Identifying Oxidative Stress-Related Genes (OSRGs) as Potential Target
for Treating Periodontitis Based on Bioinformatics Analysis

Wei      Zhou; Pengfei      Zhang; Hao      li

doi:10.2174/1386207326666230821102623

Abstract

Background: Periodontitis (PD) is a multifactorial inflammatory disease that is closely associated with periodontopathic bacteria. Numerous studies have demonstrated oxidative stress (OS) contributes to inflammation and is a prime factor in the development of PD. It is imperative to explore the function of newly discovered hub genes associated with OS in the advancement of PD, thereby identifying potential targets for therapeutic intervention.

Objectives: The goal of the current study was to identify the oxidative-stress-related genes (OSRGs) associated with periodontitis (PD) development using an integrated bioinformatics method.

Methods: DEGs from GEO gene-expression data were identified using the "limma" package. We obtained OSRGs from GeneCards and utilized a Venn diagram to uncover differentially expressed OSRGs (DEOSRGs). After receiving the DEOSRGs, we employed Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analytical tools to examine their possible functions and pathways in PD. Receiver operating characteristic (ROC) curves screened for hub genes of PD. RT-qPCR and western blot analysis were used to detect DEOSRG expression in mouse ligature-induced periodontitis gingival tissues.

Results: The investigation identified 273 OSRGs. Based on PPI analysis, we recognized 20 OSRGs as hub genes. GO and KEGG enrichment analysis indicated that these hub genes were predominantly enriched in leukocyte migration, lymphocyte proliferation, and humoral immune response, and associated with leukocyte trans-endothelial migration, cytokine-cytokine receptor interaction, and NF-κB signaling pathway. Following ROC analysis, VCAM1, ITGAM, FCGR3A, IL1A, PECAM1, and VCAM1were identified as PD prognostic gene. RT-qPCR and western blot analyses confirmed that the expression ITGAM, FCGR3A, and PECAM1 were significantly elevated in the gingival tissues obtained from mice.

Conclusion: This investigation revealed that ITGAM, FCGR3A, and PECAM1 may have a crucial function in the advancement of PD.

« Previous Next »

Graphical Abstract

[1]
Sudha, K.M.; Murugesan, G.; Subaramoniam, M.; Dutta, T.; Dhanasekar, K. A comparative study of synbiotic as an add-on therapy to standard treatment in patients with aggressive periodontitis. J. Indian Soc. Periodontol.,  2018, 22(5), 438-441.
 [http://dx.doi.org/10.4103/jisp.jisp_155_18] [PMID: 30210194]

[2]
Liu, Q.; Guo, S.; Huang, Y.; Wei, X.; Liu, L.; Huo, F.; Huang, P.; Wu, Y.; Tian, W. Inhibition of TRPA1 ameliorates periodontitis by reducing periodontal ligament cell oxidative stress and apoptosis via PERK/eIF2α/ATF-4/CHOP signal pathway. Oxid. Med. Cell. Longev.,  2022, 2022, 1-16.
 [http://dx.doi.org/10.1155/2022/4107915] [PMID: 35720191]

[3]
Riep, B.; Edesi-Neuß, L.; Claessen, F.; Skarabis, H.; Ehmke, B.; Flemmig, T.F.; Bernimoulin, J.P.; Göbel, U.B.; Moter, A. Are putative periodontal pathogens reliable diagnostic markers? J. Clin. Microbiol.,  2009, 47(6), 1705-1711.
 [http://dx.doi.org/10.1128/JCM.01387-08] [PMID: 19386852]

[4]
Munenaga, S.; Ouhara, K.; Hamamoto, Y.; Kajiya, M.; Takeda, K.; Yamasaki, S.; Kawai, T.; Mizuno, N.; Fujita, T.; Sugiyama, E.; Kurihara, H. The involvement of C5a in the progression of experimental arthritis with Porphyromonas gingivalis infection in SKG mice. Arthritis Res. Ther.,  2018, 20(1), 247.
 [http://dx.doi.org/10.1186/s13075-018-1744-3] [PMID: 30390695]

[5]
Ying, S.; Tan, M.; Feng, G.; Kuang, Y.; Chen, D.; Li, J.; Song, J. Low-intensity pulsed ultrasound regulates alveolar bone homeostasis in experimental periodontitis by diminishing oxidative stress. Theranostics,  2020, 10(21), 9789-9807.
 [http://dx.doi.org/10.7150/thno.42508] [PMID: 32863960]

