Background and objective To explore the main action targets and key pathways, along with their mechanisms of action, of Panax ginseng’s special ingredients in the treatment of ulcerative colitis using network pharmacology methods. To provide a theoretical basis for subsequent laboratory experiments and clinical trials.
Methods The main active ingredients of Panax notoginseng were obtained through the TCMSP database and the specific ingredients were screened. The targets of Panax notoginseng-specific components were obtained from the Swiss Target Prediction database. The GeneCards, OMIM, and DisGent databases were used to obtain the targets related to ulcerative colitis. The protein interaction network (PPI) of intersecting targets was constructed using the STRING database. GO function and KEGG pathway enrichment analysis were performed in R language software. Construction of the herb-component-target-disease-KEGG pathway network was achieved using Cytoscape software.
Results Seven major active ingredients of Panax notoginseng were obtained, and ginsenoside f2 was found to be a special ingredient, corresponding to 16 potential targets. A search of the disease database yielded 5,536 targets for ulcerative colitis. Eight core targets were obtained by protein interaction analysis of the intersecting targets: STAT3, VEGFA, HSP90AA1, FGF2, IL2, MET, BCL2L1, and RORC, respectively. 417 entries were obtained by GO functional enrichment analysis, and 22 statistically significant pathways were obtained by KEGG enrichment analysis.
Conclusion The mechanism of action of ginsenoside f2 in the treatment of ulcerative colitis features multi-target and multi-pathway interactions. The receptors may be related to STAT3, VEGFA, HSP90AA1, FGF2, IL2, MET, and other targets, and the main signaling pathways may be related to the PI3K-Akt signaling pathway, Th17 cell differentiation, and inflammatory bowel disease among others and this provides a theoretical basis for the next in-depth experimental study.
Acknowledgments
None to declare.
Funding
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Conflict of interest
The author has no conflict of interest related to this publication.
Author contributions
WS is the sole author of this manuscript.
Data sharing statement
The data used in support of the findings of this study are available from the corresponding author at weichensi14@outlook.com or weichens14@163.com upon request.
| [1] |
Kucharzik T, Koletzko S, Kannengiesser K, Dignass A. Ulcerative Colitis-Diagnostic and Therapeutic Algorithms. Dtsch Arztebl Int 2020; 117(33-34):564-574. doi:10.3238/arztebl.2020.0564,PMID:33148393.
|
| [2] |
Du L, Ha C. Epidemiology and Pathogenesis of Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49(4):643-654. doi:10.1016/j.gtc.2020.07.005, PMID:33121686.
|
| [3] |
Kaenkumchorn T, Wahbeh G. Ulcerative Colitis: Making the Diagno-sis. Gastroenterol Clin North Am 2020; 49(4):655-669. doi:10.1016/j.gtc.2020.07.001, PMID:33121687.
|
| [4] |
Keshteli AH, Madsen KL, Dieleman LA. Diet in the Pathogenesis and Management of Ulcerative Colitis; A Review of Randomized Controlled Dietary Interventions. Nutrients 2019; 11(7):1498. doi:10.3390/nu11071498,PMID:31262022.
|
| [5] |
Porter RJ, Kalla R, Ho GT. Ulcerative colitis: Recent advances in the un-derstanding of disease pathogenesis. F1000Res 2020; 9(F1000 Facul-ty Rev):294. doi:10.12688/f1000research.20805.1, PMID:32399194.
|
| [6] |
Feuerstein JD, Moss AC, Farraye FA. Ulcerative Colitis. Mayo Clin Proc 2019; 94(7):1357-1373. doi:10.1016/j.mayocp.2019.01.018,PMID:31272578.
|
| [7] |
Lee SD.Health Maintenance in Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49(4): xv-xvi. doi:10.1016/j.gtc.2020.09.002,PMID:33121699.
|
| [8] |
Burri E, Maillard MH, Schoepfer AM, Seibold F, Van Assche G, Riv-ière P, et al. Treatment Algorithm for Mild and Moderate-to-Severe Ulcerative Colitis: An Update. Digestion 2020; 101(Suppl 1):2-15. doi:10.1159/000504092,PMID:31945767.
|
| [9] |
Wang L, Shao L, Chen MY, Wang L, Yang P, Tan FB, et al. Panax notogin-seng Alleviates Colitis via the Regulation of Gut Microbiota. Am J Chin Med 2023; 51(1):107-127. doi:10.1142/S0192415X23500076,PMID:36408726.
