{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:50:00Z","timestamp":1777477800219,"version":"3.51.4"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IRCCS Centro Neurolesi &quot;Bonino-Pulejo\u201d, Messina, Italy","award":["current research funds 2021"],"award-info":[{"award-number":["current research funds 2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease caused by a lack of dystrophin, leading to membrane instability, cell damage, and inflammatory response. However, gene-editing alone is not enough to restore the healthy phenotype and additional treatments are required. In the present study, we have first conducted a meta-analysis of three microarray datasets, GSE38417, GSE3307, and GSE6011, to identify the differentially expressed genes (DEGs) between healthy donors and DMD patients. We have then integrated this analysis with the knowledge obtained from DisGeNET and DIAMOnD, a well-known algorithm for drug\u2013gene association discoveries in the human interactome. The data obtained allowed us to identify novel possible target genes and were used to predict potential therapeutical options that could reverse the pathological condition.<\/jats:p>","DOI":"10.3390\/genes12040543","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T10:05:21Z","timestamp":1617962721000},"page":"543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Network Medicine Approach for Drug Repurposing in Duchenne Muscular Dystrophy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6723-7019","authenticated-orcid":false,"given":"Salvo Danilo","family":"Lombardo","sequence":"first","affiliation":[{"name":"Department of Structural &amp; Computational Biology at the Max Perutz Labs, University of Vienna, 1010 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4811-4694","authenticated-orcid":false,"given":"Maria Sofia","family":"Basile","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosella","family":"Ciurleo","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Bramanti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Arcidiacono","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-4620","authenticated-orcid":false,"given":"Katia","family":"Mangano","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Placido","family":"Bramanti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-8462","authenticated-orcid":false,"given":"Ferdinando","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-1992","authenticated-orcid":false,"given":"Paolo","family":"Fagone","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Darras, B.T., Menache-Starobinski, C.C., Hinton, V., and Kunkel, L.M. (2015). Dystrophinopathies. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician\u2019s Approach, Academic Press.","DOI":"10.1016\/B978-0-12-417044-5.00030-5"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1093\/hmg\/ddn376","article-title":"Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy","volume":"18","author":"Villalta","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.15252\/emmm.201403967","article-title":"Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR 2","volume":"6","author":"Mojumdar","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18168","DOI":"10.3390\/molecules201018168","article-title":"Duchenne muscular dystrophy: From diagnosis to therapy","volume":"20","author":"Falzarano","year":"2015","journal-title":"Molecules"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.resp.2015.12.001","article-title":"Evidence of hypoxic tolerance in weak upper airway muscle from young mdx mice","volume":"226","author":"Burns","year":"2016","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1590\/0004-282x20190088","article-title":"Duchenne muscular dystrophy: An historical treatment review","volume":"77","author":"Werneck","year":"2019","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_7","first-page":"1","article-title":"Exon skipping for Duchenne muscular dystrophy: A systematic review and meta-analysis","volume":"13","author":"Murakami","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S202","DOI":"10.1016\/S1525-0016(16)34114-4","article-title":"Treatment of DMD 5\u2032 mutations through two different EXON2 skipping strategies: Intramuscular delivery of RAAV9.snrna mediated skipping and antisense morpholino oligomers","volume":"23","author":"Simmons","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_9","first-page":"247","article-title":"Exon skipping induced by nonsense\/frameshift mutations in DMD gene results in Becker muscular dystrophy","volume":"139","author":"Okubo","year":"2020","journal-title":"Qual. Life Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Shimizu-Motohashi, Y., Komaki, H., Motohashi, N., Takeda, S., Yokota, T., and Aoki, Y. (2019). Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: Current Status of Therapeutic Approaches. J. Pers. Med., 9.","DOI":"10.3390\/jpm9010001"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/dmcn.14129","article-title":"A new era in the management of Duchenne muscular dystrophy","volume":"61","author":"Korinthenberg","year":"2019","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/j.ymthe.2018.07.011","article-title":"Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy","volume":"26","author":"Duan","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/s41582-019-0203-3","article-title":"Therapeutic developments for Duchenne muscular dystrophy","volume":"15","author":"Verhaart","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_15","first-page":"56","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-020-0153-3","article-title":"Network-based drug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2","volume":"6","author":"Zhou","year":"2020","journal-title":"Cell Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.coph.2019.12.004","article-title":"Next-generation drug repurposing using human genetics and network biology","volume":"51","author":"Nabirotchkin","year":"2020","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-05116-5","article-title":"Network-based approach to prediction and population-based validation of in silico drug repurposing","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_19","first-page":"D845","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Ronzano","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ghiassian, S.D., Menche, J., and Barab\u00e1si, A.-L. (2015). A DIseAse MOdule Detection (DIAMOnD) Algorithm Derived from a Systematic Analysis of Connectivity Patterns of Disease Proteins in the Human Interactome. