Study on the molecular mechanism of Guizhi Jia Shaoyao decoction for the treatment of knee osteoarthritis by utilizing network pharmacology and molecular docking technology
Main Article Content
Keywords
Knee Osteoarthritis, Guizhi Jia Shaoyao Decoction, Network Pharmacology, Molecular Docking, Targets
Abstract
Background and objective Guizhi Jia Shaoyao decoction (GSD) is widely used in the clinical treatment of knee osteoarthritis (KOA). However, the underlying molecular mechanisms remain unclear. The aim of this study was to explore functional mechanisms of GSD in treating KOA by utilizing network pharmacology-based approaches.
Methods Candidate components and targets of GSD were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. NCBI, Genecards, Drugbank, and Therapeutic Target Database (TTD) were used to establish a target database for KOA. Then, an interactive network diagram of “drugs–active components–targets” was plotted with Cytoscape open source bioinformatics software. A protein–protein interaction network was constructed and related protein interaction relationships were analyzed based on the STRING database. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway-enrichment analysis were conducted based on intersected targets. Molecular docking provided an assessment tool for verifying binding of components and targets. It was performed by AutoDock molecular modeling simulation software.
Results In all, 103 active components were successfully identified, and corresponding 133 targets were searched for treating KOA. Functional enrichment analysis suggested that GSD exerts its pharmacological effect in treating KOA by regulating multiple pathways, such as PI3K-Akt, tumor necrosis factor, Toll-like receptor (TLR), and nuclear factor kappa B signaling pathways. Molecular docking analysis depicted that representative components bound firmly to key targets.
Conclusion This study revealed the synergistic effects of multiple components, targets, and pathways of GSD for treating KOA. This would enhance the understanding of potential molecular mechanisms of GSD for treating KOA and lay a foundation for further experimental research.
References
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2. Chen W. Guidelines for TCM diagnosis and treatment of knee osteoarthritis, 2020 edition. Traditl Chin Med Bone Setting. 2020;10(32):1–2. 10.4103/wjtcm.wjtcm_30_19
3. Zhao Z, Dai XS, Wang ZY, Bao ZQ, Guan JZ. MicroRNA-26a reduces synovial inflammation and cartilage injury in osteoarthritis of knee joints through impairing the NF-kappaB signaling pathway. Biosci Rep. 2019;39(4):2–16. 10.1042/BSR20182025
4. Georgiev T, Angelov AK. Modifiable risk factors in knee osteoarthritis: Treatment implications. Rheumatol Int. 2019;39(7):1145–57. 10.1007/s00296-019-04290-z
5. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465–74. 10.1002/acr.21596
6. Lo PC, Tsai YT, Lin SK, Lai JN. Risk of asthma exacerbation associated with nonsteroidal anti-inflammatory drugs in childhood asthma: A nationwide population-based cohort study in Taiwan. Medicine (Baltimore). 2016;95(41):1–8. 10.1097/MD.0000000000005109
7. Chen F-P, Chang C-M, Hwang S-J. Chinese herbal prescriptions for osteoarthritis in Taiwan: Analysis of national health insurance dataset. BMC Complement Altern Med. 2014;14(0):1–8. 10.1186/1472-6882-14-91
8. Li B, Xu X, Wang X, Yu H, Li X, Tao W, et al. A systems biology approach to understanding the mechanisms of action of Chinese herbs for treatment of cardiovascular disease. Int J Mol Sci. 2012;13(10):13501–16. 10.3390/ijms131013501
9. Dan L, Wei LXCHH. Zhang Qi’s experience of treating Jin Bi with guizhi and shaoyao decoction. Shandong J Tradit Chin Med. 2019;38(10):961–2.
