{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T19:15:39Z","timestamp":1782414939569,"version":"3.54.5"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T00:00:00Z","timestamp":1650672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute ischemic stroke (AIS) is among the main causes of mortality worldwide. A rapid and opportune diagnosis is crucial to improve a patient\u2019s outcomes; despite the current advanced image technologies for diagnosis, their implementation is challenging. MicroRNAs have been recognized as useful as biomarkers since they are specific and stable for characterization of AIS. However, there is still a lack of consensus over the primary miRNAs implicated in AIS. Here, we performed a systematic review of the literature covering from 2015\u20132021 regarding miRNAs expression during AIS and built structural networks to analyze and identify the most common miRNAs expressed during AIS and shared pathways, genes, and compounds that seem to influence their expression. We identified two sets of miRNAs: on one side, a set that was independent of geographical location and tissue (miR-124, miR-107, miR-221, miR-223, miR-140, miR-151a, miR-181a, miR-320b, and miR-484); and on the other side, a set that was connected (hubs) in biological networks (miR-27b-3p, miR-26b-5p, miR-124-3p, miR-570-3p, miR-19a-3p, miR-101-3p and miR-25-3p), which altered FOXO3, FOXO4, and EP300 genes. Interestingly, such genes are involved in cell death, FOXO-mediated transcription, and brain-derived neurotrophic factor signaling pathways. Finally, our pharmacological network analysis depicted a set of toxicants and drugs related to AIS for the first time.<\/jats:p>","DOI":"10.3390\/ijms23094663","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"4663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Structural and Pharmacological Network Analysis of miRNAs Involved in Acute Ischemic Stroke: A Systematic Review"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1662-0872","authenticated-orcid":false,"given":"Oscar Salvador","family":"Barrera-V\u00e1zquez","sequence":"first","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 03500, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7186-8067","authenticated-orcid":false,"given":"Juan Carlos","family":"Gomez-Verjan","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Ram\u00edrez-Aldana","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Garc\u00eda-dela","family":"Torre","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Enfermedades Neurol\u00f3gicas, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2659-6864","authenticated-orcid":false,"given":"Nadia Alejandra","family":"Rivero-Segura","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart disease and stroke statistics-2019 update: A report from the american heart association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1007\/s11655-018-2843-3","article-title":"Unique MicroRNAs signature of lymphocyte of Yang and Yin syndromes in acute ischemic stroke patients","volume":"25","author":"Zhao","year":"2019","journal-title":"Chin. J. Integr. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1161\/CIRCRESAHA.116.308427","article-title":"Cerebral vascular disease and neurovascular injury in ischemic stroke","volume":"120","author":"Hu","year":"2017","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1001\/jama.2014.3203","article-title":"Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative","volume":"311","author":"Fonarow","year":"2014","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1177\/1941874415587680","article-title":"Management of postthrombolysis hemorrhagic and orolingual angioedema complications","volume":"5","author":"Aguilar","year":"2015","journal-title":"Neurohospitalist"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1177\/1971400916678226","article-title":"Quantification of image contrast of infarcts on computed tomography scans","volume":"30","author":"Gomolka","year":"2017","journal-title":"Neuroradiol. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.4103\/0972-5229.156468","article-title":"Problems and limitations in thrombolysis of acute stroke patients at a tertiary care center","volume":"19","author":"Gurav","year":"2015","journal-title":"Indian J. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1152\/physrev.00041.2015","article-title":"Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches","volume":"96","author":"Beermann","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3502518","DOI":"10.1155\/2020\/3502518","article-title":"Identification of novel long noncoding RNAs and Their Role in Abdominal Aortic Aneurysm","volume":"2020","author":"Maitiseyiti","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.molmed.2020.02.001","article-title":"Noncoding RNAs versus protein biomarkers in cardiovascular disease","volume":"26","author":"Schulte","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1080\/14737159.2020.1777859","article-title":"Liquid biopsy markers for stroke diagnosis","volume":"20","author":"Wijerathne","year":"2020","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.pneurobio.2017.08.002","article-title":"Impact of microRNAs on ischemic stroke: From pre- to post-disease","volume":"163\u2013164","author":"Li","year":"2018","journal-title":"Prog. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1161\/STROKEAHA.118.021010","article-title":"Role of non-coding RNAs in stroke","volume":"49","author":"Tiedt","year":"2018","journal-title":"Stroke"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.neuint.2013.12.006","article-title":"MicroRNAs affect BCL-2 family proteins in the setting of cerebral ischemia","volume":"77","author":"Ouyang","year":"2014","journal-title":"Neurochem. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"971","DOI":"10.3892\/mmr.2014.2245","article-title":"Identification of miRNA-21 and miRNA-24 in plasma as potential early stage markers of acute cerebral infarction","volume":"10","author":"Zhou","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dhiraj, D.K., Chrysanthou, E., Mallucci, G.R., and Bushell, M. (2013). miRNAs-19b, -29b-2* and -339-5p show an early and sustained up-regulation in ischemic models of stroke. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083717"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1161\/CIRCRESAHA.111.300418","article-title":"MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia","volume":"112","author":"Spinetti","year":"2013","journal-title":"Circ. Res."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.procs.2017.06.132","article-title":"On the use of networks in biomedicine","volume":"110","author":"Vocaturo","year":"2017","journal-title":"Procedia Comput. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"162","DOI":"10.5853\/jos.2020.05085","article-title":"Diagnostic and prognostic circulating MicroRNA in acute stroke: A systematic and bioinformatic analysis of current evidence","volume":"23","author":"Bejleri","year":"2021","journal-title":"J. Stroke"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1177\/0963689718773361","article-title":"The roles of MicroRNAs in stroke: Possible therapeutic targets","volume":"27","author":"Xu","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.09.058","article-title":"Circulating MicroRNAs as biomarkers for acute ischemic stroke: A systematic review","volume":"27","author":"Dewdney","year":"2018","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.2147\/IJGM.S319503","article-title":"Identification of an miRNA regulatory network and candidate markers for ischemic stroke related to diabetes","volume":"14","author":"Zhou","year":"2021","journal-title":"Int. J. Gen. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Xie, Q., Zhang, X., Peng, S., Sun, J., Chen, X., Deng, Y., and Yi, L. (2020). Identification of novel biomarkers in ischemic stroke: A genome-wide integrated analysis. BMC Med. Genet., 21.","DOI":"10.1186\/s12881-020-00994-3"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., and Lin, C.Y. (2014). cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol., 8.","DOI":"10.1186\/1752-0509-8-S4-S11"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1093\/bioinformatics\/bti551","article-title":"BiNGO: A Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks","volume":"21","author":"Maere","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.1038\/s41467-019-11247-0","article-title":"Fast and covariate-adaptive method amplifies detection power in large-scale multiple hypothesis testing","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1016\/j.biochi.2012.05.029","article-title":"Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2\u2032-deoxycytidine in anaplastic large cell lymphoma","volume":"94","author":"Hassler","year":"2012","journal-title":"Biochimie"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5417","DOI":"10.2147\/IJN.S250047","article-title":"The potential anticancer activity of 5-fluorouracil loaded in cellulose fibers isolated from rice straw","volume":"15","author":"Yusefi","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112627","DOI":"10.1016\/j.ejmech.2020.112627","article-title":"MC Anticancer property of ginsenoside Rh2 from ginseng","volume":"203","author":"Li","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1289\/ehp.1002614","article-title":"Epigenetic changes induced by air toxics: Formaldehyde exposure alters miRNA expression profiles in human lung cells","volume":"119","author":"Rager","year":"2011","journal-title":"Environ. Health Perspect."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s13277-011-0259-1","article-title":"Alteration in miRNA gene expression pattern in acute promyelocytic leukemia cell induced by arsenic trioxide: A possible mechanism to explain arsenic multi-target action","volume":"33","author":"Ghaffari","year":"2012","journal-title":"Tumour Biol."