Collection of unstable angina targets

The terms “Unstable angina” and “Angina, Unstable” were entered into Online Mendelian Inheritance in Man database[15] (http://www.omim.org), GeneCards[16] (http://www.genecards.org), and Therapeutic Target Database[17] (http://db.idrblab.net/ttd/). UniProt (https://www.uniprot.org/) was used to confirm information on UA-related targets, such as protein names and gene IDs.

Construction of a compound-target network

The active components of GLXBBX and UA-related targets were imported into the Cytoscape 3.7.2 platform (https://cytoscape. org/) to build a network for GLXBBX bioactive compounds and protein targets. The connection between nodes in the network was analyzed using the CytoNCA plug-in.

Construction of a protein–protein interaction network

Targets were imported to the STRING database (https://string-db.org/) in the “Homo sapiens” setting to create a protein–protein interaction (PPI) network, which was visualized using Cytoscape 3.7.2.[18] The information on nodes' interrelationships was displayed using the following parameters: degree centrality, betweenness centrality, and closeness centrality [Table 1].
Table 1: Abbreviation list

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Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses

Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed[19],[20] using the clusterProfiler 3.14.3 package[21] in R.

Molecular docking simulations

Molecular docking was performed using AutoDock Vina.[22] The structures of the bioactive compounds were collected from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/),[23] and the protein three-dimensional structures were obtained from the Protein Data Bank (http://www.rcsb.org/pdb/home/home.do).[24] Docking results were visualized using PyMoL.


  Results Top


Compound-target network analysis

A total of 28 candidate compounds were collected from the TCMSP [Table 2], and 320 protein targets of GLXBBX associated with UA were identified. The established “GLXBBX bioactive compound-target network” includes 348 nodes (28 bioactive compounds from GLXBBX and 320 UA-related targets) and 1123 edges, which indicate compound-target interactions [Figure 1]. As shown in [Table 2], the bioactive compounds had degree values >10. Among them, baicalein (degree = 64) had the largest number of associated targets, followed by cavidine (degree = 60) and Vitamin E (degree = 59).
Figure 1: The GLXBBX bioactive compound-target network. Yellow octagons represent Fructus Trichosanthis; red octagons, Bulbus Allii Macrostemonis; blue octagons, Pinelliae Rhizoma; cyan octagons, compounds appearing in different herbs; green triangles, targets of GLXBBX in the treatment of UA. GLXBBX: Gualou Xiebai Banxia decoction, UA: Unstable angina

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Table 2: The information of the bioactive compounds of Gualou Xiebai Banxia decoction, Gualou (Fructus Trichosanthis), Xiebai (Bulbus Allii Macrostmonis), Banxia (Pinelliae Rhizoma)

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Protein–protein interaction network analysis

The obtained targets of GLXBBX involved in UA treatment were entered into the STRING online database (PPI combined score > 0.7) to establish a PPI network [Figure 2]a. The 320 UA-related targets were included in Cytoscape for the analysis. The network topology analysis plugin CytoNCA was used to screen the core PPI network [Figure 2]b. The following thresholds were set: Degree >60 (twice the median), BC >9.81546, and CC >0.96153843. A core PPI network containing 15 targets was established [Table 3]. Based on the degree screening principle, glyceraldehyde-3-phosphate dehydrogenase (GAPDH; degree = 195), RAC-alpha serine/threonine protein kinase (AKT1; degree = 192), interleukin-6 (IL-6; degree = 167), vascular endothelial growth factor A (degree = 159), and caspase-3 (CASP3; degree = 146) were selected as hub genes.
Figure 2: The process of screening core targets. (a) PPI network of GLXBBX against UA was constructed using STRING, (b) Core PPI network of related targets of GLXBBX preventing UA extracted from A, applying the cutoff values indicated in red. DC: Degree centrality, BC: Betweenness centrality, CC: Closeness centrality, PPI: Protein–protein interaction, GLXBBX: Gualou Xiebai Banxia decoction

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Table 3: Core targets of treating unstable angina of Gualou Xiebai Banxia decoction and its topological properties

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Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses

