Network Pharmacology and Molecular Docking Validation to Explore the Pharmacological Mechanism of Zhuling Decoction against Nephrotic Syndrome


Cite item

Full Text

Abstract

Background:In recent years, the incidence and prevalence of Nephrotic Syndrome (NS) have been increasing. Zhuling decoction (ZLD), a classical Chinese medicine, has been clinically proven to be effective for the treatment of NS. However, its underlying mechanism and pharmacodynamic substances remain unclear.

Objective:This study aimed to explore the mechanism of action and chemical components of ZLD against NS using network pharmacology and molecular docking.

Methods:Traditional Chinese Medicine Systems Pharmacology (TCMSP), Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicines (BATMAN-TCM), and SwissTargetPrediction databases were used to screen the principal ingredients and the associated targets of ZLD. NS-related targets were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, Therapeutic Target Database (TTD), and Drugbank databases. Shared targets were derived by the intersection of ZLD- and NS-associated targets. Protein-interaction relationships were analyzed using the STRING database and Cytoscape. A visualized drug-active compound-target network of ZLD was established using Cytoscape. Analyses of gene enrichment were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Molecular docking was performed to assess the binding activity between active components and hub targets.

Results:Polyporusterone E, cerevisterol, alisol B, and alisol B 23-acetate were the primary potential ingredients of ZLD. HMGCR, HSD11B1, NOS2, NR3C1, and NR3C2 were the hub targets of ZLD against NS. Molecular docking showed that polyporusterone E, cerevisterol, and alisol B had high binding activities with targets HMGCR, HSD11B1, and NOS2.

Conclusion:In summary, this study suggests that the main active compounds (polyporusterone E, cerevisterol, alisol B) may have important roles for ZLD acting against NS by binding to hub targets (HMGCR, HSD11B1, and NOS2) and modulating PI3K-Akt, Ras, MAPK, and HIF-1 signaling pathways.

