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Study of the therapeutic mechanism of Zuojin Pill about functional dyspepsia through network pharmacology research

네트워크 약리학 연구를 통한 좌금환의 기능성 소화불량증 치료기전 연구

  • Ju eun Lee (Department of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University) ;
  • Na Ri Choi (Department of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University) ;
  • Seung Hyeon Koo (Department of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University) ;
  • Woo Gyun Choi (Department of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University) ;
  • Byung Joo Kim (Department of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University)
  • 이주은 (부산대학교 한의학전문대학원 양생기능의학교실) ;
  • 최나리 (부산대학교 한의학전문대학원 양생기능의학교실) ;
  • 구승현 (부산대학교 한의학전문대학원 양생기능의학교실) ;
  • 최우균 (부산대학교 한의학전문대학원 양생기능의학교실) ;
  • 김병주 (부산대학교 한의학전문대학원 양생기능의학교실)
  • Received : 2024.08.10
  • Accepted : 2024.08.19
  • Published : 2024.08.31

Abstract

Objectives : Zuojin Pill, recognized as an effective herbal remedy, has undergone investigation for its potential in alleviating symptoms like indigestion, vomiting, and abdominal distension. The purpose of this study was to investigate the mechanism of digestive function activation through network pharmacology, particularly focused on improving functional dyspepsia. Methods : The two components, Coptidis Rhizoma and Evodiae Fructus, constituting Zuojin Pill were analyzed based on broad information on chemical and pharmacological properties, confirming 40 active compounds and 115 digestive-related molecular targets. Concentration analysis revealed impacts on various pathways related to digestive functions. Results : According to network pharmacological analysis of Zuojin Pill, quercetin and beta-sitosterol were exhibited relatively numerous targets, suggesting their potential significance in the therapeutic activity of Zuojin Pill and by a Protein-Protein Interaction (PPI) network, JUN, RELA, MAPK1, HSP90AA1, TP53, TNF, AKT1, IL6, MAPK14, ESR1, FOS, MYC were identified. Also, berberine exhibited the highest contribution index (92.58%), indicating that this compound may be a major contributor to the digestive activity of Zuojin Pill. Additionally, functional interaction analysis by GeneMANIA indicated that targets of Zuojin Pill could functionally interact through various mechanisms, implying similarities in pharmacological roles. Conclusions : These findings contribute valuable insights into the digestive function activation mechanism and highlight the therapeutic potential of Zuojin Pill in improving functional dyspepsia.

Keywords

Acknowledgement

이 논문은 2021년도 정부(교육부)의 재원으로 한국연구재단의 지원을 받아 수행된 기초연구사업임 (No. 2021R1I1A3042479).