10. Hopkins AL. Network pharmacology. Nat biotechnol. 2007 Oct;25(10):1110–1. 10.1038/nbt1007-1110
11. Zhang Y, Bai M, Zhang B, Liu C, Guo Q, Sun Y, et al. Uncovering pharmacological mechanisms of Wu-tou decoction acting on rheumatoid arthritis through systems approaches: drug-target prediction, network analysis and experimental validation. Sci Rep. 2015;5(0):1–13. 10.1038/srep09463
12. Li H, Zhao L, Zhang B, Jiang Y, Wang X, Guo Y, et al. A network pharmacology approach to determine active compounds and action mechanisms of ge-gen-qin-lian decoction for treatment of type 2 diabetes. Evid Based Complement Altern Med. 2014;2014(0):1–12. 10.1155/2014/180965
13. Ru J, Li P, Wang J. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014;6(13):1–6. 10.1186/1758-2946-6-13
14. 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(0):1–13. 10.1038/srep15290
15. Song X, Zhang Y, Yang N, Dai E, Wang L, Du H. Molecular mechanism of celastrol in the treatment of systemic lupus erythematosus based on network pharmacology and molecular docking technology. Life Sci. 2019;240(2020):1–8. 10.1016/j.lfs.2019.117063
16. Stelzer G, Dalah I, Stein TI, Satanower Y, Rosen N, Nativ N, et al. In-silico human genomics with GeneCards. Hum Genomics. 2011;5(6):709–17. 10.1186/1479-7364-5-6-709
17. Zhang MM, Wang D, Lu F, Zhao R, Ye X, He L, et al. 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):1–16. 10.1186/s13040-020-00232-9
18. Li YH, Yu CY, Li XX, Zhang P, Tang J, Yang Q, et al. Therapeutic target database update 2018: Enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Res. 2018;46(D1):D1121–7. 10.1093/nar/gkx1076
19. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: Protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–13. 10.1093/nar/gky1131
20. Baderan GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 2003;4(2):1–27.
21. Jie H, Xiaoyun Z, Rilan C. Huangqi guizhi wuwu decoction in the treatment of osteoarthritis: Analysis based on network pharmacology and molecular docking technology. Chin Tissue Eng Res. 2020;25(14):2224–30.
22. Feng C, Zhao M, Jiang L, Hu Z, Fan X. Mechanism of modified danggui sini decoction for knee osteoarthritis based on network pharmacology and molecular docking. Evid Based Complement Altern Med. 2021;2021(0):1–11. 10.1155/2021/8215454
23. Chen J. Clinical efficacy and safety of guizhi shaoyao decoction in the treatment of rheumatoid arthritis. Clin Ration Drug Use. 2021;14(5):132–3.
24. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):1–16. 10.1101/cshperspect.a016295
25. Glyn-Jones S, Palmer AJR, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87. 10.1016/S0140-6736(14)60802-3
26. Stannus O, Jones G, Cicuttini F, Parameswaran V, Quinn S, Burgess J, et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis Cartilage. 2010;18(11):1441–7. 10.1016/j.joca.2010.08.016
27. Li Z, Zhong L, Du Z, Chen G, Shang J, Yang Q, et al. Network analyses of differentially expressed genes in osteoarthritis to identify hub genes. Biomed Res Int. 2019;2019(0):1–9. 10.1155/2019/9083068
28. Wojdasiewicz ŁAP P, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm. 2014;2014(0):1–19. 10.1155/2014/561459
29. M Grell , E Douni, H Wajant, M Löhden, M Clauss, B Maxeiner, et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell Press. 1995;83(5):793–802. 10.1016/0092-8674(95)90192-2
30. Murahashi Y, Yano F, Chijimatsu R, Nakamoto H, Maenohara Y, Amakawa M, et al. Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion. Sci Rep. 2019;9(0):1–13. 10.1038/s41598-019-56861-6
31. Ozler KEO, Gokalp O. The association of ischemia modified albumin with osteoarthritis progression. Clin Lab. 2020;66(1):1–5. 10.7754/Clin.Lab.2019.190608
32. Mukherjee A, Rotwein P. Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol. 2012;32(2):490–500. 10.1128/MCB.06361-11
33. Komarova EA, Krivokrysenko V, Wang K. p53 is a suppressor of inflammatory response in mice. FASEB J. 2005;19(8):1030–2. 10.1096/fj.04-3213fje
34. Shatz M, Shats I, Menendez D. p53 amplifies toll-like receptor 5 response in human primary and cancer cells through interaction with multiple signal transduction pathways. Oncotarget. 2015;6(19):1–2. 10.18632/oncotarget.4435
35. Zhu X, Yang S, Lin W, Wang L, Ying J, Ding Y, et al. Roles of cell cyle regulators cyclin D1, CDK4, and p53 in knee osteoarthritis. Genet Test Mol Biomarkers. 2016;20(9):529–34. 10.1089/gtmb.2016.0020
36. Wei B, Zhang Y, Tang L, Ji Y, Yan C, Zhang X. Protective effects of quercetin against inflammation and oxidative stress in a rabbit model of knee osteoarthritis. Drug Dev Res. 2019;80(3):360–7. 10.1002/ddr.21510
37. Weihan Y and Yaohua H. Advances in the mechanism of quercetin in the treatment of osteoarthritis. Chin J Bone Joint Surg. 2019;12(6):477–80.
