DOI QR코드

DOI QR Code

Sequential anti-inflammatory and osteogenic effects of a dual drug delivery scaffold loaded with parthenolide and naringin in periodontitis

  • Rui Chen (Department of Stomatology, The First People's Hospital of Yunnan Province) ;
  • Mengting Wang (Department of Stomatology, The First People's Hospital of Yunnan Province) ;
  • Qiaoling Qi (Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University) ;
  • Yanli Tang (Department of Stomatology, The First People's Hospital of Yunnan Province) ;
  • Zhenzhao Guo (Jinan University) ;
  • Shuai Wu (Jinan University) ;
  • Qiyan Li (Department of Stomatology, The First People's Hospital of Yunnan Province)
  • 투고 : 2021.11.05
  • 심사 : 2022.06.06
  • 발행 : 2023.02.28

초록

Purpose: Our pilot study showed that a 3-dimensional dual drug delivery scaffold (DDDS) loaded with Chinese herbs significantly increased the regenerated bone volume fraction. This study aimed to confirm the synergistic anti-inflammatory and osteogenic preclinical effects of this system. Methods: The targets and pathways of parthenolide and naringin were predicted. Three cell models were used to assess the anti-inflammatory effects of parthenolide and the osteogenic effects of naringin. First, the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) and the bone mineral density (BMD) of surgical defects were measured in a rat model of periodontitis with periodontal fenestration defects. Additionally, the mRNA expression levels of matrix metallopeptidase 9 (MMP9) and alkaline phosphatase (ALP) were measured. Furthermore, the number of inflammatory cells and osteoclasts, as well as the protein expression levels of tumor necrosis factor-alpha (TNF-α) and levels of ALP were determined. Results: Target prediction suggested prostaglandin peroxidase synthase (PTGS2) as a potential target of parthenolide, while cytochrome P450 family 19 subfamily A1 (CYP19A1) and taste 2 receptor member 31 (TAS2R31) were potential targets of naringin. Parthenolide mainly targeted inflammation-related pathways, while naringin participated in steroid hormone synthesis and taste transduction. In vitro experiments revealed significant antiinflammatory effects of parthenolide on RAW264.7 cells, and significant osteogenic effects of naringin on bone marrow mesenchymal stem cells and MC3T3-E1 cells. DDDS loaded with parthenolide and naringin decreased the CEJ-ABC distance and increased BMD and ALP levels in a time-dependent manner. Inflammation was significantly alleviated after 14 days of DDDS treatment. Additionally, after 56 days, the DDDS group exhibited the highest BMD and ALP levels. Conclusions: DDDS loaded with parthenolide and naringin in a rat model achieved significant synergistic anti-inflammatory and osteogenic effects, providing powerful preclinical evidence.