[6]
Cornacchione, L.P.; Klein, B.A.; Duncan, M.J.; Hu, L.T. Interspecies Inhibition of Porphyromonas gingivalis by Yogurt-Derived Lactobacillus delbrueckii Requires Active Pyruvate Oxidase. Appl. Environ. Microbiol.,  2019, 85(18), e01271-e19.
 [http://dx.doi.org/10.1128/AEM.01271-19] [PMID: 31285191]

[7]
Jeong, S.H.; Lee, J.I.E.U.N.; Kim, B.O.B.A.E.; Ko, Y.; Park, J.B. Evaluation of the effects of Cimicifugae Rhizoma on the morphology and viability of mesenchymal stem cells. Exp. Ther. Med.,  2015, 10(2), 629-634.
 [http://dx.doi.org/10.3892/etm.2015.2578] [PMID: 26622366]

[8]
Oortgiesen, D.A.W.; Yu, N.; Bronckers, A.L.J.J.; Yang, F.; Walboomers, X.F.; Jansen, J.A. A three-dimensional cell culture model to study the mechano-biological behavior in periodontal ligament regeneration. Tissue Eng. Part C Methods,  2012, 18(2), 81-89.
 [http://dx.doi.org/10.1089/ten.tec.2011.0367] [PMID: 21913838]

[9]
Wang, L.; Xu, M.L.; Liu, J.; Wang, Y.; Hu, J.H.; Wang, M.H. Sonchus asper extract inhibits LPS-induced oxidative stress and pro-inflammatory cytokine production in RAW264.7 macrophages. Nutr. Res. Pract.,  2015, 9(6), 579-585.
 [http://dx.doi.org/10.4162/nrp.2015.9.6.579] [PMID: 26634045]

[10]
Circu, M.L.; Aw, T.Y. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic. Biol. Med.,  2010, 48(6), 749-762.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.022] [PMID: 20045723]

[11]
Su, H.; Gornitsky, M.; Velly, A.M.; Yu, H.; Benarroch, M.; Schipper, H.M. Salivary DNA, lipid, and protein oxidation in nonsmokers with periodontal disease. Free Radic. Biol. Med.,  2009, 46(7), 914-921.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2009.01.008] [PMID: 19280702]

[12]
Karna, K.K.; Choi, B.R.; You, J.H.; Shin, Y.S.; Cui, W.S.; Lee, S.W.; Kim, J.H.; Kim, C.Y.; Kim, H.K.; Park, J.K. The ameliorative effect of monotropein, astragalin, and spiraeoside on oxidative stress, endoplasmic reticulum stress, and mitochondrial signaling pathway in varicocelized rats. BMC Complement. Altern. Med.,  2019, 19(1), 333.
 [http://dx.doi.org/10.1186/s12906-019-2736-9] [PMID: 31771569]

[13]
Abidar, S.; Boiangiu, R.; Dumitru, G.; Todirascu-Ciornea, E.; Amakran, A.; Cioanca, O.; Hritcu, L.; Nhiri, M. The aqueous extract from Ceratonia siliqua leaves protects against 6-hydroxydopamine in zebrafish: Understanding the underlying mechanism. Antioxidants,  2020, 9(4), 304.
 [http://dx.doi.org/10.3390/antiox9040304] [PMID: 32276477]

[14]
Bullon, P.; Cordero, M.D.; Quiles, J.L.; Ramirez-Tortosa, M.C.; Gonzalez-Alonso, A.; Alfonsi, S.; García-Marín, R.; de Miguel, M.; Battino, M. Autophagy in periodontitis patients and gingival fibroblasts: Unraveling the link between chronic diseases and inflammation. BMC Med.,  2012, 10(1), 122.
 [http://dx.doi.org/10.1186/1741-7015-10-122] [PMID: 23075094]

[15]
Ebersole, J.L.; Kirakodu, S.S.; Gonzalez, O.A. Oral microbiome interactions with gingival gene expression patterns for apoptosis, autophagy and hypoxia pathways in progressing periodontitis. Immunology,  2021, 162(4), 405-417.
 [http://dx.doi.org/10.1111/imm.13292] [PMID: 33314069]

