Exploring mechanism of Fuling Gancao decoction against functional dyspepsia using network pharmacology, molecular docking, and molecular dynamics simulation
Abstract
Fuling Gancao Decoction (FGD) has been a typical formula for treating functional dyspepsia (FD) in China. Network pharmacology, molecular docking, and molecular dynamics simulation are applied to shed light on the comprehensive mechanisms of FGD against FD. The results showed that there were two core compounds (quercetin and kaempferol) and 16 crucial targets (KT1, SRC, EGFR, HRAS, and PIK3R1, etc.) of FGD against FD. Furthermore, 60 signaling pathways were modulated by the core targets, which contained estrogen signaling pathway, prolactin signaling pathway, cancer pathway, etc. The molecular docking analysis showed that quercetin and kaempferol had excellent binding affinity with the core targets. Molecular dynamic simulations indicated that quercetin-MAPK8 and kaempferol-AKT1 show favorable stability. The study successfully screened components, targets, and signaling pathways of FGD against FD, which provided a theoretical basis for further clinical application.
References
1. Ford AC, Mahadeva S, Carbone MF, et al. Functional dyspepsia. Functional Gastrointestinal Disorders. 2020; 396(10263):1689-1702. doi: 10.1016/S0140-6736(20)30469-4
2. Mounsey A, Barzin A, Rietz A. Functional Dyspepsia: Evaluation and Management. Am Fam Physician. 2020; 101(2): 84-88.
3. Talley NJ. Functional Dyspepsia: Advances in Diagnosis and Therapy. Gut and Liver. 2017; 11(3): 349-357. doi: 10.5009/gnl16055
4. Ford AC. Aetiopathogenesis of functional dyspepsia. Gut. 2015; 64(7): 1182-1183. doi: 10.1136/gutjnl-2014-308959
5. Ronkainen J, Aro P, Walker MM, et al. Duodenal eosinophilia is associated with functional dyspepsia and new onset gastro‐oesophageal reflux disease. Alimentary Pharmacology & Therapeutics. 2019; 50(1): 24-32. doi: 10.1111/apt.15308
6. Talley NJ, Walker MM, Holtmann G. Functional dyspepsia. Current Opinion in Gastroenterology. 2016; 32(6): 467-473. doi: 10.1097/mog.0000000000000306
7. Talley NJ. Functional dyspepsia: new insights into pathogenesis and therapy. The Korean Journal of Internal Medicine. 2016; 31(3): 444-456. doi: 10.3904/kjim.2016.091
8. Vandenberghe A, Schol J, Van den Houte K, et al. Current and emerging therapeutic options for the management of functional dyspepsia. Expert Opinion on Pharmacotherapy. 2020; 21(3): 365-376. doi: 10.1080/14656566.2019.1707805
9. Gwee K, Holtmann G, Tack J, et al. Herbal medicines in functional dyspepsia—Untapped opportunities not without risks. Neurogastroenterology & Motility. 2020; 33(2). doi: 10.1111/nmo.14044
10. Asha MK, Debraj D, Dethe S, et al. Effect of Flavonoid-Rich Extract of Glycyrrhiza glabraon Gut-Friendly Microorganisms, Commercial Probiotic Preparations, and Digestive Enzymes. Journal of Dietary Supplements. 2016; 14(3): 323-333. doi: 10.1080/19390211.2016.1223257
11. Azimi M, Zahedi MJ. Persian Herbal Medicine in Functional Dyspepsia: A Systematic Review. Current Drug Discovery Technologies. 2021; 18(2): 272-281. doi: 10.2174/1570163817666200611132831
12. Murugan S, Velusami CC, Bethapudi B, et al. Effect of Flavonoid Rich Root Extract of Glycyrrhizaglabra on Gastric Emptying and Gastrointestinal Transit in Albino Wistar Rats. SOJ Pharmacy & Pharmaceutical Sciences. 2017; 4(2): 1-4. doi: 10.15226/2374-6866/4/2/00159
