Proteomic Analysis in Nifedipine Induced Gingival Overgrowth: A Pilot Study

Year 2022, Volume: 12 Issue: 4, 1013 - 1024, 30.12.2022

Ece Yetiş Ayşen Yarat , Onur Eroğlu Hafize Öztürk Özener , Leyla Kuru

https://doi.org/10.33808/clinexphealthsci.1050418

Abstract

Objective: The aims of the present study were to investigate the proteomic profile of nifedipine induced overgrown gingiva and compare with non-overgrown gingival tissues obtained from the same patients. Methods: Seven subjects under nifedipine medication for at least 6 months and diagnosed as nifedipine induced gingival overgrowth (NIGO) participated in the study. Periodontal clinical parameters were recorded. Gingival tissue samples were harvested from overgrown (GO+ Group, n=7) and non-overgrown regions (GO- Group, n=7) of the same patients. Proteomics was performed using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) technique. The identified proteins were further classified according to their molecular functions, biological processes and cellular component distribution for functional gene ontology analysis using a web-based bioinformatics tool. Mann Whitney-U and ANOVA tests were performed to compare clinical parameters and identified proteins with proteomics, respectively. Results: Bleeding on probing and gingival overgrowth index of the GO+ group were statistically significantly higher than the GO- group (p<0.05, p<0.01, respectively). A total of 143 proteins were identified in 14 gingival tissue samples using proteomics. Among the proteins identified, 79 of them were detected in higher quantities in the GO+ group (p<0.05) whereas remaining 64 were found higher in the GO- group (p<0.05). The analysis of functional gene ontology demonstrated that certain proteins exhibit roles in either stimulatory or inhibitory processes including cell proliferation, growth and apoptosis. Conclusion: The proteomic profiles of overgrown and non-overgrown gingiva suggest that the identified proteins expressed at different levels in both groups may contribute to the pathogenesis and progression of NIGO.