|
| [10] |
Wang T, Guo R, Zhou G, Zhou X, Kou Z, Sui F, et al. Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: A review. J Ethnopharmacol 2016; 188:234-258. doi:10.1016/j.jep.2016.05.005,PMID:27154405.
|
| [11] |
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of sys-tems pharmacology for drug discovery from herbal medicines. J Chem-inform 2014; 6:13. doi:10.1186/1758-2946-6-13,PMID:24735618.
|
| [12] |
Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Ac-ids Res 2021; 49(D1):D1388-D1395. doi:10.1093/nar/gkaa971,PMID:33151290.
|
| [13] |
Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47(W1):W357-W364. doi:10.1093/nar/gkz382,PMID:31106366.
|
| [14] |
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics 2016; 54:1.30.1-1. 30.33. doi:10.1002/cpbi.5,PMID:27322403.
|
| [15] |
Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM. OMIM®), org: Online Mendelian Inheritance in Man ( an online catalog of human genes and genetic disorders. Nucleic Acids Res 2015;43(Da-tabase issue):D789-D798. doi:10.1093/nar/gku1205,PMID:25428349.
|
| [16] |
Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, Ronzano F, Cente-no E, Sanz F, et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res 2020; 48(D1):D845-D855. doi:10.1093/nar/gkz1021,PMID:31680165.
|
| [17] |
Oliveros JC. Venny: An interactive tool for comparing lists with Venn’s diagrams. 2007-2015. Available from:
|
| [18] |
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with in-creased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019; 47(D1):D607-D613. doi:10.1093/nar/gky1131,PMID:30476243.
|
| [19] |
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for compar-ing biological themes among gene clusters. OMICS 2012; 16(5):284-287. doi:10.1089/omi.2011.0118, PMID:22455463.
|
| [20] |
Yu G, Wang LG, Yan GR, He QY. DOSE: an R/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinfor-matics 2015; 31(4):608-609. doi:10.1093/bioinformatics/btu684,PMID:25677125.
|
| [21] |
Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics 2013; 29(14):1830-1831. doi:10.1093/bioinformatics/btt285,PMID:23740750.
|
| [22] |
Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in Cancer Immunotherapy. Mol Cancer 2020; 19(1):145. doi:10.1186/s12943-020-01258-7,PMID:32972405.
|
| [23] |
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immu-nity: a leading role for STAT3. Nat Rev Cancer 2009; 9(11):798-809. doi:10.1038/nrc2734,PMID:19851315.
|
| [24] |
Ouyang S, Li H, Lou L, Huang Q, Zhang Z, Mo J, et al. Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alle-viates chemoresistance in gastric cancer. Redox Biol 2022;52:102317. doi:10.1016/j.redox.2022.102317,PMID:35483272.
|
| [25] |
Zou G, Zhang X, Wang L, Li X, Xie T, Zhao J, et al. Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription. Theranostics 2020; 10(15):6839-6853. doi:10.7150/thno.43622,PMID:32550907.
|
| [26] |
Liang L, Hui K, Hu C, Wen Y, Yang S, Zhu P, et al. Autophagy inhibi-tion potentiates the anti-angiogenic property of multikinase inhibi-tor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells. J Exp Clin Cancer Res 2019; 38(1):71. doi:10.1186/s13046-019-1093-3,PMID:30755242.
|
| [27] |
Liu H, Zhang Z, Huang Y, Wei W, Ning S, Li J, et al. Plasma HSP90AA1 Predicts the Risk of Breast Cancer Onset and Distant Metastasis. Front Cell Dev Biol 2021;9:639596. doi:10.3389/fcell.2021.639596,PMID:34109171.
|
| [28] |
Shi W, Feng L, Dong S, Ning Z, Hua Y, Liu L, et al. FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1. Cell Commun Signal 2020; 18(1):100. doi:10.1186/s12964-020-00604-y,PMID:32576198.
|
| [29] |
Du C, Davis JS, Chen C, Li Z, Cao Y, Sun H, et al. FGF2/FGFR signaling promotes cumulus-oocyte complex maturation in vitro. Reproduction 2021; 161(2):205-214. doi:10.1530/REP-20-0264,PMID:33434172.
|
| [30] |
Zhang J, Liu Z, Li Y, You Q, Yang J, Jin Y, et al. FGF2: a key regula-tor augmenting tendon-to-bone healing and cartilage repair. Re-gen Med 2020; 15(9):2129-2142. doi:10.2217/rme-2019-0080,PMID:33201773.