GO enrichment analysis of the 320 UA targets indicated that they are involved in biological processes such as peptidyl-tyrosine/serine phosphorylation and positive regulation of protein serine/threonine kinase activity. The identified cellular components included membrane rafts, microdomains, and regions. The molecular function results demonstrated that these targets may exhibit protein serine/threonine and protein tyrosine kinase activities and bind to phosphatases. KEGG enrichment analysis suggested that the targets were mainly associated with the PI3K/AKT, MAPK, and HIF-1 signaling pathways [Figure 3] and [Figure 4].
Figure 3: Gene ontology enrichment analysis. (a) Bar chart of the top 20 biological processes; (b) bar chart of the top 20 cellular components; (c) bar chart of the top 20 molecular functions

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Figure 4: KEGG pathway enrichment analysis. Bar chart of the top 20 KEGG signaling pathways. KEGG: Kyoto Encyclopedia of Genes and Genomes

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Molecular docking simulations

As shown in [Figure 5], the results indicated that baicalein binds to CASP3, AKT1, and HSP90AA1 (docking scores of −8.3, −8.4, and −9.3, respectively). Cavidine showed a good correlation with CASP3, AKT1, and EGFR (docking scores of −10.2, −9.4, and −8.8, respectively) [Figure 6]. Furthermore, all bioactive ingredients of GLXBBX proved good binding with three hub proteins, GAPDH, CASP3, and AKT1, suggesting that GLXBBX may exert its therapeutic actions in UA prevention through these targets.
Figure 5: Heat map of the docking scores of core targets integrated with key compounds from GLXBBX. GLXBBX: Gualou Xiebai Banxia decoction

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Figure 6: The three-dimensional structures of the protein-compound complexes of the three key compounds and the three hub proteins, as obtained by molecular docking. (a) GAPDH-baicalein; (b) GAPDH-cavidine; (c) GAPDH-Vitamin E; (d) AKT1-baicalein; (e) AKT1-cavidine; (f) AKT1-Vitamin E; (g) CASP3-baicalein; (h) CASP3-cavidine; and (i) CASP3-Vitamin E complexes. GAPDH: Glyceraldehyde-3-phosphate dehydrogenase, AKT1: Alpha serine/threonine protein kinase, CASP3: Caspase-3

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  Discussion Top


GLXBBX is a TCM prescription comprising three herbs: Fructus Trichosanthis, Bulbus Allii Macrostemonis, and Pinelliae Rhizoma. In TCM, UA is considered to be caused by blood stasis that obstructs the heart pulse. GLXBBX has been widely prescribed for the treatment of UA in TCM.[25] However, the mechanism through which this formula alleviates UA progression remains unclear. In recent years, network pharmacology has provided a new approach for exploring potential pharmacological molecular mechanisms in TCM. In this study, 28 active compounds and 320 protein targets of GLXBBX were identified, which may be able to promote its scientific application in clinical settings.

We employed the Cytoscape software to construct a GLXBBX compound-target network for interrelationship analysis. The results demonstrated that most active compounds of GLXBBX acted on numerous targets. For instance, baicalein, cavidine, and Vitamin E interacted with 64, 60, and 59 targets, respectively. These key compounds may play important roles in the pharmacological process. Baicalein, a flavonoid derived from the roots of Scutellaria baicalensis Georgi., has different therapeutic effects, such as an antioxidant action.[26] A previous study reported that baicalein effectively prevents peripheral neuropathy induced by oxidative stress.[27] Cavidine, an active alkaloid isolated from Corydalis impatiens, has been shown to have high anti-inflammatory and antioxidant properties. One study indicated that cavidine ameliorates experimental colitis by negatively regulating the expression of oxygen metabolites and NF-κB and reducing the production of pro-inflammatory cytokines.[28] Vitamin E is an important fat-soluble vitamin and a good antioxidant. Recent investigations have shown that Vitamin E plays a crucial role in reducing inflammation and fibrosis.[29] Moreover, all these ingredients have good oral bioavailability and drug-likeness. Therefore, they may play a critical role in the pharmacological process.