Keywords

gingival overgrowth, nifedipine, proteomics

Project Number

SAG-C-DRP-110718-0437

References

• [1] Seymour RA, Ellis JS, Thomason JM. Risk factors for druginduced gingival overgrowth. J Clin Periodontol 2000;27(4):217223.
• [2] Hassell TM, Hefti AF. Drug-induced gingival overgrowth: old problem, new problem. Crit Rev Oral Biol Med 1991;2(1):103137.
• [3] Newman T, Klokkevold, Carranza. Newman and Carranza’s Clinical Periodontology. 2019;13:19-287.
• [4] Seymour RA. Calcium channel blockers and gingival overgrowth. Br Dent J 1991;170(10):376-379.
• [5] Barak S, Engelberg IS, Hiss J. Gingival hyperplasia caused by nifedipine. Histopathologic findings. J Periodontol 1987;58(9):639-642.
• [6] Steele RM, Schuna AA, Schreiber RT. Calcium antagonistinduced gingival hyperplasia. Ann Intern Med 1994;120(8):663664.
• [7] Miller CS, Damm DD. Incidence of verapamil-induced gingival hyperplasia in a dental population. J Periodontol 1992;63(5):453-456.
• [8] Gelfand EW, Cheung RK, Grinstein S, Mills GB. Characterization of the role for calcium influx in mitogen-induced triggering of human T cells. Identification of calcium-dependent and calcium-independent signals. Eur J Immunol 1986;16(8):907912.
• [9] Sooriyamoorthy M, Gower DB, Eley BM. Androgen metabolism in gingival hyperplasia induced by nifedipine and cyclosporin. J Periodontal Res 1990;25(1):25-30.
• [10] Saito K, Mori S, Iwakura M, Sakamoto S. Immunohistochemical localization of transforming growth factor beta, basic fibroblast growth factor and heparan sulphate glycosaminoglycan in gingival hyperplasia induced by nifedipine and phenytoin. J Periodontal Res 1996;31(8):545-555.
• [11] Balaji A, Balaji TM, Rao SR. Angiotensin II levels in gingival tissues from healthy individuals, patients with nifedipine induced gingival overgrowth and non nesponders on nifedipine. J Clin Diagn Res 2015;9(8):Zc92-94.
• [12] Ghallab NA. Diagnostic potential and future directions of biomarkers in gingival crevicular fluid and saliva of periodontal diseases: Review of the current evidence. Arch Oral Biol 2018;87:115-124.
• [13] Jágr M, Eckhardt A, Pataridis S, Broukal Z, Dušková J, Mikšík I. Proteomics of human teeth and saliva. Physiol Res 2014;63(Suppl 1):S141-154.
• [14] Mohd Nasri FA, Zainal Ariffin SH, Karsani SA, Megat Abdul Wahab R. Label-free quantitative proteomic analysis of gingival crevicular fluid to identify potential early markers for root resorption. BMC Oral Health 2020;20(1):256.
• [15] Fleissig Y, Reichenberg E, Redlich M, Zaks B, Deutsch O, Aframian DJ, Palmon A. Comparative proteomic analysis of human oral fluids according to gender and age. Oral Dis 2010;16(8):831-838.
• [16] Jung JY, Kang GC, Jeong YJ, Kim SH, Kwak YG, Kim WJ. Proteomic Analysis in Cyclosporin A-Induced Overgrowth of Human Gingival Fibroblasts. Biological and Pharmaceutical Bulletin 2009;32(8):1480-1485.
• [17] Silness J, Loe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964;22:121-135.
• [18] Loe H, Silness J. Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odontol Scand 1963;21:533-551.
• [19] Ellis JS, Seymour RA, Robertson P, Butler TJ, Thomason JM. Photographic scoring of gingival overgrowth. J Clin Periodontol 2001;28(1):81-85.
• [20] He F. Bradford Protein Assay. Bio-protocol 2011;1(6):e45.
• [21] Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods 2009;6(5):359-362.
• [22] Consortium TU. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res 2020;49(D1):D480-D489.
• [23] Mi H, Ebert D, Muruganujan A, Mills C, Albou L-P, Mushayamaha T, Thomas PD. PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API. Nucleic Acids Res 2020;49(D1):D394-D403.
• [24] Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000 1999;21:176-196.
• [25] Kose KN, Yilmaz S, Noyan U, Kuru B, Yildirim HS, Agrali OB, Ozener HO, Kuru L. The gingival crevicular fluid levels of growth factors in patients with amlodipine-induced gingival overgrowth: A pilot study. Niger J Clin Pract 2020;23(4):561567.
• [26] Kuru L, Yilmaz S, Kuru B, Kose KN, Noyan U. Expression of growth factors in the gingival crevice fluid of patients with phenytoin-induced gingival enlargement. Arch Oral Biol 2004;49(11):945-950.
• [27] Uzel MI, Kantarci A, Hong HH, Uygur C, Sheff MC, Firatli E, Trackman PC. Connective tissue growth factor in drug-induced gingival overgrowth. J Periodontol 2001;72(7):921-931.
• [28] Tavassoli S, Yamalik N, Caglayan F, Caglayan G, Eratalay K. The clinical effects of nifedipine on periodontal status. J Periodontol 1998;69(2):108-112.
