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Novel potential drugs for the treatment of primary open-angle glaucoma using protein-protein interaction network analysis

  • Parisima Ghaffarian Zavarzadeh (Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran) ;
  • Zahra Abedi (Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg)
  • Received : 2022.11.02
  • Accepted : 2023.01.07
  • Published : 2023.03.31

Abstract

Glaucoma is the second leading cause of irreversible blindness, and primary open-angle glaucoma (POAG) is the most common type. Due to inadequate diagnosis, treatment is often not administered until symptoms occur. Hence, approaches enabling earlier prediction or diagnosis of POAG are necessary. We aimed to identify novel drugs for glaucoma through bioinformatics and network analysis. Data from 36 samples, obtained from the trabecular meshwork of healthy individuals and patients with POAG, were acquired from a dataset. Next, differentially expressed genes (DEGs) were identified to construct a protein-protein interaction (PPI) network. In both stages, the genes were enriched by studying the critical biological processes and pathways related to POAG. Finally, a drug-gene network was constructed, and novel drugs for POAG treatment were proposed. Genes with p < 0.01 and |log fold change| > 0.3 (1,350 genes) were considered DEGs and utilized to construct a PPI network. Enrichment analysis yielded several key pathways that were upregulated or downregulated. For example, extracellular matrix organization, the immune system, neutrophil degranulation, and cytokine signaling were upregulated among immune pathways, while signal transduction, the immune system, extracellular matrix organization, and receptor tyrosine kinase signaling were downregulated. Finally, novel drugs including metformin hydrochloride, ixazomib citrate, and cisplatin warrant further analysis of their potential roles in POAG treatment. The candidate drugs identified in this computational analysis require in vitro and in vivo validation to confirm their effectiveness in POAG treatment. This may pave the way for understanding life-threatening disorders such as cancer.

