Prediction of the Molecular Mechanism of Corni Fructus-Epimedii Folium- Rehmanniae Radix Praeparata in the Treatment of Postmenopausal Osteoporosis based on Network Pharmacology and Molecular Docking


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Abstract

Introduction:In this study, core drugs of clinical postmenopausal osteoporosis were retrieved using data mining, the drug molecular action target was predicted through network pharmacology, the key nodes of interaction were identified by combining postmenopausal osteoporosis-related targets, and the pharmacological mechanism of Traditional Chinese Medicine (TCM) against postmenopausal osteoporosis and other action mechanisms was explored.

Methods:TCMISS V2.5 was used to collect TCM prescriptions of postmenopausal osteoporosis from databases, including Zhiwang, Wanfang, PubMed, etc., for selecting the highest confidence drugs. TCMSP and SwissTargetPrediction databases were selected to screen the main active ingredients of the highest confidence drugs and their targets. Relevant targets for postmenopausal osteoporosis were retrieved from GeneCards and GEO databases, PPI network diagrams construction and selection of core nodes in the network, GO and KEGG enrichment analysis, and molecular docking validation.

Results:Correlation analysis identified core drug pairs as 'Corni Fructus-Epimedii Folium- Rehmanniae Radix Praeparata' (SZY-YYH-SDH). After TCMSP co-screening and de-weighting, 36 major active ingredients and 305 potential targets were selected. PPI network graph was built from the 153 disease targets and 24 TCM disease intersection targets obtained. GO, KEGG enrichment results showed that the intersectional targets were enriched in the PI3K-Akt signalling pathway, etc. The target organs were mainly distributed in the thyroid, liver, CD33+_Myeloid, etc. Molecular docking results showed that the core active ingredients of the 'SZY-YYH-SDH' were able to bind to the pair core nodes and PTEN and EGFR.

Conclusion:The results showed that 'SZY-YYH-SDH' can provide the basis for clinical application and treat postmenopausal osteoporosis through multi-component, multi-pathway, and multitarget effects.

About the authors

Yu Zhou

, Chongqing Orthopedic Hospital of Traditional Chinese Medicine

Email: info@benthamscience.net

Xin Li

, Changchun University of Chinese Medicine

Email: info@benthamscience.net

Jinchao Wang

, Yantai Hospital of Shandong Wendeng Osteopathic ＆ Traumatology

Email: info@benthamscience.net

Rong He

, Changchun University of Chinese Medicine

Email: info@benthamscience.net

Liqi Ng

Institute of Orthopaedic and Musculoskeletal Science, University College London, Royal National Orthopaedic Hospital

Email: info@benthamscience.net

Dapeng Li

, Yantai Hospital of Shandong Wendeng Osteopathic ＆ Traumatology

Email: info@benthamscience.net

Jeremy Mortimer

Institute of Orthopaedic and Musculoskeletal Science, University College London, Royal National Orthopaedic Hospital

Email: info@benthamscience.net

Swastina Nath Varma

Institute of Orthopaedic and Musculoskeletal Science, University College London, Royal National Orthopaedic Hospital,

Email: info@benthamscience.net

Jinhua Hu

, Changchun University of Chinese Medicine

Email: info@benthamscience.net

Qing Zhao

, Tianjin University of Chinese Medicine

Email: info@benthamscience.net

Zeyu Peng

, Changchun University of Chinese Medicine

Email: info@benthamscience.net

Chaozong Liu

Institute of Orthopaedic and Musculoskeletal Science, University College London, Royal National Orthopaedic Hospital

Author for correspondence.
Email: info@benthamscience.net

Songchuan Su

, Chongqing Orthopedic Hospital of Traditional Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