13. Muhammad JS, Zaidi SF, Shaharyar S, et al. Anti-inflammatory Effect of Cinnamaldehyde in Helicobacter pylori Induced Gastric Inflammation. Biological and Pharmaceutical Bulletin. 2015; 38(1): 109-115. doi: 10.1248/bpb.b14-00609
14. Ebrahimzadeh Attari V, Somi MH, Asghari Jafarabadi M, et al. The Gastro-protective Effect of Ginger (Zingiber officinale Roscoe) in Helicobacter pylori Positive Functional Dyspepsia. Advanced Pharmaceutical Bulletin. 2019; 9(2): 321-324. doi: 10.15171/apb.2019.038
15. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database. https://old.tcmsp-e.com/tcmsp.php
16. PubChem. https://pubchem.ncbi.nlm.nih.gov/
17. PharmMapper. https://www.lilab-ecust.cn/pharmmapper/
18. Swiss Target Prediction. http://www.swisstargetprediction.ch/
19. Shi R, Chen D, Ji M, et al. Network pharmacology-based screening of the active ingredients and mechanisms of Cymbaria daurica against diabetes mellitus. Food Science and Human Wellness. 2023; 12(6): 2001-2013. doi: 10.1016/j.fshw.2023.03.022
20. Li T, Li Y, Chen J, et al. Hyperibone J exerts antidepressant effects by targeting ADK to inhibit microglial P2X7R/TLR4-mediated neuroinflammation. Journal of Advanced Research; 2024. doi: 10.1016/j.jare.2024.07.015
21. GeneCards. https://www.genecards.org/
22. UniProt. https://www.uniprot.org/
23. OmicShare. https://www.omicshare.com/
24. String. https://cn.string-db.org/
25. Guo MF, Dai YJ, Gao JR, et al. Uncovering the Mechanism of Astragalus membranaceus in the Treatment of Diabetic Nephropathy Based on Network Pharmacology. Journal of Diabetes Research. 2020; 2020: 1-13. doi: 10.1155/2020/5947304
26. Database for Annotation, Visualization, and Integrated Discovery. https://davidbioinformatics.nih.gov/
27. Zhao H, Shan Y, Ma Z, et al. A network pharmacology approach to explore active compounds and pharmacological mechanisms of epimedium for treatment of premature ovarian insufficiency. Drug Design, Development and Therapy. 2019; 13: 2997-3007. doi: 10.2147/dddt.s207823
28. PDB. https://www.rcsb.org/
29. Chen Z, Lin T, Liao X, et al. Network pharmacology based research into the effect and mechanism of Yinchenhao Decoction against Cholangiocarcinoma. Chinese Medicine. 2021; 16(1): 13-32. doi: 10.1186/s13020-021-00423-4
30. Rosen JM. Visceral hypersensitivity and electromechanical dysfunction as therapeutic targets in pediatric functional dyspepsia. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2014; 5(3): 122. doi: 10.4292/wjgpt.v5.i3.122
31. Tack J, Carbone F. Functional dyspepsia and gastroparesis. Current Opinion in Gastroenterology. 2017; 33(6): 446-454. doi: 10.1097/mog.0000000000000393
32. Wauters L, Talley NJ, Walker MM, et al. Novel concepts in the pathophysiology and treatment of functional dyspepsia. Gut. 2019; 69(3): 591-600. doi: 10.1136/gutjnl-2019-318536
33. Smith ML. Functional dyspepsia pathogenesis and therapeutic options—Implications for management. Digestive and Liver Disease. 2005; 37(8): 547-558. doi: 10.1016/j.dld.2005.04.001
34. Schäppi MG, Borrelli O, Knafelz D, et al. Mast Cell–Nerve Interactions in Children With Functional Dyspepsia. Journal of Pediatric Gastroenterology and Nutrition. 2008; 47(4): 472-480. doi: 10.1097/mpg.0b013e318186008e