References

  1. Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, Stanghellini V. Functional Gastroduodenal Disorders. Gastroenterology 2006;130:1466-1479. https://doi.org/10.1053/j.gastro.2005.11.059
  2. Ford AC, Marwaha A, Sood R, Moayyedi P. Global Prevalence of, and Risk Factors for Uninvestigated Dyspepsia: A Meta-Analysis. Gut 2015;64:1049-1057.
  3. Brook RA, Kleinman NL, Choung RS, Melkonian AK, Smeeding JE, Talley NJ. Functional Dyspepsia Impact Absenteeism and Direct and Indirect Costs. Clin Gastroenterol Hepatol. 2010;8:498-503. https://doi.org/10.1016/j.cgh.2010.03.003
  4. Talley NJ. Functional Gastrointestinal Disorders as a Public Health Problem. Neurogastroenterol Motil. 2008;20:121-129. https://doi.org/10.1111/j.1365-2982.2008.01097.x
  5. Aro P, Talley NJ, Agreus L, Johansson SE, Bolling-Sternevald E, Storskrubb T, Ronkainen J. Functional Dyspepsia Impairs Quality of Life in the Adult Population: Functional Dyspepsia and Quality of Life. Aliment Pharmacol Ther. 2011;33:1215-1224. https://doi.org/10.1111/j.1365-2036.2011.04640.x
  6. Drossman DA. Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV. Gastroenterology 2016;150:1262-1279. https://doi.org/10.1053/j.gastro.2016.02.032
  7. Otaka M, Jin M, Odashima M, Matsuhashi T, Wada I, Horikawa Y, et al. New Strategy of Therapy for Functional Dyspepsia Using Famotidine, Mosapride and Amitriptyline. Aliment Pharmacol. Ther 2005;21:42-46.
  8. Mertz H, Fass R, Kodner A, Yan-Go F, Fullerton S, Mayer EA. Effect of Amitryptiline on Symptoms, Sleep, and Visceral Perception in Patients With Functional Dyspepsia. Am J Gastroenterol 1998;93:160-165. https://doi.org/10.1111/j.1572-0241.1998.00160.x
  9. Guo W, Huang J, Wang N, Tan HY, Cheung F, Chen F, Feng Y. Integrating Network Pharmacology and Pharmacological Evaluation for Deciphering the Action Mechanism of Herbal Formula Zuojin Pill in Suppressing Hepatocellular Carcinoma. Front Pharmacol. 2019;10:1185.
  10. Li S, Huang M, Wu G, Huang W, Huang Z, Yang X, et al. Efficacy of Chinese Herbal Formula Sini Zuojin Decoction in Treating Gastroesophageal Reflux Disease: Clinical Evidence and Potential Mechanisms. Front Pharmacol. 2020;11:76.
  11. Ma Y, Zhang X, Su Z, Li N, Cao L, Ding G, Wang Z, Xiao W. Insight into the Molecular Mechanism of a Herbal Injection by Integrating Network Pharmacology and in Vitro. J Ethnopharmacol. 2015;173:91-99. https://doi.org/10.1016/j.jep.2015.07.016
  12. Chen Y, Kern TS, Kiser PD, Palczewski K. Eyes on Systems Pharmacology. Pharmacol Res. 2016;114:39-41. https://doi.org/10.1016/j.phrs.2016.09.026
  13. Li S, Zhang B. Traditional Chinese Medicine Network Pharmacology: Theory, Methodology and Application. Chin J Nat Med. 2013;11:110 -120. https://doi.org/10.3724/SP.J.1009.2013.00110
  14. 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.
  15. Wang CK, Craik DJ. Cyclic Peptide Oral Bioavailability: Lessons from the Past. Biopolymers 2016;106:901-909. https://doi.org/10.1002/bip.22878
  16. Li Y, Zhang J, Zhang L, Chen X, Pan Y, Chen SS, et al. Systems Pharmacology to Decipher the Combinational Anti-Migraine Effects of Tianshu Formula. J Ethnopharmacol. 2015;174:45-56. https://doi.org/10.1016/j.jep.2015.07.043
  17. Zhang J, Li Y, Chen X, Pan Y, Zhang S, Wang Y. Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action for Herbal Medicines in Stroke Treatment and Prevention. PLoS ONE 2014;9:e102506.
  18. Lee AY, Park W, Kang TW, Cha MH, Chun JM. Network Pharmacology-Based Prediction of Active Compounds and Molecular Targets in Yijin-Tang Acting on Hyperlipidaemia and Atherosclerosis. J Ethnopharmacol 2018;221:151 -159. https://doi.org/10.1016/j.jep.2018.04.027
  19. Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING Database in 2023: Protein-Protein Association Networks and Functional Enrichment Analyses for Any Sequenced Genome of Interest. Nucleic Acids Res. 2023;51:D638-D646.