GO enrichment analysis showed that the UA-related targets of GLXBBX may play a significant role in biological processes such as the positive regulation of protein serine/threonine kinase activity, protein autophosphorylation, and protein modification. Both MAPKs and AKTs are members of the serine/threonine protein kinase family and mediate signal transduction from the cell surface to the nucleus. Therefore, the positive regulation of protein serine/threonine kinase activity can lead to the abnormal activation of the signaling pathways mediated by these molecules.[30],[31] Previous studies have reported that once the MAPK/AKT signaling pathway is activated, numerous inflammatory cytokines, crucial for the regulation of inflammation, are released.[32],[33] Inflammation impairs normal endothelial function, accelerates the formation of unstable atherosclerotic plaque, and contributes to plaque rupture and thrombosis.[34],[35] Fibrous cap thickness is one of the most important determinants of plaque vulnerability. Vulnerable atherosclerotic plaques are heavily infiltrated by macrophage foam cells, which release multiple inflammatory mediators and cytokines, such as plasminogen activators, cathepsins, and matrix metalloproteinases; this finally results in matrix degradation, fibrous cap thinning, and plaque rupture, leading to a severe cardiovascular event.[36] It has been shown that monocyte/macrophage differentiation and recruitment are negatively regulated by the selective Mas receptor agonist AVE0991, which suppresses inflammation in the perivascular space in ApoE−/−mice, thus exerting a cardioprotective action.[37] A previous study has found that atherosclerosis exhibits identical properties of disorders of lipid metabolism, protein phosphorylation, and protein modification,[38],[39] consistent with the present study. In addition, GLXBBX might be associated with molecular functions such as serine/threonine protein kinase activity, phosphatase binding, and protein tyrosine kinase activity in the treatment of UA.

KEGG enrichment analysis suggested that the MAPK, PI3K/AKT, and HIF-1 signaling pathways had large numbers of gene enrichment. A previous study has demonstrated that the MAPK signaling pathway is a main mediator of endothelial inflammation and plays a crucial role in the pro-inflammatory maturation of endothelial cells after stimulation by TNF-α.[40] Research has suggested that the PI3K/AKT signaling pathway is closely associated with inflammation and that its activation promotes the expression of pro-inflammatory cytokines.[41] Furthermore, several studies have reported that MAPK and AKT crosstalk with NF-κB signaling pathways, suggesting that they are involved in NF-κB activation.[42],[43] In this study, the HIF-1 signaling pathway was also significantly enriched. One study has shown that hypoxia-induced reduction of cell viability can be reversed by HIF-1-mediated autophagy in H9c2 cells, proving that HIF-1 protects the ischemic myocardium.[44] Another study has suggested that HIF-1 can afford cardioprotection against myocardial infarction by reducing infarcted heart size, improving heart function, and increasing capillary density, in a rat model of myocardial infarction.[45] In addition, GLXBBX may act in other pathways, including apoptosis, platelet activation, and the FoxO and Ras signaling pathways.

According to PPI network analysis, three genes may confer cardioprotection, namely, GAPDH, CASP3, and AKT1. GAPDH is involved in nuclear events, such as apoptosis, transcription, RNA transport, DNA replication, and cytoskeleton assembly.[46] Previous research has shown that apoptotic stimuli, including oxidative or genotoxic stress, result in GAPDH translocation and accumulation into the nucleus, thereby inducing apoptosis.[47],[48] CASP3 plays a crucial role in apoptosis.[49],[50] AKT exerts its anti-apoptotic effects by phosphorylating its target proteins through a variety of downstream pathways.[51] In addition, these three key targets had binding energies lower than −5.0 kJ/mol upon docking with the 13 key compounds, which indicates that these proteins have good affinity and structural stability when bound to these compounds.


  Conclusions Top


Our research revealed potential mechanisms of action of GLXBBX in the treatment of UA. These results highlight the potential for subsequent experimental research.

Financial support and sponsorship

This study was financially supported by the National Natural Science Foundation of China (No. 81774141).

Conflicts of interest

The authors declare that they have no conflicts of interest.