About the authors

Su Su

Department of Pharmacy, Xuanwu Hospital, Capital Medical University,

Email: info@benthamscience.net

Qingxia Zhang

Department of Pharmacy, Xuanwu Hospital,, Capital Medical University

Email: info@benthamscience.net

Lan Zhang

Department of Pharmacy, Xuanwu Hospital, Capital Medical University

Author for correspondence.
Email: info@benthamscience.net

Na Chen

Department of Pharmacy, Xuanwu Hospital,, Capital Medical University,

Email: info@benthamscience.net

Yanqi Chu

Department of Pharmacy, Xuanwu Hospital, Capital Medical University

Email: info@benthamscience.net

References

  1. Zabala Ramirez MJ, Stein EJ, Jain K. Nephrotic syndrome for the internist. Med Clin North Am 2023; 107(4): 727-37. doi: 10.1016/j.mcna.2023.03.006 PMID: 37258010
  2. Mattoo TK, Sanjad S. Current understanding of nephrotic syndrome in children. Pediatr Clin North Am 2022; 69(6): 1079-98. doi: 10.1016/j.pcl.2022.08.002 PMID: 36880923
  3. Chemli J, Harbi A. Treatment of steroid-resistant idiopathic nephrotic syndrome. Arch Pediatr 2009; 16(3): 260-8. doi: 10.1016/j.arcped.2008.11.018 PMID: 19195856
  4. Boyer O, Schaefer F, Haffner D, et al. Management of congenital nephrotic syndrome: Consensus recommendations of the ERKNet-ESPN Working Group. Nat Rev Nephrol 2021; 17(4): 277-89. doi: 10.1038/s41581-020-00384-1 PMID: 33514942
  5. Zhao J, Liu Z. Treatment of nephrotic syndrome: Going beyond immunosuppressive therapy. Pediatr Nephrol 2020; 35(4): 569-79. doi: 10.1007/s00467-019-04225-7 PMID: 30904930
  6. Wang XQ, Wang L, Tu YC, Zhang YC. Traditional Chinese medicine for refractory nephrotic syndrome: Strategies and promising treatments. Evid Based Complement Alternat Med 2018; 2018: 1-11. doi: 10.1155/2018/8746349 PMID: 29507594
  7. Wu H, Zhang L, Liu Q, Ren B, Li J. Clinical efficacy of adjuvant treatment of primary nephrotic syndrome in pediatric patients with Chinese medicine. J Healthc Eng 2022; 2022: 1-5. doi: 10.1155/2022/1516633 PMID: 35126899
  8. Chen N, Guo JX, Chu YQ, Gong LL, Zhang L. Historical evolution and clinical application of classical prescription Zhulingtang. Zhongguo Shiyan Fangjixue Zazhi 2023; 29: 146-55.
  9. Zhuang XY, Lv J. Research rogress in the treatment of renal diseases with Zhuling decoction. J China Prescription Drug 2022; 20(05): 152-4.
  10. Wang ZY, Feng DJ. Research progress on the diagnosis and treatment of Zhuling decoction. Zhongguo Zhongyiyao Xiandai Yuancheng Jiaoyu 2017; 15(03): 143-5.
  11. Li L. Clinical study on modified Zhuling decoction in the treatment of pediatric nephrotic syndrome. Asian Tradit Med 2022; 18(02): 140-3.
  12. Zhao YY. Traditional uses, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus (Pers.) Fries: A review. J Ethnopharmacol 2013; 149(1): 35-48. doi: 10.1016/j.jep.2013.06.031 PMID: 23811047
  13. Nie A, Chao Y, Zhang X, Jia W, Zhou Z, Zhu C. Phytochemistry and pharmacological activities of Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb. Front Pharmacol 2020; 11: 505249. doi: 10.3389/fphar.2020.505249 PMID: 33071776
  14. Liu Y, Zhou S, Huang X, Rehman HM. Mechanistic insight of the potential of geraniol against Alzheimer’s disease. Eur J Med Res 2022; 27(1): 93. doi: 10.1186/s40001-022-00699-8 PMID: 35701806
  15. Qin T, Wu L, Hua Q, Song Z, Pan Y, Liu T. Prediction of the mechanisms of action of Shenkang in chronic kidney disease: A network pharmacology study and experimental validation. J Ethnopharmacol 2020; 246: 112128. doi: 10.1016/j.jep.2019.112128 PMID: 31386888
  16. Tiwari P, Ali SA, Puri B, Kumar A, Datusalia AK. Tinospora cordifolia Miers enhances the immune response in mice immunized with JEV-vaccine: A network pharmacology and experimental approach. Phytomedicine 2023; 119: 154976. doi: 10.1016/j.phymed.2023.154976 PMID: 37573808