  20. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. 2003;13:2498-2504. https://doi.org/10.1101/gr.1239303
  21. Barabasi AL, Oltvai ZN. Network Biology: Understanding the Cell's Functional Organization. Nat Rev Genet. 2004;5:101-113. https://doi.org/10.1038/nrg1272
  22. Yue SJ, Xin LT, Fan YC, Li SJ, Tang YP, Duan JA, Guan HS, Wang CY. Herb Pair Danggui-Honghua: Mechanisms Underlying Blood Stasis Syndrome by System Pharmacology Approach. Sci Rep. 2017;7:40318.
  23. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, Vilo J. G:Profiler: A Web Server for Functional Enrichment Analysis and Conversions of Gene Lists (2019 Update). Nucleic Acids Res. 2019;47: W191-W198. https://doi.org/10.1093/nar/gkz369
  24. Kanehisa M. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 2000;28:27-30. https://doi.org/10.1093/nar/28.1.27
  25. Montojo J, Zuberi K, Rodriguez H, Bader GD, Morris Q. GeneMANIA: Fast Gene Network Construction and Function Prediction for Cytoscape. F1000Res. 2014;3:153.
  26. Cho DY, Kim YA, Przytycka TM. Chapter 5: Network Biology Approach to Complex Diseases. PLoS Comput Biol. 2012;8:e1002820.
  27. Jeong H, Mason SP, Barabasi AL, Oltvai ZN. Lethality and Centrality in Protein Networks. Nature 2001;411: 41-42. https://doi.org/10.1038/35075138
  28. Zhu J, Yi X, Zhang Y, Pan Z, Zhong L, Huang P. Systems Pharmacology-Based Approach to Comparatively Study the Independent and Synergistic Mechanisms of Danhong Injection and Naoxintong Capsule in Ischemic Stroke Treatment. eCAM. 2019;2019:1-17. https://doi.org/10.1155/2019/1056708
  29. Zhong J, Liu Z, Zhou X, Xu J. Synergic Anti-Pruritus Mechanisms of Action for the Radix Sophorae Flavescentis and Fructus Cnidii Herbal Pair. Molecules 2017;22:1465.
  30. Wagner EF, Nebreda AR. Signal Integration by JNK and P38 MAPK Pathways in Cancer Development. Nat Rev Cancer 2009;9:537-549. https://doi.org/10.1038/nrc2694
  31. Ramos Pittol JM, Oruba A, Mittler G, Saccani S, Van Essen D. Zbtb7a Is a Transducer for the Control of Promoter Accessibility by NF-Kappa B and Multiple Other Transcription Factors. PLoS Biol 2018;16: e2004526.
  32. Xiang DC, Yang JY, Xu YJ, Zhang S, Li M, Zhu C, Zhang CL, Liu D. Protective Effect of Andrographolide on 5-Fu Induced Intestinal Mucositis by Regulating P38 MAPK Signaling Pathway. Life Sciences 2020;252: 117612.
  33. Zhang M, Wang D, Lu F, Zhao R, Ye X, He L, Ai L, Wu C. Identification of the Active Substances and Mechanisms of Ginger for the Treatment of Colon Cancer Based on Network Pharmacology and Molecular Docking. BioData Min. 2021;14:1.
  34. Zhang S, Mo Z, Zhang S, Li, X. A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia Annua on the Treatment of Hepatocellular Carcinoma. eCAM. 2021;2021:1-9. https://doi.org/10.1155/2021/8947304
  35. Zhang S, Zhou J, Gober HJ, Leung WT, Wang L. Effect and Mechanism of Berberine against Polycystic Ovary Syndrome. Biomed Pharmacother. 2021;138:111468.
  36. Chattopadhyay I, Ambati R, Gundamaraju R. Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer. Mediators Inflamm. 2021;2021:1-13. https://doi.org/10.1155/2021/9918379
  37. Plata-Salaman CR. Cytokines and Feeding. Physiology 1998;13:298-304. https://doi.org/10.1152/physiologyonline.1998.13.6.298
  38. Cannon JG. Inflammatory Cytokines in Nonpathological States. Physiology 2000;15:298 -303. https://doi.org/10.1152/physiologyonline.2000.15.6.298
  39. Dantzer R. Cytokine-Induced Sickness Behavior: Mechanisms and Implications. Ann N Y Acad Sci. 2001; 933:222-234. https://doi.org/10.1111/j.1749-6632.2001.tb05827.x
  40. Ronnstrand L. Signal Transduction via the Stem Cell Factor Receptor/c-Kit. Cell. Mol Life Sci. 2004;61: 2535-2548. https://doi.org/10.1007/s00018-004-4189-6