References

  1. Yang, K.; Cao, F.; Xue, Y.; Tao, L.; Zhu, Y. Three classes of antioxidant defense systems and the development of postmenopausal osteoporosis. Front. Physiol., 2022, 13, 840293. doi: 10.3389/fphys.2022.840293 PMID: 35309045
  2. Yu, B.; Wang, C.Y. Osteoporosis and periodontal diseases – An update on their association and mechanistic links. Periodontol. 2000, 2022, 89(1), 99-113. doi: 10.1111/prd.12422 PMID: 35244945
  3. Hsu, E.; Pacifici, R. From osteoimmunology to osteomicrobiology: How the microbiota and the immune system regulate bone. Calcif. Tissue Int., 2018, 102(5), 512-521. doi: 10.1007/s00223-017-0321-0 PMID: 29018933
  4. Liu, P.; Wang, W.; Li, Z.; Li, Y.; Yu, X.; Tu, J.; Zhang, Z. Ferroptosis: A new regulatory mechanism in osteoporosis. Oxid. Med. Cell. Longev., 2022, 2022, 1-10. doi: 10.1155/2022/2634431 PMID: 35082963
  5. Hamad, M.; Bajbouj, K.; Taneera, J. The case for an estrogen-iron axis in health and disease. Experimental and clinical endocrinology & diabetes: Official journal, german society of endocrinology. Exp. Clin. Endocrinol. Diabetes, 2020, 128(4), 270-277. doi: 10.1055/a-0885-1677 PMID: 30978727
  6. Kanis, J. A.; Cooper, C.; Rizzoli, R.; Reginster, J. Y. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis Int., 2019, 30(1), 3-44. doi: 10.1007/s00198-018-4704-5
  7. Wu, W.T.; Li, Y.J.; Feng, A.Z.; Li, L.; Huang, T.; Xu, A.D.; Lyu, J. Data mining in clinical big data: The frequently used databases, steps, and methodological models. Mil. Med. Res., 2021, 8(1), 44. doi: 10.1186/s40779-021-00338-z PMID: 34380547
  8. Yang, J.; Li, Y.; Liu, Q.; Li, L.; Feng, A.; Wang, T.; Zheng, S.; Xu, A.; Lyu, J. Brief introduction of medical database and data mining technology in big data era. J. Evid. Based Med., 2020, 13(1), 57-69. doi: 10.1111/jebm.12373 PMID: 32086994
  9. Luo, T.; Lu, Y.; Yan, S.; Xiao, X.; Rong, X.; Guo, J. Network pharmacology in research of chinese medicine formula: Methodology, application and prospective. Chin. J. Integr. Med., 2020, 26(1), 72-80. doi: 10.1007/s11655-019-3064-0 PMID: 30941682
  10. Kaur, T.; Madgulkar, A.; Bhalekar, M.; Asgaonkar, K. Molecular docking in formulation and development. Curr. Drug Discov. Technol., 2019, 16(1), 30-39. doi: 10.2174/1570163815666180219112421 PMID: 29468973
  11. Tang, S.H.; Shen, D.; Yang, H.J. Analysis on composition rules of chinese patent drugs treating pain-related diseases based on data mining method. Chin. J Integr. Med., 2019, 25(11), 861-866. doi: 10.1007/s11655-017-2957-z
  12. Chen, R.B.; Yang, Y.D.; Sun, K.; Liu, S.; Guo, W.; Zhang, J.X.; Li, Y. Potential mechanism of Ziyin Tongluo Formula in the treatment of postmenopausal osteoporosis: Based on network pharmacology and ovariectomized rat model. Chin. Med., 2021, 16(1), 88. doi: 10.1186/s13020-021-00503-5 PMID: 34530875
  13. Yuan, Z.; Min, J.; Zhao, Y.; Cheng, Q.; Wang, K.; Lin, S.; Luo, J.; Liu, H. Quercetin rescued TNF-alpha-induced impairments in bone marrow-derived mesenchymal stem cell osteogenesis and improved osteoporosis in rats. Am. J. Transl. Res., 2018, 10(12), 4313-4321. PMID: 30662673
  14. Aziz, N.; Kim, M.Y.; Cho, J.Y. Anti-inflammatory effects of luteolin: A review of in vitro, in vivo and in silico studies. J. Ethnopharmacol., 2018, 225, 342-358. doi: 10.1016/j.jep.2018.05.019 PMID: 29801717
  15. Imran, M.; Rauf, A.; Abu-Izneid, T.; Nadeem, M.; Shariati, M.A.; Khan, I.A.; Imran, A.; Orhan, I.E.; Rizwan, M.; Atif, M.; Gondal, T.A.; Mubarak, M.S. Luteolin, a flavonoid, as an anticancer agent: A review. Biomed Pharmacother., 2019, 112, 108612. doi: 10.1016/j.biopha.2019.108612