  17. Zhang W, Huai Y, Miao Z, Qian A, Wang Y. Systems pharmacology for investigation of the mechanisms of action of traditional Chinese medicine in drug discovery. Front Pharmacol 2019; 10: 743. doi: 10.3389/fphar.2019.00743 PMID: 31379563
  18. Zhao L, Zhang H, Li N, et al. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol 2023; 309: 116306. doi: 10.1016/j.jep.2023.116306 PMID: 36858276
  19. Poornima P, Kumar JD, Zhao Q, Blunder M, Efferth T. Network pharmacology of cancer: From understanding of complex interactomes to the design of multi-target specific therapeutics from nature. Pharmacol Res 2016; 111: 290-302. doi: 10.1016/j.phrs.2016.06.018 PMID: 27329331
  20. Zhou Z, Chen B, Chen S, et al. Applications of network pharmacology in traditional Chinese medicine research. Evid Based Complement Alternat Med 2020; 2020: 1-7. doi: 10.1155/2020/1646905 PMID: 32148533
  21. Li X, Liu Z, Liao J, Chen Q, Lu X, Fan X. Network pharmacology approaches for research of traditional Chinese medicines. Chin J Nat Med 2023; 21(5): 323-32. doi: 10.1016/S1875-5364(23)60429-7 PMID: 37245871
  22. Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: Methods and applications. Nat Rev Drug Discov 2004; 3(11): 935-49. doi: 10.1038/nrd1549 PMID: 15520816
  23. Ferreira L, dos Santos R, Oliva G, Andricopulo A. Molecular docking and structure-based drug design strategies. Molecules 2015; 20(7): 13384-421. doi: 10.3390/molecules200713384 PMID: 26205061
  24. Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13. doi: 10.1186/1758-2946-6-13 PMID: 24735618
  25. Liu Z, Guo F, Wang Y, et al. BATMAN-TCM: A bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine. Sci Rep 2016; 6(1): 21146. doi: 10.1038/srep21146 PMID: 26879404
  26. Ahmed SSSJ, Ramakrishnan V. Systems biological approach of molecular descriptors connectivity: Optimal descriptors for oral bioavailability prediction. PLoS One 2012; 7(7): e40654. doi: 10.1371/journal.pone.0040654 PMID: 22815781
  27. Kim S, Chen J, Cheng T, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021; 49(D1): D1388-95. doi: 10.1093/nar/gkaa971 PMID: 33151290
  28. 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): W357-64. doi: 10.1093/nar/gkz382 PMID: 31106366
  29. Bateman A, Martin M-J, Orchard S, et al. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res 2021; 49(D1): D480-9. doi: 10.1093/nar/gkaa1100 PMID: 33237286
  30. Amberger JS, Hamosh A. Searching Online Mendelian Inheritance in Man (OMIM): A knowledgebase of human genes and genetic phenotypes. Curr Protoc Bioinformatics 2017; 58: 1.2.1-1.2.12.
  31. Stelzer G, Rosen N, Plaschkes I, 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.
  32. Zhou Y, Zhang Y, Zhao D, et al. TTD: Therapeutic target database describing target druggability information. Nucleic Acids Res 2024; 52(D1): D1465-77. doi: 10.1093/nar/gkad751 PMID: 37713619
  33. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res 2018; 46(D1): D1074-82. doi: 10.1093/nar/gkx1037 PMID: 29126136
  34. Szklarczyk D, Kirsch R, Koutrouli M, 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(D1): D638-46. doi: 10.1093/nar/gkac1000 PMID: 36370105
  35. Suratanee A, Plaimas K. Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions. PLoS One 2018; 13(6): e0199435. doi: 10.1371/journal.pone.0199435 PMID: 29949603
  36. Sherman BT, Huang DW, Tan Q, et al. DAVID Knowledgebase: A gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics 2007; 8(1): 426. doi: 10.1186/1471-2105-8-426 PMID: 17980028
  37. Nguyen NT, Nguyen TH, Pham TNH, et al. Autodock Vina adopts more accurate binding poses but Autodock4 forms better binding affinity. J Chem Inf Model 2020; 60(1): 204-11. doi: 10.1021/acs.jcim.9b00778 PMID: 31887035
  38. Gaillard T. Evaluation of AutoDock and AutoDock Vina on the CASF-2013 Benchmark. J Chem Inf Model 2018; 58(8): 1697-706. doi: 10.1021/acs.jcim.8b00312 PMID: 29989806
  39. Bagga A, Sinha A. Individualizing treatment of steroid-resistant nephrotic syndrome: registries to the fore. Clin J Am Soc Nephrol 2020; 15(7): 920-2. doi: 10.2215/CJN.08080520 PMID: 32601094