  41. Beg Ml, Abdullah N, Thowfeik FS, Altorki NK, McGraw TE. Distinct Akt Phosphorylation States Are Required for Insulin Regulated Glut4 and Glut1-Mediated Glucose Uptake. eLife. 2017;6:e26896.
  42. Wang Y, Wang X, Jiang K, Yang K, Ling J. Network Pharmacology and Experimental Studies for Deciphering the Molecular Targets and Mechanisms of Chaihu Shugan Powder in the Treatment of Functional Dyspepsia. Technol Health Care. 2023;31:449-462. https://doi.org/10.3233/THC-236039
  43. Li Y, Xu J, Jiang F, Jiang Z, Liu C, Li L, et al. G Protein-coupled Estrogen Receptor Is Involved in Modulating Colonic Motor Function via Nitric Oxide Release in C57 BL /6 Female Mice. Neurogastroenterol Motil. 2016;28:432-442. https://doi.org/10.1111/nmo.12743
  44. Yue SJ, Liu J, Feng WW, Zhang FL, Chen JX, Xin LT, et al. System Pharmacology-Based Dissection of the Synergistic Mechanism of Huangqi and Huanglian for Diabetes Mellitus. Front Pharmacol. 2017;8:694.
  45. Wei Y, Ren S, Wang R, Jing M, Liu H, Wang M, Song H, Zhao Y. Based on Network Pharmacology to Explore the Potential Bioactive Compounds and Mechanisms of Zuojin Pill for the Treatment of Ulcerative Colitis. eCAM. 2021;2021:1-12. https://doi.org/10.1155/2021/7567025
  46. Liu Y, Cao Q, Ren S, Li X. Network Pharmacology and Molecular Docking to Explore the Pharmacological Mechanism of the Zuojin Pill in Treating CAG. J Biol Regul Homeost Agents. 2023;37:5653-5668.
  47. Wang QS, Cui YL, Dong TJ, Zhang XF, Lin KM. Ethanol Extract from a Chinese Herbal Formula, "Zuojin Pill", Inhibit the Expression of Inflammatory Mediators in Lipopolysaccharide-Stimulated RAW 264.7 Mouse Macrophages. J Ethnopharmacol. 2012;141:377-385. https://doi.org/10.1016/j.jep.2012.02.049
  48. Wen J, Wu S, Ma X, Zhao Y. Zuojin Pill Attenuates Helicobacter Pylori-Induced Chronic Atrophic Gastritis in Rats and Improves Gastric Epithelial Cells Function in GES-1 Cells. J Ethnopharmacol. 2022;285:114855.
  49. Page AJ, Li H. Meal-Sensing Signaling Pathways in Functional Dyspepsia. Front Syst Neurosci. 2018;12:10.
  50. Browning KN. Stress-induced Modulation of Vagal Afferents. Neurogastroenterol Motil. 2019;31:e13758.
  51. Bielefeldt K, Tuteja A, Nusrat S. Disorders of Gastrointestinal Hypomotility. F1000Res. 2016;5:1897.
  52. Gracie DJ, Hamlin PJ, Ford AC. The Influence of the Brain-Gut Axis in Inflammatory Bowel Disease and Possible Implications for Treatment. Lancet Gastroenterol Hepatol. 2019;4:632-642. https://doi.org/10.1016/S2468-1253(19)30089-5
  53. Fakhre-Yaseri H, Baradaran-Moghaddam A, Shekaraby M, Baradaran HR, Soltani-Arabshahi SK. Evaluating the Relationship between Serum Immunoglobulin G (IgG) and A (IgA) Anti-CagA Antibody and the cagA Gene in Patients with Dyspepsia. Iran J Microbiol. 2017;9:97-102.
  54. Fischbach W, Malfertheiner P. Helicobacter Pylori Infection. Dtsch Arztebl Int. 2018;115:429-436. https://doi.org/10.3238/arztebl.2018.0429
  55. Wang D, Zhang J, Yang D, Wang J, Li J, Han Y, Kang Z, Zhang H. Electroacupuncture Restores Intestinal Mucosal Barrier through TLR4/NF-κB P65 Pathway in Functional Dyspepsia-like Rats. Anat Rec. (Hoboken) 2023;306:2927-2938. https://doi.org/10.1002/ar.24800
  56. Squecco R, Garella R, Idrizaj E, Nistri S, Francini F, Baccari MC. Relaxin Affects Smooth Muscle Biophysical Properties and Mechanical Activity of the Female Mouse Colon. Endocrinology. 2015;156:4398-4410. https://doi.org/10.1210/en.2015-1428
  57. Chumpitazi BP, Kearns GL, Shulman RJ. Review Article: The Physiological Effects and Safety of Peppermint Oil and Its Efficacy in Irritable Bowel Syndrome and Other Functional Disorders. Aliment Pharmacol Ther. 2018;47:738-752. https://doi.org/10.1111/apt.14519
  58. Oustamanolakis P, Tack J. Dyspepsia: Organic Versus Functional. J Clin Gastroenterol 2012;46:175-190. https://doi.org/10.1097/MCG.0b013e318241b335