38. Zhang J, Yin J, Zhao D, Wang C, Zhang Y, Wang Y, et al. Therapeutic effect and mechanism of action of quercetin in a rat model of osteoarthritis. J Int Med Res. 2020;48(3):1–9. 10.1177/0300060519873461
39. Zhuang Z, Ye G, Huang B. Kaempferol alleviates the interleukin-1beta-induced inflammation in rat osteoarthritis chondrocytes via suppression of NF-kappaB. Med Sci Monit. 2017;23(0):3925–31. 10.12659/MSM.902491
40. Yoon HY, Lee EG, Lee H, Cho IJ, Choi YJ, Sung MS, et al. Kaempferol inhibits IL-1beta-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs. Int J Mol Med. 2013;32(4):971–7. 10.3892/ijmm.2013.1468
41. Estakhri F, Panjehshahin MR, Tanideh N, Gheisari R, Mahmoodzadeh A, Azarpira N, et al. The effect of kaempferol and apigenin on allogenic synovial membrane-derived stem cells therapy in knee osteoarthritic male rats. Knee. 2020;27(3):817–32. 10.1016/j.knee.2020.03.005
42. Chao CL, Weng CS, Chang NC, Lin JS, Kao ST, Ho FM. Naringenin more effectively inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in macrophages than in microglia. Nutr Res. 2010;30(12):858–64. 10.1016/j.nutres.2010.10.011
43. Hamalainen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm. 2007;2007(0):1–10. 10.1155/2007/45673
44. Bodet C, La VD, Epifano F, Grenier D. Naringenin has anti-inflammatory properties in macrophage and ex vivo human whole-blood models. J Periodontal Res. 2008;43(4):400–7. 10.1111/j.1600-0765.2007.01055.x
45. Vafeiadou K, Vauzour D, Lee HY, Rodriguez-Mateos A, Williams RJ, Spencer JP. The citrus flavanone naringenin inhibits inflammatory signaling in glial cells and protects against neuroinflammatory injury. Arch Biochem Biophys. 2009;484(1):100–9. 10.1016/j.abb.2009.01.016
46. Lin WC, Lin JY. Five bitter compounds display different anti-inflammatory effects through modulating cytokine secretion using mouse primary splenocytes in vitro. J Agric Food Chem. 2011;59(0):184–92. 10.1021/jf103581r
47. Jin L, Zeng W, Zhang F, Zhang C, Liang W. Naringenin ameliorates acute inflammation by regulating intracellular cytokine degradation. J Immunol. 2017;199(10):3466–77. 10.4049/jimmunol.1602016
48. Kang H, Kim H. Astaxanthin and beta-carotene in helicobacter pylori-induced gastric inflammation: A mini-review on action mechanisms. J Cancer Prev. 2017;22(2):57–61. 10.15430/JCP.2017.22.2.57
49. Li R, Li L, Hong P, Lang W, Hui J, Yang Y, et al. beta-Carotene prevents weaning-induced intestinal inflammation by modulating gut microbiota in piglets. Asian-Australas J Anim Sci. 2021;34(7):1221–34. 10.5713/ajas.19.0499
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Nov 1, 2021
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Deng, P., Liang, H., Xie, K., Huang, F., Liu, H., Zhu, H., Huang, Z., Wu, Q., Tao, J., Li, L., & Chen, Z. (2021). Study on the molecular mechanism of Guizhi Jia Shaoyao decoction for the treatment of knee osteoarthritis by utilizing network pharmacology and molecular docking technology (J. Han , Trans.). Allergologia Et Immunopathologia, 49(6), 16-30. https://doi.org/10.15586/aei.v49i6.484
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Research Article
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
How to Cite
Deng, P., Liang, H., Xie, K., Huang, F., Liu, H., Zhu, H., Huang, Z., Wu, Q., Tao, J., Li, L., & Chen, Z. (2021). Study on the molecular mechanism of Guizhi Jia Shaoyao decoction for the treatment of knee osteoarthritis by utilizing network pharmacology and molecular docking technology (J. Han , Trans.). Allergologia Et Immunopathologia, 49(6), 16-30. https://doi.org/10.15586/aei.v49i6.484