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004120"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1093\/bioinformatics\/bty060","article-title":"L1000FWD: Fireworks visualization of drug-induced transcriptomic signatures","volume":"34","author":"Wang","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D1068","DOI":"10.1093\/nar\/gkx1143","article-title":"DGIdb 3.0: A redesign and expansion of the drug\u2013gene interaction database","volume":"46","author":"Cotto","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D1138","DOI":"10.1093\/nar\/gkaa891","article-title":"Comparative Toxicogenomics Database (CTD): Update 2021","volume":"49","author":"Davis","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1093\/brain\/awl023","article-title":"Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb\u2013MyoD pathways in muscle regeneration","volume":"129","author":"Bakay","year":"2006","journal-title":"Brain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1083\/jcb.201402079","article-title":"Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy","volume":"207","author":"Dadgar","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1096\/fj.06-7285com","article-title":"Gene expression profiling in the early phases of DMD: A constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression","volume":"21","author":"Pescatori","year":"2007","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W234","DOI":"10.1093\/nar\/gkz240","article-title":"NetworkAnalyst 3.0: A visual analytics platform for comprehensive gene expression profiling and meta-analysis","volume":"47","author":"Zhou","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1093\/bioinformatics\/btp444","article-title":"Moderated effect size and P-value combinations for microarray meta-analyses","volume":"25","author":"Marot","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_30","first-page":"1","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41596-018-0103-9","article-title":"Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap","volume":"14","author":"Reimand","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein\u2013protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.nmd.2014.03.008","article-title":"A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy","volume":"24","author":"Mah","year":"2014","journal-title":"Neuromuscul. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1093\/hmg\/ddv001","article-title":"A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma","volume":"24","author":"Sharma","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sonawane, A.R., Weiss, S.T., Glass, K., and Sharma, A. (2019). Network Medicine in the Age of Biomedical Big Data. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00294"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fiscon, G., Conte, F., Farina, L., and Paci, P. (2018). Network-Based Approaches to Explore Complex Biological Systems towards Network Medicine. Genes, 9.","DOI":"10.3390\/genes9090437"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lombardo, S.D., Mazzon, E., Mangano, K., Basile, M.S., Cavalli, E., Mammana, S., Fagone, P., Nicoletti, F., and Petralia, M.C. (2019). Transcriptomic Analysis Reveals Involvement of the Macrophage Migration Inhibitory Factor Gene Network in Duchenne Muscular Dystrophy. Genes, 10.","DOI":"10.3390\/genes10110939"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0022-510X(78)90183-1","article-title":"Experimental (\u2212) emetine myopathy","volume":"39","author":"Bindoff","year":"1978","journal-title":"J. Neurol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/BF00314772","article-title":"Emetine-induced myopathy and carnitine deficiency","volume":"237","author":"Kuntzer","year":"1990","journal-title":"J. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1073\/pnas.0800979105","article-title":"Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1 and oxidative phosphorylation","volume":"105","author":"Arany","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4928","DOI":"10.1074\/jbc.273.9.4928","article-title":"Microtubule-interfering Agents Activate c-Jun N-terminal Kinase\/Stress-activated Protein Kinase through Both Ras and Apoptosis Signal-regulating Kinase Pathways","volume":"273","author":"Wang","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-06068-6","article-title":"Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy","volume":"9","author":"Malecova","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Madaro, L., Torcinaro, A., De Bardi, M., Contino, F.F., Pelizzola, M., Diaferia, G.R., Imeneo, G., Bouch\u00e8, M., Puri, P.L., and De Santa, F. (2019). Macrophages fine tune satellite cell fate in dystrophic skeletal muscle of mdx mice. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008408"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1093\/hmg\/ddv469","article-title":"Dasatinib as a treatment for Duchenne muscular dystrophy","volume":"25","author":"Lipscomb","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Sanarica, F., Mantuano, P., Conte, E., Cozzoli, A., Capogrosso, R., Giustino, A., Cutrignelli, A., Cappellari, O., Rolland, J., and De Bellis, M. (2019). Proof-of-concept validation of the mechanism of action of Src tyrosine kinase inhibitors in dystrophic mdx mouse muscle: In vivo and in vitro studies. Pharmacol. Res., 145.","DOI":"10.1016\/j.phrs.2019.104260"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bajanca, F., and Vandel, L. (2017). Epigenetic Regulators Modulate Muscle Damage in Duchenne Muscular Dystrophy Model. PLoS Curr., 9.","DOI":"10.1371\/currents.md.f1e2379fa632f8135577333dd92ca83b"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1172\/JCI89401","article-title":"Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity","volume":"127","author":"Teveroni","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ma, Z., Zhong, Z., Zheng, Z., Shi, X.-M., and Zhang, W. (2014). Inhibition of Glycogen Synthase Kinase-3\u03b2 Attenuates Glucocorticoid-Induced Suppression of Myogenic Differentiation In Vitro. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105528"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Verhees, K.J.P., Pansters, N.A.M., Baarsma, H.A., Remels, A.H.V., Haegens, A., de Theije, C.C., Schols, A.M.W.J., Gosens, R., and Langen, R.C.J. (2013). Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: II. Effects on skeletal muscle atrophy. Respir. Res., 14.","DOI":"10.1186\/1465-9921-14-117"},{"key":"ref_50","first-page":"13","article-title":"Evaluation of neural damage in Duchenne muscular dystrophy patients","volume":"33","author":"Salam","year":"2014","journal-title":"Acta Myol. Myopathies Cardiomyopathies Off. J. Mediterr. Soc. Myol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sharma, K.R., Mynhier, M.A., and Miller, R.G. (1993). Cyclosporine increases muscular force generation in Duhenne muscular dystrophy. Neurology, 43.","DOI":"10.1212\/WNL.43.3_Part_1.527"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S1474-4422(10)70196-4","article-title":"Treatment of Duchenne muscular dystrophy with ciclosporin A: A randomised, double-blind, placebo-controlled multicentre trial","volume":"9","author":"Kirschner","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12887-019-1503-x","article-title":"Observational study of clinical outcomes for testosterone treatment of pubertal delay in Duchenne muscular dystrophy","volume":"19","author":"Wood","year":"2019","journal-title":"BMC Pediatr."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/4\/543\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:26:36Z","timestamp":1760361996000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/4\/543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["genes12040543"],"URL":"https:\/\/doi.org\/10.3390\/genes12040543","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]}}}