|
| [31] |
Jung D, Shin S, Kang SM, Jung I, Ryu S, Noh S, et al. Reprogramming of T cell-derived small extracellular vesicles using IL2 surface engi-neering induces potent anti-cancer effects through miRNA delivery. J Extracell Vesicles 2022; 11(12):e12287. doi:10.1002/jev2.12287,PMID:36447429.
|
| [32] |
Abbas AK, Trotta E, R Simeonov D, Marson A, Bluestone JA. Revisiting IL-2: Biology and therapeutic prospects. Sci Immunol 2018; 3(25):eaat1482. doi:10.1126/sciimmunol.aat1482,PMID:29980618.
|
| [33] |
Yang X, Liao HY, Zhang HH. Roles of MET in human cancer. Clin Chim Acta 2022; 525:69-83. doi:10.1016/j.cca.2021.12.017,PMID:34951962.
|
| [34] |
Dong Y, Xu J, Sun B, Wang J, Wang Z. MET-Targeted Therapies and Clinical Outcomes: A Systematic Literature Review. Mol Diagn Ther 2022; 26(2):203-227. doi:10.1007/s40291-021-00568-w,PMID:35266116.
|
| [35] |
Warren CFA, Wong-Brown MW, Bowden NA. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis 2019; 10(3):177. doi:10.1038/s41419-019-1407-6,PMID:30792387.
|
| [36] |
Xu J, Guo Z, Yuan S, Li H. BCL2L 1 is identified as a target of nar-ingenin in regulating ovarian cancer progression. Mol Cell Bio-chem 2022; 477(5):1541-1553. doi:10.1007/s11010-022-04389-1,PMID:35184257.
|
| [37] |
Cornelissen F, Aparicio Domingo P, Reijmers RM, Cupedo T. Activation and effector functions of human RORC+ innate lymphoid cells. Curr Opin Immunol 2011; 23(3):361-367. doi:10.1016/j.coi.2011.03.002,PMID:21561752.
|
| [38] |
Michelini S, Ricci M, Serrani R, Stuppia L, Beccari T, Veselenyiova D, et al. Possible Role of the RORC Gene in Primary and Secondary Lymphedema: Review of the Literature and Genetic Study of Two Rare Causative Variants. Lymphat Res Biol 2021; 19(2):129-133. doi:10.1089/lrb.2020.0030,PMID:32960152.
|
| [39] |
Xu W, Yang Z, Lu N.A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr 2015; 9(4):317-324. doi:10.1080/19336918.2015.1016686,PMID:26241004.
|
| [40] |
Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and op-portunities. Nat Rev Drug Discov 2014; 13(2):140-156. doi:10.1038/nrd4204,PMID:24481312.
|
| [41] |
Asati V, Mahapatra DK, Bharti SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem 2016; 109:314-341. doi:10.1016/j.ejmech.2016.01.012, PMID:26807863.
|
| [42] |
Sharma A, Mehan S. Targeting PI3K-AKT/mTOR signaling in the pre-vention of autism. Neurochem Int 2021;147:105067. doi:10.1016/j.neuint.2021.105067, PMID:33992742.
|
| [43] |
Chen X, Liu G, Yuan Y, Wu G, Wang S, Yuan L. NEK 7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling. Cell Death Dis 2019; 10(12):906. doi:10.1038/s41419-019-2157-1,PMID:31787755.
|
| [44] |
Lu Y, Li X, Liu S, Zhang Y, Zhang D. Toll-like Receptors and Inflamma-tory Bowel Disease. Front Immunol 2018;9:72. doi:10.3389/fim-mu.2018.00072,PMID:29441063.
|
| [45] |
Wallace KL, Zheng LB, Kanazawa Y, Shih DQ. Immunopathology of in-flammatory bowel disease. World J Gastroenterol 2014; 20(1):6-21. doi:10.3748/wjg.v20.i1.6,PMID:24415853.
|
| [46] |
Yan JB, Luo MM, Chen ZY, He BH. The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease. J Immunol Res 2020; 2020:8813558. doi:10.1155/2020/8813558,PMID:33381606.
|
| [47] |
Xie Z, Wang Y, Yang G, Han J, Zhu L, Li L, et al. The role of the Hippo path-way in the pathogenesis of inflammatory bowel disease. Cell Death Dis 2021; 12(1):79. doi:10.1038/s41419-021-03395-3,PMID:33436549.
|