  16. Kim, T.H.; Jung, J.W.; Ha, B.G.; Hong, J.M.; Park, E.K.; Kim, H.J.; Kim, S.Y. The effects of luteolin on osteoclast differentiation, function in vitro and ovariectomy-induced bone loss. J. Nutr. Biochem., 2011, 22(1), 8-15. doi: 10.1016/j.jnutbio.2009.11.002 PMID: 20233653
  17. Morgan, L.V.; Petry, F.; Scatolin, M.; de Oliveira, P.V.; Alves, B.O.; Zilli, G.A.L.; Volfe, C.R.B.; Oltramari, A.R.; de Oliveira, D.; Scapinello, J.; Müller, L.G. Investigation of the anti-inflammatory effects of stigmasterol in mice: Insight into its mechanism of action. Behav. Pharmacol., 2021, 32(8), 640-651. doi: 10.1097/FBP.0000000000000658 PMID: 34657071
  18. Sampath, S.J.P.; Rath, S.N.; Kotikalapudi, N.; Venkatesan, V. Beneficial effects of secretome derived from mesenchymal stem cells with stigmasterol to negate IL-1β-induced inflammation in-vitro using rat chondrocytes-OA management. Inflammopharmacology, 2021, 29(6), 1701-1717. doi: 10.1007/s10787-021-00874-z PMID: 34546477
  19. Sharma, N.; Tan, M.A.; An, S.S.A. Phytosterols: Potential metabolic modulators in neurodegenerative diseases. Int. J. Mol. Sci., 2021, 22(22), 12255. doi: 10.3390/ijms222212255 PMID: 34830148
  20. Marahatha, R.; Gyawali, K.; Sharma, K.; Gyawali, N.; Tandan, P.; Adhikari, A.; Timilsina, G.; Bhattarai, S.; Lamichhane, G.; Acharya, A.; Pathak, I.; Devkota, H.P.; Parajuli, N. Pharmacologic activities of phytosteroids in inflammatory diseases: Mechanism of action and thera-peutic potentials. Phytother. Res., 2021, 35(9), 5103-5124. doi: 10.1002/ptr.7138 PMID: 33957012
  21. Wang, T.; Li, S.; Yi, C.; Wang, X.; Han, X. Protective role of β-Sitosterol in glucocorticoid-induced osteoporosis in rats via the RANKL/OPG pathway. Altern. Ther. Health Med., 2022, 28(7), 18-25. PMID: 35648689
  22. Yoon, H.S.; Park, C. Chrysoeriol ameliorates COX-2 expression through NF-κB, AP-1 and MAPK regulation via the TLR4/MyD88 signaling pathway in LPS-stimulated murine macrophages. Exp. Ther. Med., 2021, 22(1), 718. doi: 10.3892/etm.2021.10150 PMID: 34007327
  23. Tai, B.H.; Cuong, N.M.; Huong, T.T.; Choi, E.M.; Kim, J.A.; Kim, Y.H. Chrysoeriol isolated from the leaves of Eurya ciliata stimulates proliferation and differentiation of osteoblastic MC3T3-E1 cells. J. Asian Nat. Prod. Res., 2009, 11(9), 817-823. doi: 10.1080/10286020903117317 PMID: 20183330
  24. Buettmann, E. G.; McKenzie, J.A.; Migotsky, N.; Sykes, D.A.; Hu, P.; Yoneda, S.; Silva, M.J. VEGFA from early osteoblast lineage cells (Osterix+) is required in mice for fracture healing. J Bone Miner. Res., 2019, 34(9), 1690-1706. doi: 10.1002/jbmr.3755
  25. Yu, T.; You, X.; Zhou, H.; He, W.; Li, Z.; Li, B.; Xia, J.; Zhu, H.; Zhao, Y.; Yu, G.; Xiong, Y.; Yang, Y. MiR-16-5p regulates postmenopausal osteoporosis by directly targeting VEGFA. Aging, 2020, 12(10), 9500-9514. doi: 10.18632/aging.103223 PMID: 32427128
  26. Rajandran, S.N.; Ma, C.A.; Tan, J.R.; Liu, J.; Wong, S.B.S.; Leung, Y.Y. Exploring the association of innate immunity biomarkers with MRI features in both early and late stages osteoarthritis. Front. Med., 2020, 7, 554669. doi: 10.3389/fmed.2020.554669 PMID: 33282885
  27. Sun, G.; Ba, C.L.; Gao, R.; Liu, W.; Ji, Q. Association of IL-6, IL-8, MMP-13 gene polymorphisms with knee osteoarthritis susceptibility in the Chinese Han population. Biosci. Rep., 2019, 39(2), BSR20181346. doi: 10.1042/BSR20181346 PMID: 30635366