키워드

참고문헌

  1. Straka M, Straka-Trapezanlidis M, Deglovic J, Varga I. Periodontitis and osteoporosis. Neuroendocrinol Lett 2015;36:401-6.
  2. Killoy WJ. The clinical significance of local chemotherapies. J Clin Periodontol 2002;29 Suppl 2:22-9. https://doi.org/10.1034/j.1600-051X.29.s2.2.x
  3. McAllister BS, Haghighat K. Bone augmentation techniques. J Periodontol 2007;78:377-96. https://doi.org/10.1902/jop.2007.060048
  4. Cho YD, Seol YJ, Lee YM, Rhyu IC, Ryoo HM, Ku Y. An overview of biomaterials in periodontology and implant dentistry. Adv Mater Sci Eng 2017;2017:1-7. https://doi.org/10.1155/2017/1948241
  5. Ma ZW, Zhang YJ, Wu ZF, Wang R, Zhu H, Li Y, et al. A study on the effect of the chitosan thermosensitive hydrogel loading recombinant human bone morphogenetic protein-2 on repairing periodontal defects. Hua Xi Kou Qiang Yi Xue Za Zhi 2008;26:23-6.
  6. Guo Z, Bo D, He P, Li H, Wu G, Li Z, et al. Sequential controlled-released dual-drug loaded scaffold for guided bone regeneration in a rat fenestration defect model. J Mater Chem B Mater Biol Med 2017;5:7701-10. https://doi.org/10.1039/C7TB00909G
  7. Wang M, Li Q. Parthenolide could become a promising and stable drug with anti-inflammatory effects. Nat Prod Res 2015;29:1092-101. https://doi.org/10.1080/14786419.2014.981541
  8. Li S, Gao X, Wu X, Wu Z, Cheng L, Zhu L, et al. Parthenolide inhibits LPS-induced inflammatory cytokines through the toll-like receptor 4 signal pathway in THP-1 cells. Acta Biochim Biophys Sin (Shanghai) 2015;47:368-75. https://doi.org/10.1093/abbs/gmv019
  9. Li N, Jiang Y, Wooley PH, Xu Z, Yang SY. Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis. J Orthop Sci 2013;18:478-85. https://doi.org/10.1007/s00776-013-0362-9
  10. Pang WY, Wang XL, Mok SK, Lai WP, Chow HK, Leung PC, et al. Naringin improves bone properties in ovariectomized mice and exerts oestrogen-like activities in rat osteoblast-like (UMR-106) cells. Br J Pharmacol 2010;159:1693-703. https://doi.org/10.1111/j.1476-5381.2010.00664.x
  11. Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotechnol 2007;25:197-206. https://doi.org/10.1038/nbt1284
  12. Liu X, Vogt I, Haque T, Campillos M. HitPick: a web server for hit identification and target prediction of chemical screenings. Bioinformatics 2013;29:1910-2. https://doi.org/10.1093/bioinformatics/btt303
  13. 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:W357-64. https://doi.org/10.1093/nar/gkz382
  14. Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 2010;38:W214-20. https://doi.org/10.1093/nar/gkq537
  15. Snel B, Lehmann G, Bork P, Huynen MA. STRING: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene. Nucleic Acids Res 2000;28:3442-4. https://doi.org/10.1093/nar/28.18.3442
  16. Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, et al. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet 2015;47:569-76. https://doi.org/10.1038/ng.3259
  17. Seol YJ, Pellegrini G, Franco LM, Chang PC, Park CH, Giannobile WV. Preclinical methods for the evaluation of periodontal regeneration in vivo. Methods Mol Biol 2010;666:285-307. https://doi.org/10.1007/978-1-60761-820-1_18
  18. Parsa A, Ibrahim N, Hassan B, van der Stelt P, Wismeijer D. Bone quality evaluation at dental implant site using multislice CT, micro-CT, and cone beam CT. Clin Oral Implants Res 2015;26:e1-7. https://doi.org/10.1111/clr.12315
  19. Yang X, Zhang H, Wang J, Zhang Z, Li C. Puerarin decreases bone loss and collagen destruction in rats with ligature-induced periodontitis. J Periodontal Res 2015;50:748-57. https://doi.org/10.1111/jre.12261
  20. Zhou Y, Zhou H, Hua L, Hou C, Jia Q, Chen J, et al. Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis. Free Radic Biol Med 2021;171:55-68. https://doi.org/10.1016/j.freeradbiomed.2021.05.009
  21. da Silva-Junior IA, Dalmaso B, Herbster S, Lepique AP, Jancar S. Platelet-activating factor receptor ligands protect tumor cells from radiation-induced cell death. Front Oncol 2018;8:10.
  22. Shi FD, Flodstrom M, Kim SH, Pakala S, Cleary M, Ljunggren HG, et al. Control of the autoimmune response by type 2 nitric oxide synthase. J Immunol 2001;167:3000-6. https://doi.org/10.4049/jimmunol.167.5.3000
  23. Di Nardo G, Zhang C, Marcelli AG, Gilardi G. Molecular and structural evolution of cytochrome P450 aromatase. Int J Mol Sci 2021;22:631.
  24. Zhang J, Guo S, Wu Y, Zheng ZC, Wang Y, Zhao Y. P4HB, a novel hypoxia target gene related to gastric cancer invasion and metastasis. BioMed Res Int 2019;2019:9749751.
  25. Yin P, Tu Z, Yin A, Zhao T, Yan S, Guo X, et al. Aged monkey brains reveal the role of ubiquitin-conjugating enzyme UBE2N in the synaptosomal accumulation of mutant huntingtin. Hum Mol Genet 2015;24:1350-62. https://doi.org/10.1093/hmg/ddu544
  26. Li Q, Valerio MS, Kirkwood KL. MAPK usage in periodontal disease progression. J Signal Transduct 2012;2012:308943.
  27. Smallie T, Ross EA, Ammit AJ, Cunliffe HE, Tang T, Rosner DR, et al. Dual-specificity phosphatase 1 and tristetraprolin cooperate to regulate macrophage responses to lipopolysaccharide. J Immunol 2015;195:277-88. https://doi.org/10.4049/jimmunol.1402830
  28. Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol 2001;8:759-66. https://doi.org/10.1016/S1074-5521(01)00049-7
  29. Wang D, Wang H, Fu S, Cheng X, Yang F, Zhang Q, et al. Parthenolide ameliorates Concanavalin A-induced acute hepatitis in mice and modulates the macrophages to an anti-inflammatory state. Int Immunopharmacol 2016;38:132-8. https://doi.org/10.1016/j.intimp.2016.05.024
  30. Feng D, Ling WH, Duan RD. Lycopene suppresses LPS-induced NO and IL-6 production by inhibiting the activation of ERK, p38MAPK, and NF-kappaB in macrophages. Inflamm Res 2010;59:115-21. https://doi.org/10.1007/s00011-009-0077-8
  31. de Oliveira RR, Schwartz-Filho HO, Novaes AB Jr, Taba M Jr. Antimicrobial photodynamic therapy in the non-surgical treatment of aggressive periodontitis: a preliminary randomized controlled clinical study. J Periodontol 2007;78:965-73. https://doi.org/10.1902/jop.2007.060494
  32. Carda C, Silvestrini G, Gomez de Ferraris ME, Peydro A, Bonucci E. Osteoprotegerin (OPG) and RANKL expression and distribution in developing human craniomandibular joint. Tissue Cell 2005;37:247-55. https://doi.org/10.1016/j.tice.2005.03.002
  33. Chen LL, Lei LH, Ding PH, Tang Q, Wu YM. Osteogenic effect of Drynariae rhizoma extracts and Naringin on MC3T3-E1 cells and an induced rat alveolar bone resorption model. Arch Oral Biol 2011;56:1655-62. https://doi.org/10.1016/j.archoralbio.2011.06.008
  34. Yin L, Cheng W, Qin Z, Yu H, Yu Z, Zhong M, et al. Effects of naringin on proliferation and osteogenic differentiation of human periodontal ligament stem cells in vitro and in vivo. Stem Cells Int 2015;2015:758706.
  35. Jo S, Han J, Lee YL, Yoon S, Lee J, Wang SE, et al. Regulation of osteoblasts by alkaline phosphatase in ankylosing spondylitis. Int J Rheum Dis 2019;22:252-61. https://doi.org/10.1111/1756-185X.13419
  36. Ji Y, Wang L, Watts DC, Qiu H, You T, Deng F, et al. Controlled-release naringin nanoscaffold for osteoporotic bone healing. Dent Mater 2014;30:1263-73. https://doi.org/10.1016/j.dental.2014.08.381