Identification of Cross-talk Pathways and Ferroptosis-related Genes in Periodontitis and Type 2 Diabetes Mellitus by Bioinformatics Analysis and Experimental Validation

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Oct 17

PMID 36248844

Authors

Shengyuan Pan

Bo Hu

Jicheng Sun

Zun Yang

Wenliang Yu

Zangmin He

Xiang Gao

Jinlin Song

Affiliations

Soon will be listed here.

Abstract

Purpose: There is a bidirectional relationship between periodontitis and type 2 diabetes mellitus (T2DM). The aim of this study was to further explore the pathogenesis of this comorbidity, screen out ferroptosis-related genes involved in the pathological process, and predict potential drug targets to develop new therapeutic strategies.

Methods: Common cross-talk genes were identified from periodontitis datasets (GSE16134, GSE10334 and GSE106090) and T2DM databases (DisGeNET and GeneCard). Then, GO and KEGG enrichment analyses, PPI network analysis and hub gene identification were performed. The association between ferroptosis and periodontitis with T2DM was investigated by Pearson correlation analysis. Core ferroptosis-related cross-talk genes were identified and verified by qRT-PCR. Potential drugs targeting these core genes were predicted DGIDB.

Results: In total, 67 cross-talk genes and two main signalling pathways (immuno-inflammatory pathway and AGE-RAGE signalling pathway) were identified. Pearson correlation analysis indicated that ferroptosis served as a crucial target in the pathological mechanism and treatment of periodontitis with T2DM. IL-1β, IL-6, NFE2L2 and ALOX5 were identified as core ferroptosis-related genes and the qRT-PCR detection results were statistically different. In total, 13 potential drugs were screened out, among which, Echinacea and Ibudilast should be developed first.

Conclusions: This study contributes to a deeper understanding of the common pathogenesis of periodontitis and T2DM and provides new insights into the role of ferroptosis in this comorbidity. In addition, two drugs with potential clinical application value were identified. The potential utility of these drugs requires further experimental investigation.

Citing Articles

Single-Cell and Transcriptome Analysis of Periodontitis: Molecular Subtypes and Biomarkers Linked to Mitochondrial Dysfunction and Immunity.

Ma S, He H, Ren X J Inflamm Res. 2025; 17:11659-11678.

PMID: 39741754 PMC: 11687296. DOI: 10.2147/JIR.S498739.

Targeting protein tyrosine phosphatase non-receptor type 6 (PTPN6) as a therapeutic strategy in acute myeloid leukemia.

Wang X, Li Z, Shen J, Liu L Cell Biol Toxicol. 2024; 41(1):11.

PMID: 39707066 PMC: 11662038. DOI: 10.1007/s10565-024-09965-3.

The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative Review.

Ghemis L, Goriuc A, Jipu R, Foia L, Luchian I Int J Mol Sci. 2024; 25(23.

PMID: 39684494 PMC: 11641189. DOI: 10.3390/ijms252312784.

Identification of CAPG as a potential prognostic biomarker associated with immune cell infiltration and ferroptosis in uterine corpus endometrial carcinoma.

Liu J, Zhu W, Xia L, Zhu Q, Mao Y, Shen Y Front Endocrinol (Lausanne). 2024; 15:1452219.

PMID: 39600941 PMC: 11588481. DOI: 10.3389/fendo.2024.1452219.

Bioinformatics analysis based on extracted ingredients combined with network pharmacology, molecular docking and molecular dynamics simulation to explore the mechanism of Jinbei oral liquid in the therapy of idiopathic pulmonary fibrosis.

Han X, Zhang A, Meng Z, Wang Q, Liu S, Wang Y Heliyon. 2024; 10(18):e38173.

PMID: 39364246 PMC: 11447332. DOI: 10.1016/j.heliyon.2024.e38173.