  28. Christiansen, B.A.; Bhatti, S.; Goudarzi, R.; Emami, S. Management of osteoarthritis with avocado/soybean unsaponifiables. Cartilage, 2015, 6(1), 30-44. doi: 10.1177/1947603514554992 PMID: 25621100
  29. Yu, T.; You, X.; Zhou, H.; Kang, A.; He, W.; Li, Z.; Li, B.; Xia, J.; Zhu, H.; Zhao, Y.; Yu, G.; Xiong, Y.; Yang, Y. p53 plays a central role in the development of osteoporosis. Aging, 2020, 12(11), 10473-10487. doi: 10.18632/aging.103271 PMID: 32484789
  30. Arranz, A.; Doxaki, C.; Vergadi, E.; Martinez de la Torre, Y.; Vaporidi, K.; Lagoudaki, E.D.; Ieronymaki, E.; Androulidaki, A.; Venihaki, M.; Margioris, A.N.; Stathopoulos, E.N.; Tsichlis, P.N.; Tsatsanis, C. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc. Natl. Acad. Sci. USA, 2012, 109(24), 9517-9522. doi: 10.1073/pnas.1119038109 PMID: 22647600
  31. Wang, Z.; Qi, G.; Li, Z.; Cui, X.; Guo, S.; Zhang, Y.; Cai, P.; Wang, X. Effects of urolithin A on osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand via bone morphogenic protein 2. Bioengineered, 2022, 13(3), 5064-5078. doi: 10.1080/21655979.2022.2036893 PMID: 35164658
  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. doi: 10.1128/MCB.06361-11 PMID: 22064480
  33. Wang, Y.; Liu, L.; Qu, Z.; Wang, D.; Huang, W.; Kong, L.; Yan, L. Tanshinone ameliorates glucocorticoid-induced bone loss via activation of AKT1 signaling pathway. Front. Cell Dev. Biol., 2022, 10, 878433. doi: 10.3389/fcell.2022.878433 PMID: 35419360
  34. Jia, H.; Ma, X.; Tong, W.; Doyran, B.; Sun, Z.; Wang, L.; Zhang, X.; Zhou, Y.; Badar, F.; Chandra, A.; Lu, X.L.; Xia, Y.; Han, L.; Enomoto-Iwamoto, M.; Qin, L. EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation. Proc. Natl. Acad. Sci., 2016, 113(50), 14360-14365. doi: 10.1073/pnas.1608938113 PMID: 27911782
  35. Filardo, E.J.; Quinn, J.A.; Bland, K.I.; Frackelton, A.R., Jr Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol., 2000, 14(10), 1649-1660. doi: 10.1210/mend.14.10.0532 PMID: 11043579
  36. Zhang, X.; Tamasi, J.; Lu, X.; Zhu, J.; Chen, H.; Tian, X.; Lee, T.C.; Threadgill, D.W.; Kream, B.E.; Kang, Y.; Partridge, N.C.; Qin, L. Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo. J Bone Miner Res., 2011, 26(5), 1022-34. doi: 10.1002/jbmr.295
  37. Chandra, A.; Lan, S.; Zhu, J.; Siclari, V.A.; Qin, L. Epidermal growth factor receptor (EGFR) signaling promotes proliferation and survival in osteoprogenitors by increasing early growth response 2 (EGR2) expression. J. Biol. Chem., 2013, 288(28), 20488-20498. doi: 10.1074/jbc.M112.447250 PMID: 23720781
  38. Yang, F.; Lin, Z.W.; Huang, T.Y.; Chen, T.T.; Cui, J.; Li, M.Y.; Hua, Y.Q. Ligustilide, a major bioactive component of Angelica sinensis, promotes bone formation via the GPR30/EGFR pathway. Sci. Rep., 2019, 9(1), 6991. doi: 10.1038/s41598-019-43518-7 PMID: 31061445
  39. Vanden Berghe, W.; Plaisance, S.; Boone, E.; De Bosscher, K.; Schmitz, M.L.; Fiers, W.; Haegeman, G. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor. J. Biol. Chem., 1998, 273(6), 3285-3290. doi: 10.1074/jbc.273.6.3285 PMID: 9452444
  40. Shuai, Y.; Jiang, Z.; Yuan, Q.; Tu, S.; Zeng, F. Deciphering the underlying mechanism of eucommiae cortex against osteoporotic fracture by network pharmacology. Evid. Based Complement. Alternat. Med., 2020, 2020, 7049812. doi: 10.1155/2020/7049812