  40. Marahatha R, Gyawali K, Sharma K, et al. Pharmacologic activities of phytosteroids in inflammatory diseases: Mechanism of action and therapeutic potentials. Phytother Res 2021; 35(9): 5103-24. doi: 10.1002/ptr.7138 PMID: 33957012
  41. Alam MB, Chowdhury NS, Sohrab MH, Rana MS, Hasan CM, Lee SH. Cerevisterol alleviates inflammation via suppression of MAPK/NF-κB/AP-1 and activation of the Nrf2/HO-1 signaling cascade. Biomolecules 2020; 10(2): 199. doi: 10.3390/biom10020199
  42. Long H, Qiu X, Cao L, Han R. Discovery of the signal pathways and major bioactive compounds responsible for the anti-hypoxia effect of Chinese cordyceps. J Ethnopharmacol 2021; 277: 114215. doi: 10.1016/j.jep.2021.114215 PMID: 34033902
  43. Shu Z, Pu J, Chen L, et al. Alisma orientale: Ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. Am J Chin Med 2016; 44(2): 227-51. doi: 10.1142/S0192415X16500142 PMID: 27080939
  44. Zhang J, Luan ZL, Huo XK, et al. Direct targeting of sEH with alisol B alleviated the apoptosis, inflammation, and oxidative stress in cisplatin-induced acute kidney injury. Int J Biol Sci 2023; 19(1): 294-310. doi: 10.7150/ijbs.78097 PMID: 36594097
  45. Yang L, Li L, Lu Q, et al. Alisol B blocks the development of HFD-induced obesity by triggering the LKB1-AMPK signaling in subcutaneous adipose tissue. Eur J Pharmacol 2023; 956: 175942. doi: 10.1016/j.ejphar.2023.175942 PMID: 37536624
  46. Chen H, Wang MC, Chen YY, et al. Alisol B 23-acetate attenuates CKD progression by regulating the renin–angiotensin system and gut–kidney axis. Ther Adv Chronic Dis 2020; 11 doi: 10.1177/2040622320920025 PMID: 32547719
  47. Luan ZL, Ming WH, Sun XW, et al. A naturally occurring FXR agonist, alisol B 23-acetate, protects against renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2021; 321(5): F617-28. doi: 10.1152/ajprenal.00193.2021 PMID: 34569253
  48. Xu F, Yu H, Lu C, Chen J, Gu W. The cholesterol-lowering effect of alisol acetates based on HMG-CoA reductase and its molecular mechanism. Evid Based Complement Alternat Med 2016; 2016: 1-11. doi: 10.1155/2016/4753852 PMID: 27872650
  49. Chen DQ, Feng YL, Tian T, et al. Diuretic and anti-diuretic activities of fractions of Alismatis rhizoma. J Ethnopharmacol 2014; 157: 114-8. doi: 10.1016/j.jep.2014.09.022 PMID: 25256686
  50. Jo Y, DeBose-Boyd RA. Post-translational regulation of HMG CoA reductase. Cold Spring Harb Perspect Biol 2022; 14(12): a041253. doi: 10.1101/cshperspect.a041253 PMID: 35940903
  51. Scheuer H, Gwinner W, Hohbach J, et al. Oxidant stress in hyperlipidemia-induced renal damage. Am J Physiol Renal Physiol 2000; 278(1): F63-74. doi: 10.1152/ajprenal.2000.278.1.F63 PMID: 10644656
  52. Johnson ACM, Yabu JM, Hanson S, Shah VO, Zager RA. Experimental glomerulopathy alters renal cortical cholesterol, SR-B1, ABCA1, and HMG CoA reductase expression. Am J Pathol 2003; 162(1): 283-91. doi: 10.1016/S0002-9440(10)63819-9 PMID: 12507911
  53. Tomlinson JW, Walker EA, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response. Endocr Rev 2004; 25(5): 831-66. doi: 10.1210/er.2003-0031 PMID: 15466942
  54. Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294(5549): 2166-70. doi: 10.1126/science.1066285 PMID: 11739957
  55. Hsu CN, Tain YL. Regulation of nitric oxide production in the developmental programming of hypertension and kidney disease. Int J Mol Sci 2019; 20(3): 681. doi: 10.3390/ijms20030681 PMID: 30764498
  56. Vilela VR, Samson N, Nachbar R, et al. Adipocyte-specific Nos2 deletion improves insulin resistance and dyslipidemia through brown fat activation in diet-induced obese mice. Mol Metab 2022; 57: 101437. doi: 10.1016/j.molmet.2022.101437 PMID: 35033724
  57. Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids-new mechanisms for old drugs. N Engl J Med 2005; 353(16): 1711-23. doi: 10.1056/NEJMra050541 PMID: 16236742