[16]
Kuang, Y.; Hu, B.; Feng, G.; Xiang, M.; Deng, Y.; Tan, M.; Li, J.; Song, J. Metformin prevents against oxidative stress-induced senescence in human periodontal ligament cells. Biogerontology,  2020, 21(1), 13-27.
 [http://dx.doi.org/10.1007/s10522-019-09838-x] [PMID: 31559522]

[17]
Chapple, I.L.C.; Milward, M.R.; Dietrich, T. The prevalence of inflammatory periodontitis is negatively associated with serum antioxidant concentrations. J. Nutr.,  2007, 137(3), 657-664.
 [http://dx.doi.org/10.1093/jn/137.3.657] [PMID: 17311956]

[18]
Chen, M.; Cai, W.; Zhao, S.; Shi, L.; Chen, Y.; Li, X.; Sun, X.; Mao, Y.; He, B.; Hou, Y.; Zhou, Y.; Zhou, Q.; Ma, J.; Huang, S. Oxidative stress‐related biomarkers in saliva and gingival crevicular fluid associated with chronic periodontitis: A systematic review and meta‐analysis. J. Clin. Periodontol.,  2019, 46(6), 608-622.
 [http://dx.doi.org/10.1111/jcpe.13112] [PMID: 30989678]

[19]
Pacios, S.; Kang, J.; Galicia, J.; Gluck, K.; Patel, H.; Ovaydi-Mandel, A.; Petrov, S.; Alawi, F.; Graves, D.T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation. FASEB J.,  2012, 26(4), 1423-1430.
 [http://dx.doi.org/10.1096/fj.11-196279] [PMID: 22179526]

[20]
Geng, F.; Liu, J.; Yin, C.; Zhang, S.; Pan, Y.; Sun, H. Porphyromonas gingivalis lipopolysaccharide induced RIPK3/MLKL-mediated necroptosis of oral epithelial cells and the further regulation in macrophage activation. J. Oral Microbiol.,  2022, 14(1), 2041790.
 [http://dx.doi.org/10.1080/20002297.2022.2041790] [PMID: 35251521]

[21]
Riccia, D.N.D.; Bizzini, F.; Perilli, M.G.; Polimeni, A.; Trinchieri, V.; Amicosante, G.; Cifone, M.G. Anti-inflammatory effects of Lactobacillus brevis (CD2) on periodontal disease. Oral Dis.,  2007, 13(4), 376-385.
 [http://dx.doi.org/10.1111/j.1601-0825.2006.01291.x] [PMID: 17577323]

[22]
Zhuang, Z.; Yoshizawa-Smith, S.; Glowacki, A.; Maltos, K.; Pacheco, C.; Shehabeldin, M.; Mulkeen, M.; Myers, N.; Chong, R.; Verdelis, K.; Garlet, G.P.; Little, S.; Sfeir, C. Induction of M2 macrophages prevents bone loss in murine periodontitis models. J. Dent. Res.,  2019, 98(2), 200-208.
 [http://dx.doi.org/10.1177/0022034518805984] [PMID: 30392438]

[23]
Lee, S.; Kim, S.; Kim, S.; Lee, I. Assessment of phytotoxicity of ZnO NPs on a medicinal plant, Fagopyrum esculentum. Environ. Sci. Pollut. Res. Int.,  2013, 20(2), 848-854.
 [http://dx.doi.org/10.1007/s11356-012-1069-8] [PMID: 22814961]

[24]
Zhao, M.; Tang, S.; Xin, J.; Wei, Y.; Liu, D. Reactive oxygen species induce injury of the intestinal epithelium during hyperoxia. Int. J. Mol. Med.,  2018, 41(1), 322-330.
 [PMID: 29138796]

[25]
Araújo, A.A.; Pereira, A.S.B.F.; Medeiros, C.A.C.X.; Brito, G.A.C.; Leitão, R.F.C.; Araújo, L.S.; Guedes, P.M.M.; Hiyari, S.; Pirih, F.Q.; Araújo Júnior, R.F. Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS One,  2017, 12(8), e0183506.
 [http://dx.doi.org/10.1371/journal.pone.0183506] [PMID: 28847008]