 
  References Top

1.
Braunwald E, Morrow DA. Unstable angina: Is it time for a requiem? Circulation 2013;127:2452-7.  Back to cited text no. 1
    
2.
Li S, Geng Q, Chen H, Zhang J, Cao C, Zhang F, et al. The potential inhibitory effects of miR-19b on vulnerable plaque formation via the suppression of STAT3 transcriptional activity. Int J Mol Med 2018;41:859-67.  Back to cited text no. 2
    
3.
Chen Y, Xiao X, Xu X, Zhang Z, Deng Y. Traditional Chinese Medicine in the prevention and treatment of stable angina pectoris in patients with coronary heart disease based on the theory of “phlegm and blood stasis” under guidance of evidence-based medicine: A prospective cohort study. J Tradit Chin Med 2021;41:150-6.  Back to cited text no. 3
    
4.
Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e179-347.  Back to cited text no. 4
    
5.
Reddy S, Mathew M, Patel N, Rahman S. Analyzing the efficacy and cost-effectiveness of anti-platelet therapy in unstable angina/non-ST elevation myocardial infarction: A decision analysis. Cureus 2019;11:e5321.  Back to cited text no. 5
    
6.
Skalski B, Kontek B, Rolnik A, Olas B, Stochmal A, Żuchowski J. Anti-platelet properties of phenolic extracts from the leaves and twigs of Elaeagnus rhamnoides (L.) A. Nelson. Molecules 2019;24:3620.  Back to cited text no. 6
    
7.
Zhang L, Li Y, Yang BS, Li L, Wang XZ, Ge ML, et al. A multicenter, randomized, double-blind, and placebo-controlled study of the effects of tongxinluo capsules in acute coronary syndrome patients with high on-treatment platelet reactivity. Chin Med J (Engl) 2018;131:508-15.  Back to cited text no. 7
    
8.
Liu C, Duan L, Huang M, Li J, Xiong X, Chen G, et al. Effectiveness and safety of Suxiao Jiuxin pill in treating acute coronary syndrome: A systematic review and Meta-analysis. J Tradit Chin Med 2020;40:518-29.  Back to cited text no. 8
    
9.
Jiang Y, Liu N, Zhu S, Hu X, Chang D, Liu J. Elucidation of the mechanisms and molecular targets of yiqi shexue formula for treatment of primary immune thrombocytopenia based on network pharmacology. Front Pharmacol 2019;10:1136.  Back to cited text no. 9
    
10.
Zhu N, Hou J. Exploring the mechanism of action Xianlingubao Prescription in the treatment of osteoporosis by network pharmacology. Comput Biol Chem 2020;85:107240.  Back to cited text no. 10
    
11.
Li B, Rui J, Ding X, Chen Y, Yang X. Deciphering the multicomponent synergy mechanisms of SiNiSan prescription on irritable bowel syndrome using a bioinformatics/network topology based strategy. Phytomedicine 2019;63:152982.  Back to cited text no. 11
    
12.
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014;6:13.  Back to cited text no. 12
    
13.
Li J, Zhao P, Li Y, Tian Y, Wang Y. Systems pharmacology-based dissection of mechanisms of Chinese medicinal formula Bufei Yishen as an effective treatment for chronic obstructive pulmonary disease. Sci Rep 2015;5:15290.  Back to cited text no. 13
    
14.
Zhou J, Wang Q, Xiang Z, Tong Q, Pan J, Wan L, et al. Network pharmacology analysis of traditional Chinese medicine formula Xiao Ke Yin Shui treating type 2 diabetes mellitus. Evid Based Complement Alternat Med 2019;2019:4202563.  Back to cited text no. 14
    
15.
Liu J, Li Y, Zhang Y, Huo M, Sun X, Xu Z, et al. A network pharmacology approach to explore the mechanisms of Qishen granules in heart failure. Med Sci Monit 2019;25:7735-45.  Back to cited text no. 15
    
16.
Li K, Li H, Xu W, Liu W, Du Y, He JF, et al. Research on the potential mechanism of gypenosides on treating thyroid-associated ophthalmopathy based on network pharmacology. Med Sci Monit 2019;25:4923-32.  Back to cited text no. 16
    
17.
Wan Y, Xu L, Liu Z, Yang M, Jiang X, Zhang Q, et al. Utilising network pharmacology to explore the underlying mechanism of Wumei Pill in treating pancreatic neoplasms. BMC Complement Altern Med 2019;19:158.  Back to cited text no. 17
    