  58. Liu J, Wan Z, Song Q, et al. NR3C1 gene polymorphisms are associated with steroid resistance in patients with primary nephrotic syndrome. Pharmacogenomics 2018; 19(1): 45-60. doi: 10.2217/pgs-2017-0084 PMID: 29207898
  59. Parvin MN, Aziz MA, Rabbi SNI, et al. Assessment of the link of ABCB1 and NR3C1 gene polymorphisms with the prednisolone resistance in pediatric nephrotic syndrome patients of Bangladesh: A genotype and haplotype approach. J Adv Res 2021; 33: 141-51. doi: 10.1016/j.jare.2021.02.001 PMID: 34603785
  60. Fuller PJ, Yang J, Young MJ. Mechanisms of mineralocorticoid receptor signaling. Vitam Horm 2019; 109: 37-68. doi: 10.1016/bs.vh.2018.09.004 PMID: 30678864
  61. Zhao C, Gu Y, Chen L, Su X. Upregulation of FoxO3a expression through PI3K/Akt pathway attenuates the progression of lupus nephritis in MRL/lpr mice. Int Immunopharmacol 2020; 89(Pt A): 107027. doi: 10.1016/j.intimp.2020.107027 PMID: 33039957
  62. Zhao Y, Feng X, Li B, et al. Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Front Pharmacol 2020; 11: 128. doi: 10.3389/fphar.2020.00128 PMID: 32158395
  63. Qin M, Zhang T. Danggui Shaoyaosan attenuates doxorubicin induced nephrotic syndrome through regulating on PI3K/Akt pathway. Funct Integr Genomics 2023; 23(2): 148. doi: 10.1007/s10142-023-01071-7 PMID: 37147481
  64. Chen J, Yuan S, Zhou J, et al. Danshen injection induces autophagy in podocytes to alleviate nephrotic syndrome via the PI3K/AKT/mTOR pathway. Phytomedicine 2022; 107: 154477. doi: 10.1016/j.phymed.2022.154477 PMID: 36215790
  65. Sadeghi Shaker M, Rokni M, Mahmoudi M, Farhadi E. Ras family signaling pathway in immunopathogenesis of inflammatory rheumatic diseases. Front Immunol 2023; 14: 1151246. doi: 10.3389/fimmu.2023.1151246 PMID: 37256120
  66. Wang YN, Miao H, Hua MR, et al. Moshen granule ameliorates membranous nephropathy by blocking intrarenal renin-angiotensin system signalling via the Wnt1/β-catenin pathway. Phytomedicine 2023; 114: 154763. doi: 10.1016/j.phymed.2023.154763 PMID: 37001295
  67. Wei X, Zhu X, Jiang L, et al. Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis. Int Urol Nephrol 2020; 52(7): 1287-95. doi: 10.1007/s11255-020-02474-2 PMID: 32378138
  68. Liu G, He L. Salidroside Attenuates adriamycin-induced focal segmental glomerulosclerosis by inhibiting the hypoxia-inducible factor-1α expression through phosphatidylinositol 3-kinase/protein kinase B pathway. Nephron J 2019; 142(3): 243-52. doi: 10.1159/000497821 PMID: 30840958
  69. Aghadavod E, Khodadadi S, Baradaran A, Nasri P, Bahmani M, Rafieian-Kopaei M. Role of oxidative stress and inflammatory factors in diabetic kidney disease. Iran J Kidney Dis 2016; 10(6): 337-43. PMID: 27903991
  70. Munkonda MN, Akbari S, Landry C, et al. Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36. J Extracell Vesicles 2018; 7(1): 1432206. doi: 10.1080/20013078.2018.1432206 PMID: 29435202
  71. Saima LS, Latha S, Sharma R, Kumar A. Role of network pharmacology in prediction of mechanism of neuroprotective compounds. Methods Mol Biol 2024; 2761: 159-79. doi: 10.1007/978-1-0716-3662-6_13 PMID: 38427237
  72. Hopkins AL. Network pharmacology: The next paradigm in drug discovery. Nat Chem Biol 2008; 4(11): 682-90. doi: 10.1038/nchembio.118 PMID: 18936753
  73. Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt HHHW. Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci 2022; 43(2): 136-50. doi: 10.1016/j.tips.2021.11.004 PMID: 34895945
  74. Gupta M, Sharma R, Kumar A. Docking techniques in toxicology: An overview. Curr Bioinform 2020; 15(6): 600-10. doi: 10.2174/1574893614666191003125540
  75. Saikia S, Bordoloi M. Molecular docking: Challenges, advances and its use in drug discovery perspective. Curr Drug Targets 2019; 20(5): 501-21. doi: 10.2174/1389450119666181022153016 PMID: 30360733

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2024 Bentham Science Publishers