35. Qin HY, Zang KH, Zuo X, et al. Quercetin Attenuates Visceral Hypersensitivity and 5-Hydroxytryptamine Availability in Postinflammatory Irritable Bowel Syndrome Rats: Role of Enterochromaffin Cells in the Colon. Journal of Medicinal Food. 2019; 22(7): 663-671. doi: 10.1089/jmf.2018.4264
36. Modzelewska B, Drygalski K, Kleszczewski T, et al. Quercetin relaxes human gastric smooth muscles directly through ATP‐sensitive potassium channels and not depending on the nitric oxide pathway. Neurogastroenterology & Motility. 2021; 33(7): 1-13. doi: 10.1111/nmo.14093
37. Chang Y, Wei W, Tong L, et al. Weikangning therapy in functional dyspepsia and the protective role of Nrf2. Experimental and Therapeutic Medicine. 2017; 14(4): 2885-2894. doi: 10.3892/etm.2017.4892
38. Yao X, Mei Y, Mao W. Quercetin Improves Mitochondrial Function and Inflammation in H2O2-Induced Oxidative Stress Damage in the Gastric Mucosal Epithelial Cell by Regulating the PI3K/AKT Signaling Pathway. Yong YK, ed. Evidence-Based Complementary and Alternative Medicine. 2021; 2021: 1-10. doi: 10.1155/2021/1386078
39. Alkushi AGR, Elsawy NAM. Quercetin attenuates, indomethacin-induced acute gastric ulcer in rats. Folia Morphologica. 2017; 76(2): 252-261. doi: 10.5603/fm.a2016.0067
40. Li Q, Hu X, Xuan Y, et al. Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO. Acta Biochimica et Biophysica Sinica. 2018; 50(3): 246-253. doi: 10.1093/abbs/gmy002
41. Shi H, Zhu S, Qin B, et al. Nerve growth factor and Tropomyosin receptor kinase A are increased in the gastric mucosa of patients with functional dyspepsia. BMC Gastroenterology. 2019; 19(1): 221-228. doi: 10.1186/s12876-019-1133-7
42. Winston JH, Sarna SK. Developmental Origins of Functional Dyspepsia-Like Gastric Hypersensitivity in Rats. Gastroenterology. 2013; 144(3): 570-579.e3. doi: 10.1053/j.gastro.2012.11.001
43. Li Q, Winston JH, Sarna SK. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2016; 310(3): R235-R242. doi: 10.1152/ajpregu.00342.2015
44. Chang MJ, Xiao JH, Wang Y, et al. 2, 3, 5, 4′-Tetrahydroxystilbene-2-O-Beta-D-Glucoside Improves Gastrointestinal Motility Disorders in STZ-Induced Diabetic Mice. Tache Y, ed. PLoS ONE. 2012; 7(12): e50291. doi: 10.1371/journal.pone.0050291
45. Song MH, Zhu GJ, Ma L, et al. Comparative analysis of bilirubin in correlation to albumin between nephrotic syndrome patients and postoperative gastroparesis syndrome patients. Genetics and Molecular Research. 2014; 13(4): 9403-9411. doi: 10.4238/2014.february.14.13
46. Wu XF, Chen XL, Zheng XN, et al. Effects of electroacupuncture with different stimulation intensities on gastrointestinal motor function and expression of sinus smooth muscle Ras homologue genome member A/associated coiled-coil protein kinase signaling in diabetic gastroparesis rats (Chinese). Zhen Ci Yan Jiu. 2018; 43(3):169-174. doi: 10.13702/j.1000-0607.170299.
47. Burns M, Muthupalani S, Ge Z, et al. Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice. Boneca IG, ed. PLOS ONE. 2015; 10(11): e0142630. doi: 10.1371/journal.pone.0142630
48. Kinoshita H, Hayakawa Y, Konishi M, et al. Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium. The Journal of Pathology. 2018; 247(1): 35-47. doi: 10.1002/path.5163
49. Mansouri V, Tavirani SR, Zadeh-Esmaeel MM, et al. Comparative study of gastric cancer and chronic gastritis via network analysis. Gastroenterol Hepatol Bed Bench. 2018; 11(4):343-351.