18.
Yang H, Zhang X, Xin G. Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network. Ren Fail 2018;40:136-45.  Back to cited text no. 18
    
19.
Gene Ontology Consortium. Gene Ontology Consortium: Going forward. Nucleic Acids Res 2015;43:D1049-56.  Back to cited text no. 19
    
20.
Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000;28:27-30.  Back to cited text no. 20
    
21.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012;16:284-7.  Back to cited text no. 21
    
22.
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455-61.  Back to cited text no. 22
    
23.
Alizadeh AA, Jafari B, Dastmalchi S. Alignment independent 3D-QSAR studies and molecular dynamics simulations for the identification of potent and selective S1P1 receptor agonists. J Mol Graph Model 2020;94:107459.  Back to cited text no. 23
    
24.
PDBe-KB consortium. PDBe-KB: A community-driven resource for structural and functional annotations. Nucleic Acids Res 2020;48:D344-53.  Back to cited text no. 24
    
25.
Liu W, Xiong X, Yang X, Chu F, Liu H. The effect of Chinese herbal medicine gualouxiebaibanxia decoction for the treatment of angina pectoris: A systematic review. Evid Based Complement Alternat Med 2016;2016:8565907.  Back to cited text no. 25
    
26.
Zhou Y, Mao S, Zhou M. Effect of the flavonoid baicalein as a feed additive on the growth performance, immunity, and antioxidant capacity of broiler chickens. Poult Sci 2019;98:2790-9.  Back to cited text no. 26
    
27.
Jeong JY, Cha HJ, Choi EO, Kim CH, Kim GY, Yoo YH, et al. Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of baicalein against oxidative stress-induced DNA damage and apoptosis in HEI193 Schwann cells. Int J Med Sci 2019;16:145-55.  Back to cited text no. 27
    
28.
Niu X, Liu F, Li W, Zhi W, Zhang H, Wang X, et al. Cavidine ameliorates lipopolysaccharide-induced acute lung injury via NF-κB signaling pathway in vivo and in vitro. J Inflamm 2017;40:1111-22.  Back to cited text no. 28
    
29.
Presa N, Clugston RD, Lingrell S, Kelly SE, Merrill AH Jr., Jana S, et al. Vitamin E alleviates non-alcoholic fatty liver disease in phosphatidylethanolamine N-methyltransferase deficient mice. Biochim Biophys Acta Mol Basis Dis 2019;1865:14-25.  Back to cited text no. 29
    
30.
Zhang DD, Shi N, Fang H, Ma L, Wu WP, Zhang YZ, et al. Vildagliptin, a DPP4 inhibitor, alleviates diabetes-associated cognitive deficits by decreasing the levels of apoptosis-related proteins in the rat hippocampus. Exp Ther Med 2018;15:5100-6.  Back to cited text no. 30
    
31.
Giambelluca MS, Pouliot M. Early tyrosine phosphorylation events following adenosine A2A receptor in human neutrophils: Identification of regulated pathways. J Leukoc Biol 2017;102:829-36.  Back to cited text no. 31
    
32.
Sun LF, An DQ, Niyazi GL, Ma WH, Xu ZW, Xie Y. Effects of Tianxiangdan Granule treatment on atherosclerosis via NFκB and p38 MAPK signaling pathways. Mol Med Rep 2018;17:1642-50.  Back to cited text no. 32
    
33.
Chen S, Li X, Wang Y, Mu P, Chen C, Huang P, et al. Ginsenoside Rb1 attenuates intestinal ischemia/reperfusion-induced inflammation and oxidative stress via activation of the PI3K/Akt/Nrf2 signaling pathway. Mol Med Rep 2019;19:3633-41.  Back to cited text no. 33
    
34.
Ferencik M, Mayrhofer T, Bittner DO, Emami H, Puchner SB, Lu MT, et al. Use of high-risk coronary atherosclerotic plaque detection for risk stratification of patients with stable chest pain: A secondary analysis of the PROMISE randomized clinical trial. JAMA Cardiol 2018;3:144-52.  Back to cited text no. 34
    
35.
Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: A comprehensive review of studies in mice. Cardiovasc Res 2008;79:360-76.  Back to cited text no. 35
    