  59. Wang J, Gu S, Qin B. Overexpression of microRNA-211 in Functional Dyspepsia via Downregulation of the Glial Cell Line-Derived Neurotrophic Factor (GDNF) by Increasing Phosphorylation of P38 MAPK Pathway. Can J Gastroenterol Hepatol. 2022;2022:1-10. https://doi.org/10.1155/2022/9394381
  60. Porter CK, Choi D, Cash B, Pimentel M, Murray J, May L, Riddle MS. Pathogen-Specific Risk of Chronic Gastrointestinal Disorders Following Bacterial Causes of Foodborne Illness. BMC Gastroenterol. 2013;13:46.
  61. Teschke R, Wolff A, Frenzel C, Eickhoff A, Schulze J. Herbal Traditional Chinese Medicine and Its Evidence Base in Gastrointestinal Disorders. World J Gastroenterol. 2015;21:4466 -4490. https://doi.org/10.3748/wjg.v21.i15.4466
  62. Thumann TA, Pferschy-Wenzig EM, Moissl-Eichinger C, Bauer R. The Role of Gut Microbiota for the Activity of Medicinal Plants Traditionally Used in the European Union for Gastrointestinal Disorders. J Ethnopharmacol. 2019;245:112153.
  63. Azimi M, Zahedi MJ. Persian Herbal Medicine in Functional Dyspepsia: A Systematic Review. Curr Drug Discov Technol. 2021;18:272-281. https://doi.org/10.2174/1570163817666200611132831
  64. Mahady GB, Pendland SL, Stoia A, Hamill FA, Fabricant D, Dietz BM, Chadwick LR. In Vitro Susceptibility ofHelicobacter Pylori to Botanical Extracts Used Traditionally for the Treatment of Gastrointestinal Disorders. Phytother Res. 2005;19:988-991. https://doi.org/10.1002/ptr.1776
  65. Wang K, Miao X, Kong F, Huang S, Mo J, Jin C, Zheng Y. Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment. Drug Des Devel Ther. 2021;15:3749-3764. https://doi.org/10.2147/DDDT.S323360
  66. Zhang J, Liu J, Zhu S, Fang Y, Wang B, Jia Q, et al. Berberine Alleviates Visceral Hypersensitivity in Rats by Altering Gut Microbiome and Suppressing Spinal Microglial Activation. Acta Pharmacol Sin 2021;42:1821-1833. https://doi.org/10.1038/s41401-020-00601-4
  67. Tang SM, Deng XT, Zhou J, Li QP, Ge XX, Miao L. Pharmacological Basis and New Insights of Quercetin Action in Respect to Its Anti-Cancer Effects. Biomed Pharmacother. 2020;121:109604.
  68. Modzelewska B, Drygalski K, Kleszczewski T, Chomentowski A, Korycinski K, Kielczewska A, Pawluszewicz P, Razak Hady H. Quercetin Relaxes Human Gastric Smooth Muscles Directly through ATP-sensitive Potassium Channels and Not Depending on the Nitric Oxide Pathway. Neurogastroenterol Motil. 2021;33:e14093.
  69. 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. eCAM. 2021;2021:1-10. https://doi.org/10.1155/2021/1386078
  70. Zhu L, Zhang L, Zhang J, Chang G, Liu G, Yu D, Yu X, Zhao M, Ye B. Evodiamine Inhibits High-Fat Diet-Induced Colitis-Associated Cancer in Mice through Regulating the Gut Microbiota. J Integr Med. 2021;19: 56-65. https://doi.org/10.1016/j.joim.2020.11.001
  71. Wang L, Hu CP, Deng PY, Shen SS, Zhu HQ, Ding JS, Tan GS, Li YJ. The Protective Effects of Rutaecarpine on Gastric Mucosa Injury in Rats. Planta med. 2005;71:416-419. https://doi.org/10.1055/s-2005-864135
  72. Tan L, Li C, Chen H, Mo Z, Zhou J, Liu Y, et al. Epiberberine, a Natural Protoberberine Alkaloid, Inhibits Urease of Helicobacter Pylori and Jack Bean: Susceptibility and Mechanism. Eur J Pharm Sci. 2017;110:77-86. https://doi.org/10.1016/j.ejps.2017.02.004
  73. Tang Q, Ma Z, Tang X, Liu Y, Wu H, Peng Y, et al. Coptisine Inhibits Helicobacter Pylori and Reduces the Expression of CagA to Alleviate Host Inflammation in Vitro and in Vivo. J Ethnopharmacol. 2023;314:116618.
  74. Shah D, Makharia GK, Ghoshal UC, Varma S, Ahuja V, Hutfless S. Burden of Gastrointestinal and Liver Diseases in India, 1990-2016. Indian J Gastroenterol. 2018;37:439-445. https://doi.org/10.1007/s12664-018-0892-3
  75. Shin CM, Huh KC. Diagnosis and treatment of functional dyspepsia. J Korean Med Assoc. 2016;59:311.