  41. Xiao, L.; Zhong, M.; Huang, Y.; Zhu, J.; Tang, W.; Li, D.; Shi, J.; Lu, A.; Yang, H.; Geng, D.; Li, H.; Wang, Z. Puerarin alleviates osteoporosis in the ovariectomy-induced mice by suppressing osteoclastogenesis via inhibition of TRAF6/ROSdependent MAPK/NF-κB signaling pathways. Aging, 2020, 12(21), 21706-21729. doi: 10.18632/aging.103976 PMID: 33176281
  42. Ghafouri-Fard, S.; Abak, A.; Shoorei, H.; Mohaqiq, M.; Majidpoor, J.; Sayad, A.; Taheri, M. Regulatory role of microRNAs on PTEN signaling. Biomed Pharmacother., 2021, 133, 110986. doi: 10.1016/j.biopha.2020.110986
  43. Alzahrani, A.S. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59, 125-132. doi: 10.1016/j.semcancer.2019.07.009 PMID: 31323288
  44. Guo, K.; Wang, T.; Luo, E.; Leng, X.; Yao, B. Use of network pharmacology and molecular docking technology to analyze the mechanism of action of velvet antler in the treatment of postmenopausal osteoporosis. Evid Based Complement Alternat Med., 2021, 2012, 7144529. doi: 10.1155/2021/7144529
  45. Wu, C.M.; Chen, P.C.; Li, T.M.; Fong, Y.C.; Tang, C.H. Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-κB signaling pathways in osteoblasts. BMC Complement. Altern. Med., 2013, 13(1), 277. doi: 10.1186/1472-6882-13-277 PMID: 24156308
  46. Gong, W.; Chen, X.; Shi, T.; Shao, X.; An, X.; Qin, J.; Chen, X.; Jiang, Q.; Guo, B. Network pharmacology-based strategy for the investigation of the anti-osteoporosis effects and underlying mechanism of zhuangguguanjie formulation. Front. Pharmacol., 2021, 12, 727808. doi: 10.3389/fphar.2021.727808 PMID: 34658868
  47. Qin, L.; Liu, W.; Cao, H.; Xiao, G. Molecular mechanosensors in osteocytes. Bone Res., 2020, 8(1), 23. doi: 10.1038/s41413-020-0099-y PMID: 32550039
  48. Zintzaras, E.; Doxani, C.; Koufakis, T.; Kastanis, A.; Rodopoulou, P.; Karachalios, T. Synopsis and meta-analysis of genetic association studies in osteoporosis for the focal adhesion family genes: The CUMAGAS-OSTEOporosis information system. BMC Med., 2011, 9(1), 9. doi: 10.1186/1741-7015-9-9 PMID: 21269451
  49. Yang, M.; Li, C.J.; Sun, X.; Guo, Q.; Xiao, Y.; Su, T.; Tu, M.L.; Peng, H.; Lu, Q.; Liu, Q.; He, H.B.; Jiang, T.J.; Lei, M.X.; Wan, M.; Cao, X.; Luo, X.H. MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity. Nat. Commun., 2017, 8(1), 16003. doi: 10.1038/ncomms16003 PMID: 28685750
  50. Duncan Bassett, J.H.; Williams, G.R. The molecular actions of thyroid hormone in bone. Trends Endocrinol. Metab., 2003, 14(8), 356-364. doi: 10.1016/S1043-2760(03)00144-9 PMID: 14516933
  51. Kim, H.Y.; Mohan, S. Role and mechanisms of actions of thyroid hormone on the skeletal development. Bone Res., 2013, 1(2), 146-161. doi: 10.4248/BR201302004 PMID: 26273499
  52. Baliram, R.; Sun, L.; Cao, J.; Li, J.; Latif, R.; Huber, A.K.; Yuen, T.; Blair, H.C.; Zaidi, M.; Davies, T.F. Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling. J. Clin. Invest., 2012, 122(10), 3737-3741. doi: 10.1172/JCI63948 PMID: 22996689
  53. Wu, D.; Cline-Smith, A.; Shashkova, E.; Perla, A.; Katyal, A.; Aurora, R. T-cell mediated inflammation in postmenopausal osteoporosis. Front. Immunol., 2021, 12, 687551. doi: 10.3389/fimmu.2021.687551 PMID: 34276675
  54. Faltas, C.L.; LeBron, K.A.; Holz, M.K. Unconventional estrogen signaling in health and disease. Endocrinology, 2020, 161(4), bqaa030. doi: 10.1210/endocr/bqaa030 PMID: 32128594
  55. Fischer, V.; Haffner-Luntzer, M. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin. Cell Dev. Biol., 2022, 123, 14-21. doi: 10.1016/j.semcdb.2021.05.014 PMID: 34024716

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