},{"key":"ref_34","unstructured":"Enna, S.J., and Bylund, D.B. (2009). xPharm: The Comprehensive Pharmacology Reference, Elsevier."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.foodchem.2019.05.144","article-title":"Gallotannin 1,2,6-tri-O-galloyl-\u03b2-d-glucopyranose: Its availability and changing patterns in tea (Camellia sinensis)","volume":"296","author":"Wei","year":"2019","journal-title":"Food Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1713540","DOI":"10.1080\/20013078.2020.1713540","article-title":"Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes","volume":"9","author":"Kalani","year":"2020","journal-title":"J. Extracell. Vesicles"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"166","DOI":"10.5853\/jos.2016.01368","article-title":"Emerging roles of microRNAs in ischemic stroke: As possible therapeutic agents","volume":"19","author":"Khoshnam","year":"2017","journal-title":"J. Stroke"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.4103\/1673-5374.219025","article-title":"MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury","volume":"12","author":"Martinez","year":"2017","journal-title":"Neural Regen. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Condrat, C.E., Thompson, D.C., Barbu, M.G., Bugnar, O.L., Boboc, A., Cretoiu, D., Suciu, N., Cretoiu, S.M., and Voinea, S.C. (2020). miRNAs as biomarkers in disease: Latest findings regarding their role in diagnosis and prognosis. Cells, 9.","DOI":"10.3390\/cells9020276"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bulygin, K.V., Beeraka, N.M., Saitgareeva, A.R., Nikolenko, V.N., Gareev, I., Beylerli, O., Akhmadeeva, L.R., Mikhaleva, L.M., Torres Solis, L.F., and Sol\u00eds Herrera, A. (2020). Can miRNAs be considered as diagnostic and therapeutic molecules in ischemic stroke pathogenesis?-Current status. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186728"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e9881","DOI":"10.1590\/1414-431x20209881","article-title":"Circulating nucleic acids in the plasma and serum as potential biomarkers in neurological disorders","volume":"53","author":"Bruno","year":"2020","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.atherosclerosis.2019.08.002","article-title":"Increased plasma levels of miR-124-3p, miR-125b-5p and miR-192-5p are associated with outcomes in acute ischaemic stroke patients receiving thrombolysis","volume":"289","author":"He","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_43","first-page":"925350","article-title":"FOXO transcription factors: Their clinical significance and regulation","volume":"2014","author":"Wang","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.neuropharm.2012.06.035","article-title":"Activation of Akt\/FoxO and inactivation of MEK\/ERK pathways contribute to induction of neuroprotection against transient global cerebral ischemia by delayed hypoxic postconditioning in adult rats","volume":"63","author":"Zhan","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/s11064-011-0648-2","article-title":"FoxO3a changes in pyramidal neurons and expresses in non-pyramidal neurons and astrocytes in the gerbil hippocampal CA1 region after transient cerebral ischemia","volume":"37","author":"Yoo","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1080\/00207454.2018.1564290","article-title":"FoxO3 transcription factor promotes autophagy after transient cerebral ischemia\/reperfusion","volume":"129","author":"Zhou","year":"2019","journal-title":"Int. J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4314\/tjpr.v20i1.4","article-title":"Downregulation of FOxO4 promotes neuronal survival by mediating oxidative-stress\u2013induced apoptosis after cerebral ischemia\/reperfusion injury","volume":"20","author":"Deng","year":"2021","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/bs.pmbts.2019.05.006","article-title":"Chapter ten\u2014The dark proteome of cancer: Intrinsic disorderedness and functionality of HIF-1\u03b1 along with its interacting proteins","volume":"Volume 166","author":"Uversky","year":"2019","journal-title":"Progress in Molecular Biology and Translational Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/bs.apcsb.2017.07.004","article-title":"Probing the protein-protein interaction network of proteins causing maturity onset diabetes of the young","volume":"110","author":"Sneha","year":"2018","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tibs.2004.12.002","article-title":"Regulation of FoxO activity by CBP\/p300-mediated acetylation","volume":"30","author":"Smidt","year":"2005","journal-title":"Trends Biochem. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4663\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:59:17Z","timestamp":1760137157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,23]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23094663"],"URL":"https:\/\/doi.org\/10.3390\/ijms23094663","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,23]]}}}