36.
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014;114:1852-66.  Back to cited text no. 36
    
37.
Skiba DS, Nosalski R, Mikolajczyk TP, Siedlinski M, Rios FJ, Montezano AC, et al. Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis. Br J Pharmacol 2017;174:4055-69.  Back to cited text no. 37
    
38.
Bernal-Lopez MR, Garrido-Sanchez L, Gomez-Carrillo V, Gallego-Perales JL, Llorente-Cortes V, Calleja F, et al. Antioxidized LDL antibodies are associated with different metabolic pathways in patients with atherosclerotic plaque and type 2 diabetes. Diabetes Care 2013;36:1006-11.  Back to cited text no. 38
    
39.
Walker AE, Breevoort SR, Durrant JR, Liu Y, Machin DR, Dobson PS, et al. The pro-atherogenic response to disturbed blood flow is increased by a western diet, but not by old age. Sci Rep 2019;9:2925.  Back to cited text no. 39
    
40.
Li R, Dong Z, Zhuang X, Liu R, Yan F, Chen Y, et al. Salidroside prevents tumor necrosis factor-α-induced vascular inflammation by blocking mitogen-activated protein kinase and NF-κB signaling activation. Exp Ther Med 2019;18:4137-43.  Back to cited text no. 40
    
41.
Liu Y, Tie L. Apolipoprotein M and sphingosine-1-phosphate complex alleviates TNF-α-induced endothelial cell injury and inflammation through PI3K/AKT signaling pathway. BMC Cardiovasc Disord 2019;19:279.  Back to cited text no. 41
    
42.
Joshi RN, Fernandes SJ, Shang MM, Kiani NA, Gomez-Cabrero D, Tegnér J, et al. Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression. J Leukoc Biol 2019;106:413-30.  Back to cited text no. 42
    
43.
Lee MH, Hong SH, Park C, Han MH, Kim SO, Hong SH, et al. Anti-inflammatory effects of Daehwangmokdantang, a traditional herbal formulation, in lipopolysaccharide-stimulated RAW 264.7 macrophages. Exp Ther Med 2017;14:5809-16.  Back to cited text no. 43
    
44.
Gui L, Liu B, Lv G. Hypoxia induces autophagy in cardiomyocytes via a hypoxia-inducible factor 1-dependent mechanism. Exp Ther Med 2016;11:2233-9.  Back to cited text no. 44
    
45.
Jianqiang P, Ping Z, Xinmin F, Zhenhua Y, Ming Z, Ying G. Expression of hypoxia-inducible factor 1 alpha ameliorate myocardial ischemia in rat. Biochem Biophys Res Commun 2015;465:691-5.  Back to cited text no. 45
    
46.
Liu W, Shang FF, Xu Y, Belegu V, Xia L, Zhao W, et al. eIF5A1/RhoGDIα pathway: A novel therapeutic target for treatment of spinal cord injury identified by a proteomics approach. Sci Rep 2015;5:16911.  Back to cited text no. 46
    
47.
Li W, Zeng Z, Gui C, Zheng H, Huang W, Wei H, et al. Proteomic analysis of mitral valve in Lewis rat with acute rheumatic heart disease. Int J Clin Exp Pathol 2015;8:14151-60.  Back to cited text no. 47
    
48.
Liang S, Aiqun M, Figtree G, Ping Z. GAPDH-silence preserves H9C2 cells from acute hypoxia and reoxygenation injury. Int J Biol Macromol 2015;81:375-86.  Back to cited text no. 48
    
49.
Zhao X, Feng X, Wang C, Peng D, Zhu K, Song JL. Anticancer activity of Nelumbo nucifera stamen extract in human colon cancer HCT-116 cells in vitro. Oncol Lett 2017;13:1470-8.  Back to cited text no. 49
    
50.
Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res 2017;63:e12419.  Back to cited text no. 50
    
51.
Huang X, Zuo L, Lv Y, Chen C, Yang Y, Xin H, et al. Asiatic acid attenuates myocardial ischemia/reperfusion injury via Akt/GSK-3β/HIF-1α signaling in rat H9c2 cardiomyocytes. Molecules 2016;21:1248.  Back to cited text no. 51
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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