References

Kassebaum N, Bernabe E, Dahiya M, Bhandari B, Murray C, Marcenes W . Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J Dent Res. 2014; 93(11):1045-53. PMC: 4293771. DOI: 10.1177/0022034514552491. View

Borgnakke W, Ylostalo P, Taylor G, Genco R . Effect of periodontal disease on diabetes: systematic review of epidemiologic observational evidence. J Clin Periodontol. 2013; 40 Suppl 14:S135-52. DOI: 10.1111/jcpe.12080. View

Zheng Y, Ley S, Hu F . Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2017; 14(2):88-98. DOI: 10.1038/nrendo.2017.151. View

Polak D, Sanui T, Nishimura F, Shapira L . Diabetes as a risk factor for periodontal disease-plausible mechanisms. Periodontol 2000. 2020; 83(1):46-58. DOI: 10.1111/prd.12298. View

Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M, Telser J . Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2006; 39(1):44-84. DOI: 10.1016/j.biocel.2006.07.001. View

Christgen S, Tweedell R, Kanneganti T . Programming inflammatory cell death for therapy. Pharmacol Ther. 2021; 232:108010. PMC: 8930427. DOI: 10.1016/j.pharmthera.2021.108010. View

. 2. Classification and Diagnosis of Diabetes: . Diabetes Care. 2020; 44(Suppl 1):S15-S33. DOI: 10.2337/dc21-S002. View

Alikhani M, Alikhani Z, Boyd C, MacLellan C, Raptis M, Liu R . Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 2006; 40(2):345-53. PMC: 1913208. DOI: 10.1016/j.bone.2006.09.011. View

Clanchy F, Williams R . Ibudilast Inhibits Chemokine Expression in Rheumatoid Arthritis Synovial Fibroblasts and Exhibits Immunomodulatory Activity in Experimental Arthritis. Arthritis Rheumatol. 2018; 71(5):703-711. DOI: 10.1002/art.40787. View

10.

Shou Y, Yang L, Yang Y, Xu J . Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation. Cell Death Dis. 2021; 12(11):1009. PMC: 8551323. DOI: 10.1038/s41419-021-04284-5. View

11.

Yu Y, Yan Y, Niu F, Wang Y, Chen X, Su G . Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov. 2021; 7(1):193. PMC: 8313570. DOI: 10.1038/s41420-021-00579-w. View

12.

Byun K, Yoo Y, Son M, Lee J, Jeong G, Park Y . Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases. Pharmacol Ther. 2017; 177:44-55. DOI: 10.1016/j.pharmthera.2017.02.030. View

13.

Lalla E, Papapanou P . Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat Rev Endocrinol. 2011; 7(12):738-48. DOI: 10.1038/nrendo.2011.106. View

14.

Yang B, Chen Y, Shi J . Reactive Oxygen Species (ROS)-Based Nanomedicine. Chem Rev. 2019; 119(8):4881-4985. DOI: 10.1021/acs.chemrev.8b00626. View

15.

Lubcke P, Ebbers M, Volzke J, Bull J, Kneitz S, Engelmann R . Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss. Sci Rep. 2019; 9(1):8128. PMC: 6544621. DOI: 10.1038/s41598-019-44512-9. View

16.

Kinane D, Stathopoulou P, Papapanou P . Periodontal diseases. Nat Rev Dis Primers. 2017; 3:17038. DOI: 10.1038/nrdp.2017.38. View

17.

Zimmet P, Magliano D, Herman W, Shaw J . Diabetes: a 21st century challenge. Lancet Diabetes Endocrinol. 2014; 2(1):56-64. DOI: 10.1016/S2213-8587(13)70112-8. View

18.

de Souza Malta F, Napimoga M, Marins L, Miranda T, de Oliveira F, Posch A . Lithium chloride assuages bone loss in experimental periodontitis in estrogen-deficient rats. Clin Oral Investig. 2019; 24(6):2025-2036. DOI: 10.1007/s00784-019-03067-9. View

19.

Freshour S, Kiwala S, Cotto K, Coffman A, McMichael J, Song J . Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res. 2020; 49(D1):D1144-D1151. PMC: 7778926. DOI: 10.1093/nar/gkaa1084. View

20.

Yin M, Zhou L, Ji Y, Lu R, Ji W, Jiang G . identification and verification of ferroptosis-related genes in type 2 diabetic islets. Front Endocrinol (Lausanne). 2022; 13:946492. PMC: 9388850. DOI: 10.3389/fendo.2022.946492. View