50. Shin KK, Park JG, Hong YH, et al. Anti-Inflammatory Effects of Licania macrocarpa Cuatrec Methanol Extract Target Src- and TAK1-Mediated Pathways. Evidence-Based Complementary and Alternative Medicine. 2019; 2019: 1-13. doi: 10.1155/2019/4873870
51. Tafreshi M, Guan J, Gorrell RJ, et al. Helicobacter pylori Type IV Secretion System and Its Adhesin Subunit, CagL, Mediate Potent Inflammatory Responses in Primary Human Endothelial Cells. Frontiers in Cellular and Infection Microbiology. 2018; 8: 1-15. doi: 10.3389/fcimb.2018.00022
52. Meng X, Zhao Y, Liu J, et al. Comprehensive analysis of histone modification associated genes on differential gene expression and prognosis in gastric cancer. Experimental and Therapeutic Medicine. 2019; 18(3):2219-2230. doi: 10.3892/etm.2019.7808.
53. Wang J, Cui S, Zhang X, et al. High Expression of Heat Shock Protein 90 Is Associated with Tumor Aggressiveness and Poor Prognosis in Patients with Advanced Gastric Cancer. PLOS ONE. 2013; 8(4): e62876. doi: 10.1371/journal.pone.0062876
54. Xu L, Zhou C, Pan R, et al. PTPN11 hypomethylation is associated with gastric cancer progression. Oncology Letters. 2020; 19(3): 1693-1700. doi: 10.3892/ol.2020.11250.
55. Ye B, Duan B, Deng W, et al. EGF Stimulates Rab35 Activation and Gastric Cancer Cell Migration by Regulating DENND1A-Grb2 Complex Formation. Frontiers in Pharmacology. 2018; 9: 1-12. doi: 10.3389/fphar.2018.01343
56. Yu QX. Clinical presentations of gastric small gastrointestinal stromal tumors mimics functional dyspepsia symptoms. World Journal of Gastroenterology. 2014; 20(33): 11800-11807. doi: 10.3748/wjg.v20.i33.11800
57. Cheng X. A Comprehensive Review of HER2 in Cancer Biology and Therapeutics. Genes. 2024; 15(7): 903. doi: 10.3390/genes15070903
58. Chanpong A, Alves MM, Bonora E, et al. Evaluating the molecular and genetic mechanisms underlying gut motility disorders. Expert Review of Gastroenterology & Hepatology. 2023; 17(12): 1301-1312. doi: 10.1080/17474124.2023.2296558
59. Weaver SA, Ward SG. Phosphoinositide 3-kinases in the gut: a link between inflammation and cancer?. Trends Mol Med. 2001; 7(10): 455-462. doi: 10.1016/S1471-4914(01)02107-4
60. Nourshargh S, Alon R. Leukocyte Migration into Inflamed Tissues. Immunity. 2014; 41(5): 694-707. doi: 10.1016/j.immuni.2014.10.008
61. Frysz-Naglak D, Fryc B, Klimacka-Nawrot E, et al. Expression, localization and systemic concentration of vascular endothelial growth factor (VEGF) and its receptors in patients with ulcerative colitis. International Immunopharmacology. 2011; 11(2): 220-225. doi: 10.1016/j.intimp.2010.11.023
62. Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Advances in Protein Chemistry and Structural Biology. 2019; 116:135-170. doi: 10.1016/bs.apcsb.2019.01.001.
63. Tuo B, Wen G, Wei J, et al. Estrogen Regulation of Duodenal Bicarbonate Secretion and Sex-Specific Protection of Human Duodenum. Gastroenterology. 2011; 141(3): 854-863. doi: 10.1053/j.gastro.2011.05.044
64. Nie X, Xie R, Tuo B. Effects of Estrogen on the Gastrointestinal Tract. Digestive Diseases and Sciences. 2018; 63(3): 583-596. doi: 10.1007/s10620-018-4939-1
65. Accarie A, Toth J, Wauters L, et al. Estrogens Play a Critical Role in Stress-Related Gastrointestinal Dysfunction in a Spontaneous Model of Disorders of Gut–Brain Interaction. Cells. 2022; 11(7): 1214. doi: 10.3390/cells11071214
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