[26]
Bullon, P.; Morillo, J.M.; Ramirez-Tortosa, M.C.; Quiles, J.L.; Newman, H.N.; Battino, M. Metabolic syndrome and periodontitis: Is oxidative stress a common link? J. Dent. Res.,  2009, 88(6), 503-518.
 [http://dx.doi.org/10.1177/0022034509337479] [PMID: 19587154]

[27]
Konečná, B.; Chobodová, P.; Janko, J.; Baňasová, L.; Bábíčková, J.; Celec, P.; Tóthová, Ľ. The effect of melatonin on periodontitis. Int. J. Mol. Sci.,  2021, 22(5), 2390.
 [http://dx.doi.org/10.3390/ijms22052390] [PMID: 33673616]

[28]
Zhong, M.; Huang, J.; Wu, Z.; Chan, K.G.; Wang, L.; Li, J.; Lee, L.H.; Law, J.W.F. Potential roles of selectins in periodontal diseases and associated systemic diseases: Could they be targets for immunotherapy? Int. J. Mol. Sci.,  2022, 23(22), 14280.
 [http://dx.doi.org/10.3390/ijms232214280] [PMID: 36430760]

[29]
Räisänen, I.T.; Umeizudike, K.A.; Pärnänen, P.; Heikkilä, P.; Tervahartiala, T.; Nwhator, S.O.; Grigoriadis, A.; Sakellari, D.; Sorsa, T. Periodontal disease and targeted prevention using aMMP-8 point-of-care oral fluid analytics in the COVID-19 era. Med. Hypotheses,  2020, 144, 110276.
 [http://dx.doi.org/10.1016/j.mehy.2020.110276] [PMID: 33254580]

[30]
Folwaczny, M.; Karnesi, E.; Berger, T.; Paschos, E. Clinical association between chronic periodontitis and the leukocyte extravasation inhibitors developmental endothelial locus-1 and pentraxin-3. Eur. J. Oral Sci.,  2017, 125(4), 258-264.
 [http://dx.doi.org/10.1111/eos.12357] [PMID: 28643381]

[31]
Lam, F.W.; Brown, C.A.; Valladolid, C.; Emebo, D.C.; Palzkill, T.G.; Cruz, M.A. The vimentin rod domain blocks P-selectin-P-selectin glycoprotein ligand 1 interactions to attenuate leukocyte adhesion to inflamed endothelium. PLoS One,  2020, 15(10), e0240164.
 [http://dx.doi.org/10.1371/journal.pone.0240164] [PMID: 33048962]

[32]
Morgan, M.J.; Liu, Z. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res.,  2011, 21(1), 103-115.
 [http://dx.doi.org/10.1038/cr.2010.178] [PMID: 21187859]

[33]
Azizidoost, S.; Asnafi, A.A.; Saki, N. Signaling–chemokine axis network in brain as a sanctuary site for metastasis. J. Cell. Physiol.,  2019, 234(4), 3376-3382.
 [http://dx.doi.org/10.1002/jcp.27305] [PMID: 30187487]

[34]
Ruytinx, P.; Proost, P.; Van Damme, J.; Struyf, S. Chemokine-induced macrophage polarization in inflammatory conditions. Front. Immunol.,  2018, 9, 1930.
 [http://dx.doi.org/10.3389/fimmu.2018.01930] [PMID: 30245686]

[35]
Zeng, Y.; Cao, S.; Chen, M. Integrated analysis and exploration of potential shared gene signatures between carotid atherosclerosis and periodontitis. BMC Med. Genomics,  2022, 15(1), 227.
 [http://dx.doi.org/10.1186/s12920-022-01373-y] [PMID: 36316672]

[36]
Pan, Y.; Yu, C.; Huang, J.; Rong, Y.; Chen, J.; Chen, M. Bioinformatics analysis of vascular RNA-seq data revealed hub genes and pathways in a novel Tibetan minipig atherosclerosis model induced by a high fat/cholesterol diet. Lipids Health Dis.,  2020, 19(1), 54.
 [http://dx.doi.org/10.1186/s12944-020-01222-w] [PMID: 32213192]

[37]
Alpdogan, S.; Clemens, R.; Hescheler, J.; Neumaier, F.; Schneider, T. Non-Mendelian inheritance during inbreeding of Cav3.2 and Cav2.3 deficient mice. Sci. Rep.,  2020, 10(1), 15993.
 [http://dx.doi.org/10.1038/s41598-020-72912-9] [PMID: 33009476]