Keywords

References

  1. Suo L, Dai W, Qin X, Li G, Zhang D, Cheng T, et al. Screening of primary open-angle glaucoma diagnostic markers based on immune-related genes and immune infiltration. BMC Genom Data 2022;23:67.
  2. Imperato JS, Zou KH, Li JZ, Hassan TA. Clinical practice management of primary open-angle glaucoma in the United States: an analysis of real-world evidence. Patient Prefer Adherence 2022;16:2213-2227. https://doi.org/10.2147/PPA.S367443
  3. Hosseini SS, Abedi Z, Maghsoudloo M, Sheikh Beig Goharrizi MA, Shojaei A. Investigation of genes associated with primary open-angle glaucoma (POAG) using expression profile analysis. J Ophthalmol Optom Sci 2019;3:37-54.
  4. Weinreb RN, Leung CK, Crowston JG, Medeiros FA, Friedman DS, Wiggs JL, et al. Primary open-angle glaucoma. Nat Rev Dis Primers 2016;2:16067.
  5. Gharahkhani P, Jorgenson E, Hysi P, Khawaja AP, Pendergrass S, Han X, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nat Commun 2021;12:1258.
  6. Storgaard L, Tran TL, Freiberg JC, Hauser AS, Kolko M. Glaucoma clinical research: trends in treatment strategies and drug development. Front Med (Lausanne) 2021;8:733080.
  7. Al Owaifeer AM, Al Taisan AA. The role of diet in glaucoma: a review of the current evidence. Ophthalmol Ther 2018;7:19-31. https://doi.org/10.1007/s40123-018-0120-3
  8. Schmidl D, Schmetterer L, Garhofer G, Popa-Cherecheanu A. Pharmacotherapy of glaucoma. J Ocul Pharmacol Ther 2015;31:63-77. https://doi.org/10.1089/jop.2014.0067
  9. Abedi Z, MotieGhader H, Maghsoudloo M, Sheikh Beig Goharrizi MA, Shojaei A, Masoudi-Nejad A. Novel potential drugs for therapy of age-related molecular degeneration using protein-protein interaction network (PPI) analysis. J Ophthalmic Optom Sci 2019;3:11-23.
  10. Liu Y, Allingham RR, Qin X, Layfield D, Dellinger AE, Gibson J, et al. Gene expression profile in human trabecular meshwork from patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2013;54:6382-6389. https://doi.org/10.1167/iovs.13-12128
  11. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015;43:e47.
  12. Chen SJ, Liao DL, Chen CH, Wang TY, Chen KC. Construction and analysis of protein-protein interaction network of heroin use disorder. Sci Rep 2019;9:4980.
  13. Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res 2022;50:W216-W221. https://doi.org/10.1093/nar/gkac194
  14. Li M, Wang J, Chen J. A fast agglomerate algorithm for mining functional modules in protein interaction networks. In: 2008 International Conference on BioMedical Engineering and Informatics, 2008 May 27-30, Sanya, China. New York: Institute of Electrical and Electronics Engineers, 2008.
  15. Freshour SL, Kiwala S, Cotto KC, Coffman AC, McMichael JF, Song JJ, et al. Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res 2021;49:D1144-D1151. https://doi.org/10.1093/nar/gkaa1084
  16. O'Callaghan J, Cassidy PS, Humphries P. Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway. Expert Opin Ther Targets 2017;21:1037-1050. https://doi.org/10.1080/14728222.2017.1386174
  17. Keller KE, Peters DM. Pathogenesis of glaucoma: extracellular matrix dysfunction in the trabecular meshwork. A review. Clin Exp Ophthalmol 2022;50:163-182.
  18. Tezel G, Wax MB. The immune system and glaucoma. Curr Opin Ophthalmol 2004;15:80-84. https://doi.org/10.1097/00055735-200404000-00003
  19. Mun Y, Hwang JS, Shin YJ. Role of neutrophils on the ocular surface. Int J Mol Sci 2021;22:10386.
  20. Gauthier AC, Liu J. Epigenetics and signaling pathways in glaucoma. Biomed Res Int 2017;2017:5712341.
  21. Kumar A, Li X. PDGF-C and PDGF-D in ocular diseases. Mol Aspects Med 2018;62:33-43. https://doi.org/10.1016/j.mam.2017.10.002
  22. Nickells RW. Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv Ophthalmol 1999;43 Suppl 1:S151-S161. https://doi.org/10.1016/S0039-6257(99)00029-6
  23. Mabuchi F, Sakurada Y, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S. Lack of association between p53 gene polymorphisms and primary open angle glaucoma in the Japanese population. Mol Vis 2009;15:1045-1049.
  24. Dimasi DP, Hewitt AW, Green CM, Mackey DA, Craig JE. Lack of association of p53 polymorphisms and haplotypes in high and normal tension open angle glaucoma. J Med Genet 2005;42:e55.
  25. Poyomtip T. Roles of toll-like receptor 4 for cellular pathogenesis in primary open-angle glaucoma: a potential therapeutic strategy. J Microbiol Immunol Infect 2019;52:201-206. https://doi.org/10.1016/j.jmii.2018.12.006
  26. George R, Asokan R, Vijaya L. Association of metformin use among diabetics and the incidence of primary open-angle glaucoma: the Chennai Eye Disease Incidence Study. Indian J Ophthalmol 2021;69:3336-3338. https://doi.org/10.4103/ijo.IJO_1486_21
  27. Lin HC, Stein JD, Nan B, Childers D, Newman-Casey PA, Thompson DA, et al. Association of geroprotective effects of metformin and risk of open-angle glaucoma in persons with diabetes mellitus. JAMA Ophthalmol 2015;133:915-923. https://doi.org/10.1001/jamaophthalmol.2015.1440
  28. Park J, Cho J, Song EJ. Ubiquitin-proteasome system (UPS) as a target for anticancer treatment. Arch Pharm Res 2020;43:1144-1161. https://doi.org/10.1007/s12272-020-01281-8
  29. Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, et al. The proteasome as a druggable target with multiple therapeutic potentialities: cutting and non-cutting edges. Pharmacol Ther 2020;213:107579.
  30. Abedi S, Yung G, Atilano SR, Thaker K, Chang S, Chwa M, et al. Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups. PeerJ 2020;8:e9908.
  31. De Potter P. Current treatment of retinoblastoma. Curr Opin Ophthalmol 2002;13:331-336. https://doi.org/10.1097/00055735-200210000-00007