• [29] Ogita M, Tsuchida S, Aoki A, Satoh M, Kado S, Sawabe M, Nanbara H, Kobayashi H, Takeuchi Y, Mizutani K, Sasaki Y, Nomura F, Izumi Y. Increased cell proliferation and differential protein expression induced by low-level Er:YAG laser irradiation in human gingival fibroblasts: proteomic analysis. Lasers Med Sci 2015;30(7):1855-166.
• [30] George A, George SP, John S, George N, Joe S, Mathew R. Changes in inflammatory markers in bacterial – and nifedipineinduced gingival inflammation. J Int Oral Health 2015;7(Suppl 2):64-67.
• [31] Ju Y, Huang L, Wang S, Zhao S. Transcriptional analysis reveals key genes in the pathogenesis of nifedipineinduced gingival overgrowth. Anal Cell Pathol (Amst) 2020;2020:6128341.
• [32] Gong Q, Zhang X, Liang A, Huang S, Tian G, Yuan M, Ke Q, Cai Y, Yan B, Wang J, Wang J. Proteomic screening of potential N-glycoprotein biomarkers for colorectal cancer by TMT labeling combined with LC-MS/MS. Clin Chim Acta 2021;521:122-130.
• [33] Xu L, Tan B, Huang D, Yuan M, Li T, Wu M, Ye C. Remdesivir inhibits tubulointerstitial fibrosis in obstructed kidneys. Front Pharmacol 2021;12:626510.
• [34] Tsuchida S, Satoh M, Kawashima Y, Sogawa K, Kado S, Sawai S, Nishimura M, Ogita M, Takeuchi Y, Kobyashi H, Aoki A, Kodera Y, Matsushita K, Izumi Y, Nomura F. Application of quantitative proteomic analysis using tandem mass tags for discovery and identification of novel biomarkers in periodontal disease. Proteomics 2013;13(15):2339-2350.
• [35] McKnight H, Kelsey WP, Hooper DA, Hart TC, Mariotti A. Proteomic analyses of human gingival and periodontal ligament fibroblasts. J Periodontol 2014;85(6):810-818.
• [36] Yang HY, Kwon J, Kook MS, Kang SS, Kim SE, Sohn S, Jung S, Kwon SO, Kim HS, Lee JH, Lee TH. Proteomic analysis of gingival tissue and alveolar bone during alveolar bone healing. Mol Cell Proteomics 2013;12(10):2674-2688.
• [37] Reichenberg E, Redlich M, Cancemi P, Zaks B, Pitaru S, Fontana S, Pucci-Minafra I, Palmon A. Proteomic analysis of protein components in periodontal ligament fibroblasts. J Periodontol 2005;76(10):1645-1653.
• [38] Monari E, Cuoghi A, Bellei E, Bergamini S, Lucchi A, Tomasi A, Cortellini P, Zaffe D, Bertoldi C. Analysis of protein expression in periodontal pocket tissue: a preliminary study. Proteome Sci 2015;13:33.
• [39] Tuganova A, Boulatnikov I, Popov KM. Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex. Biochem J 2002;366(Pt 1):129-136.
• [40] Zhang S, Hulver MW, McMillan RP, Cline MA, Gilbert ER. The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutr Metab (Lond) 2014;11(1):10.
• [41] Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 2013;3:38.
• [42] Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S. Macrophage migration inhibitory factor (MIF): A multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther 2021:108024.
• [43] Subramani T, Rathnavelu V, Alitheen NB. The possible potential therapeutic targets for drug induced gingival overgrowth. Mediators Inflamm 2013;2013:639468.
• [44] Zhang F, Zhou X, Zou H, Liu L, Li X, Ruan Y, Xie Y, Shi M, Xiao Y, Wang Y, Zhou Y, Wu Y, Guo B. SAA1 is transcriptionally activated by STAT3 and accelerates renal interstitial fibrosis by inducing endoplasmic reticulum stress. Exp Cell Res 2021;408(1):112856.
• [45] Lim HI, Hajjar KA. Annexin A2 in fibrinolysis, inflammation and fibrosis. Int J Mol Sci 2021;22(13).
• [46] Schuliga M, Jaffar J, Berhan A, Langenbach S, Harris T, Waters D, Lee PVS, Grainge C, Westall G, Knight D, Stewart AG. Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity. Am J Physiol Lung Cell Mol Physiol 2017;312(5):L772-l82.
• [47] Hofmann B, Hecht HJ, Flohé L. Peroxiredoxins. Biol Chem 2002;383(3-4):347-64.
• [48] Yuan D, Zhao Y, Wang Y, Che J, Tan W, Jin Y, Wang F, Li P, Fu S, Liu Q, Zhu W. Effect of integrin-linked kinase gene silencing on microRNA expression in ovarian cancer. Mol Med Rep 2017;16(5):7267-7276.
• [49] Potrony M, Haddad TS, Tell-Martí G, Gimenez-Xavier P, Leon C, Pevida M, Mateu J, Badenas C, Carrera C, Malvehy J, Aguilera P, Llames S, Escámez MJ, Puig-Butillé JA, Del Río M, Puig S. DNA repair and immune response pathways are deregulated in melanocyte-keratinocyte co-cultures derived from the healthy skin of familial melanoma patients. Front Med (Lausanne) 2021;8:692341.
• [50] Yamane H, Isozaki H, Takeyama M, Ochi N, Kudo K, Honda Y, Yamagishi T, Kubo T, Kiura K, Takigawa N. Programmed cell death protein 1 and programmed death-ligand 1 are expressed on the surface of some small-cell lung cancer lines. Am J Cancer Res 2015;5(4):1553-1557.