[38]
Larjava, H.; Koivisto, L.; Heino, J.; Häkkinen, L. Integrins in periodontal disease. Exp. Cell Res.,  2014, 325(2), 104-110.
 [http://dx.doi.org/10.1016/j.yexcr.2014.03.010] [PMID: 24662197]

[39]
Ebersole, J.L.; Orraca, L.; Novak, M.J.; Kirakodu, S.; Gonzalez-Martinez, J.; Gonzalez, O.A. Comparative analysis of gene expression patterns for oral epithelium-related functions with aging. Adv. Exp. Med. Biol.,  2019, 1197, 143-163.
 [http://dx.doi.org/10.1007/978-3-030-28524-1_11] [PMID: 31732940]

[40]
Guzeldemir-Akcakanat, E.; Alkan, B.; Sunnetci-Akkoyunlu, D.; Gurel, B.; Balta, V.M.; Kan, B.; Akgun, E.; Yilmaz, E.B.; Baykal, A.T.; Cine, N.; Olgac, V.; Gumuslu, E.; Savli, H. Molecular signatures of chronic periodontitis in gingiva: A genomic and proteomic analysis. J. Periodontol.,  2019, 90(6), 663-673.
 [http://dx.doi.org/10.1002/JPER.18-0477] [PMID: 30653263]

[41]
Chai, L.; Song, Y.Q.; Zee, K.Y.; Leung, W.K. SNPs of Fc-gamma receptor genes and chronic periodontitis. J. Dent. Res.,  2010, 89(7), 705-710.
 [http://dx.doi.org/10.1177/0022034510365444] [PMID: 20439936]

[42]
Pavkovic, M.; Petlichkovski, A.; Karanfilski, O.; Cevreska, L.; Stojanovic, A. FC gamma receptor polymorphisms in patients with immune thrombocytopenia. Hematology,  2018, 23(3), 163-168.
 [http://dx.doi.org/10.1080/10245332.2017.1377902] [PMID: 28942727]

[43]
Ning, W.; Acharya, A.; Sun, Z.; Ogbuehi, A.C.; Li, C.; Hua, S.; Ou, Q.; Zeng, M.; Liu, X.; Deng, Y.; Haak, R.; Ziebolz, D.; Schmalz, G.; Pelekos, G.; Wang, Y.; Hu, X. Deep learning reveals key immunosuppression genes and distinct immunotypes in periodontitis. Front. Genet.,  2021, 12, 648329.
 [http://dx.doi.org/10.3389/fgene.2021.648329] [PMID: 33777111]

[44]
Kobayashi, T.; Yamamoto, K.; Sugita, N.; van der Pol, W.L.; Yasuda, K.; Kaneko, S.; van de Winkel, J.G.J.; Yoshie, H. The Fc gamma receptor genotype as a severity factor for chronic periodontitis in Japanese patients. J. Periodontol.,  2001, 72(10), 1324-1331.
 [http://dx.doi.org/10.1902/jop.2001.72.10.1324] [PMID: 11699473]

[45]
Privratsky, J.R.; Newman, D.K.; Newman, P.J. PECAM-1:] Conflicts of interest in inflammation. Life Sci.,  2010, 87(3-4), 69-82.
 [http://dx.doi.org/10.1016/j.lfs.2010.06.001] [PMID: 20541560]

[46]
Liu, Y.; Zhang, Z.; Li, W.; Tian, S. PECAM1 Combines with CXCR4 to trigger inflammatory cell infiltration and pulpitis progression through activating the NF-κB signaling pathway. Front. Cell Dev. Biol.,  2020, 8, 593653.
 [http://dx.doi.org/10.3389/fcell.2020.593653] [PMID: 33425898]

[47]
Farrugia, C.; Stafford, G.P.; Potempa, J.; Wilkinson, R.N.; Chen, Y.; Murdoch, C.; Widziolek, M. Mechanisms of vascular damage by systemic dissemination of the oral pathogen Porphyromonas gingivalis. FEBS J.,  2021, 288(5), 1479-1495.
 [http://dx.doi.org/10.1111/febs.15486] [PMID: 32681704]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207326666230821102623	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Identifying Oxidative Stress-Related Genes (OSRGs) as Potential Target for Treating Periodontitis Based on Bioinformatics Analysis

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract