{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T22:51:38Z","timestamp":1777503098249,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T00:00:00Z","timestamp":1685059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNPq","award":["406360\/2022-7"],"award-info":[{"award-number":["406360\/2022-7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>The World Health Organization has estimated the annual occurrence of approximately 392 million dengue virus (DENV) infections in more than 100 countries where the virus is endemic, which represents a serious threat to humanity. DENV is a serologic group with four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) belonging to the genus Flavivirus, in the family Flaviviridae. Dengue is the most widespread mosquito-borne disease in the world. The ~10.7 kb DENV genome encodes three structural proteins (capsid (C), pre-membrane (prM), and envelope (E)) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The NS1 protein is a membrane-associated dimer and a secreted, lipid-associated hexamer. Dimeric NS1 is found on membranes both in cellular compartments and cell surfaces. Secreted NS1 (sNS1) is often present in patient serum at very high levels, which correlates with severe dengue symptoms. This study was conducted to discover how the NS1 protein, microRNAs-15\/16 (miRNAs-15\/16), and apoptosis are related during DENV-4 infection in human liver cell lines. Huh 7.5 and HepG2 cells were infected with DENV-4, and miRNAs-15\/16, viral load, NS1 protein, and caspases-3\/7 were quantified after different durations of infection. This study demonstrated that miRNAs-15\/16 were overexpressed during the infection of HepG2 and Huh 7.5 cells with DENV-4 and had a relationship with NS1 protein expression, viral load, and the activity of caspases-3\/7, thus making these miRNAs potential injury markers during DENV infection in human hepatocytes.<\/jats:p>","DOI":"10.3390\/cimb45060291","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T02:24:37Z","timestamp":1685067877000},"page":"4589-4599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Experimental Dengue Virus Type 4 Infection Increases the Expression of MicroRNAs-15\/16, Triggering a Caspase-Induced Apoptosis Pathway"],"prefix":"10.3390","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7419-3381","authenticated-orcid":false,"given":"Samir Mansour Moraes","family":"Casseb","sequence":"first","affiliation":[{"name":"Experimental Pathology Section, Evandro Chagas Institute, Ananindeua 67030-000, PA, Brazil"},{"name":"Oncology Research Center, Federal University of Par\u00e1, Bel\u00e9m 66075-110, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla Fabiane Lopes de","family":"Melo","sequence":"additional","affiliation":[{"name":"Experimental Pathology Section, Evandro Chagas Institute, Ananindeua 67030-000, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6615-1387","authenticated-orcid":false,"given":"Carlos Alberto Marques de","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Par\u00e1 State, Bel\u00e9m 66050-540, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina Ramos dos","family":"Santos","sequence":"additional","affiliation":[{"name":"Experimental Pathology Section, Evandro Chagas Institute, Ananindeua 67030-000, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edna Cristina Santos","family":"Franco","sequence":"additional","affiliation":[{"name":"Experimental Pathology Section, Evandro Chagas Institute, Ananindeua 67030-000, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6603-5527","authenticated-orcid":false,"given":"Pedro Fernando da Costa","family":"Vasconcelos","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Par\u00e1 State, Bel\u00e9m 66050-540, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Horstick, O., Tozan, Y., and Wilder-Smith, A. (2015). Reviewing dengue: Still a neglected tropical disease?. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003632"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.yjmcc.2018.09.002","article-title":"Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles","volume":"123","author":"Li","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3201\/eid1101.031091","article-title":"Dengue and dengue hemorrhagic fever, Brazil, 1981-2002","volume":"11","author":"Siqueira","year":"2005","journal-title":"Emerg. Infect. Dis."},{"key":"ref_4","first-page":"1","article-title":"Clinical and Laboratory Profile of Zika and Dengue Infected Patients: Lessons Learned from the Co-circulation of Dengue, Zika and Chikungunya in Brazil","volume":"10","author":"Azeredo","year":"2018","journal-title":"PLoS Curr. Influenza"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.virusres.2018.10.018","article-title":"Dengue virus potentially promotes migratory responses on endothelial cells by enhancing pro-migratory soluble factors and miRNAs","volume":"259","year":"2019","journal-title":"Virus Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1016\/j.celrep.2017.11.094","article-title":"A global interactome map of the dengue virus NS1 identifies virus restriction and dependency host factors","volume":"21","author":"Hafirassou","year":"2017","journal-title":"Cell. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.12688\/f1000research.19197.1","article-title":"Recent advances in understanding dengue. [version 1; peer review: 2 approved]","volume":"8","author":"Halstead","year":"2019","journal-title":"F1000Res"},{"key":"ref_8","first-page":"857","article-title":"NS1, Dengue\u2019s Dagger","volume":"221","author":"Halstead","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yen, P.-S., Chen, C.-H., Sreenu, V., Kohl, A., and Failloux, A.-B. (2019). Assessing the potential interactions between cellular miRNA and arboviral genomic RNA in the yellow fever mosquito, Aedes aegypti. Viruses, 11.","DOI":"10.3390\/v11060540"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3389\/fendo.2018.00402","article-title":"Overview of microrna biogenesis, mechanisms of actions, and circulation","volume":"9","author":"Hayder","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s13105-010-0050-6","article-title":"Biological functions of microRNAs: A review","volume":"67","author":"Huang","year":"2011","journal-title":"J. Physiol. Biochem."},{"key":"ref_12","first-page":"E6659","article-title":"Degradation of unmethylated miRNA\/miRNA*s by a DEDDy-type 3\u2019 to 5\u2019 exoribonuclease Atrimmer 2 in Arabidopsis","volume":"115","author":"Wang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1672-0229(08)60044-3","article-title":"A brief review on the mechanisms of miRNA regulation","volume":"7","author":"Cai","year":"2009","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5242","DOI":"10.1038\/s41467-018-07667-z","article-title":"Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection","volume":"9","author":"Jayathilaka","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-virology-101416-041848","article-title":"The good, the bad, and the shocking: The multiple roles of dengue virus nonstructural protein 1 in protection and pathogenesis","volume":"5","author":"Glasner","year":"2018","journal-title":"Annu. Rev. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jep.2016.12.049","article-title":"Honeysuckle aqueous extract and induced let-7a suppress dengue virus type 2 replication and pathogenesis","volume":"198","author":"Lee","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4977","DOI":"10.1128\/JCM.43.10.4977-4983.2005","article-title":"Serotype-specific detection of dengue viruses in a fourplex real-time reverse transcriptase PCR assay","volume":"43","author":"Johnson","year":"2005","journal-title":"J. Clin. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4238\/gmr.15027891","article-title":"Drosha, DGCR8, and Dicer mRNAs are down-regulated in human cells infected with dengue virus 4, and play a role in viral pathogenesis","volume":"15","author":"Casseb","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4238\/gmr.15039050","article-title":"Letter to the Editor \u201cDrosha, DGCR8, and Dicer mRNAs are downregulated in human cells infected with dengue virus 4\u201d - Genet. Mol. Res. 15 (2): Gmr.15027891\u2014Drosha, Dicer, and TRBP mRNA are downregulated in Vero cells with the 3\u2019UTR of Dengue virus","volume":"15","author":"Castillo","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1089\/vim.2016.0149","article-title":"Yellow Fever Virus Modulates the Expression of Key Proteins Related to the microRNA Pathway in the Human Hepatocarcinoma Cell Line HepG2","volume":"30","author":"Holanda","year":"2017","journal-title":"Viral Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fmicb.2020.00024","article-title":"The E3 ubiquitin ligase SIAH1 targets myd88 for proteasomal degradation during dengue virus infection","volume":"11","author":"Smith","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1016\/j.celrep.2019.07.064","article-title":"miR-15\/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival","volume":"28","author":"Gagnon","year":"2019","journal-title":"Cell. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.3389\/fimmu.2019.03079","article-title":"The Interplay Between Viral-Derived miRNAs and Host Immunity During Infection","volume":"10","author":"Mishra","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fnmol.2018.00116","article-title":"Autoimmune neurological conditions associated with zika virus infection","volume":"11","author":"Monsalve","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"304ra142","DOI":"10.1126\/scitranslmed.aaa3863","article-title":"Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity","volume":"7","author":"Modhiran","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Alhoot, M.A., Wang, S.M., and Sekaran, S.D. (2012). RNA interference mediated inhibition of dengue virus multiplication and entry in HepG2 cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034060"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/cdd.2009.69","article-title":"miR-15a and miR-16-1 in cancer: Discovery, function and future perspectives","volume":"17","author":"Aqeilan","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5554","DOI":"10.1038\/s41598-020-72892-w","article-title":"Differential expression analysis and profiling of hepatic miRNA and isomiRNA in dengue hemorrhagic fever","volume":"11","author":"Pagliari","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.4049\/jimmunol.1201976","article-title":"Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3\u03b2 and NF-\u03baB activation","volume":"191","author":"Chen","year":"2013","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.4049\/jimmunol.1302675","article-title":"Dengue viral protease interaction with NF-\u03baB inhibitor \u03b1\/\u03b2 results in endothelial cell apoptosis and hemorrhage development","volume":"193","author":"Lin","year":"2014","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"195","DOI":"10.7150\/ijms.13996","article-title":"Dysregulated Serum MiRNA Profile and Promising Biomarkers in Dengue-infected Patients","volume":"13","author":"Ouyang","year":"2016","journal-title":"Int. J. Med. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s00705-021-05298-2","article-title":"Mammalian animal models for dengue virus infection: A recent overview","volume":"167","author":"Kayesh","year":"2021","journal-title":"Arch. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nanaware, N., Banerjee, A., Mullick Bagchi, S., Bagchi, P., and Mukherjee, A. (2021). Dengue virus infection: A tale of viral exploitations and host responses. Viruses, 13.","DOI":"10.3390\/v13101967"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12929-019-0614-x","article-title":"Role of microRNAs in antiviral responses to dengue infection","volume":"27","author":"Wong","year":"2020","journal-title":"J. Biomed. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1128\/MCB.02005-06","article-title":"Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression","volume":"27","author":"Linsley","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s40291-015-0148-1","article-title":"Circulating miRNA-122, miRNA-199a, and miRNA-16 as Biomarkers for Early Detection of Hepatocellular Carcinoma in Egyptian Patients with Chronic Hepatitis C Virus Infection","volume":"19","author":"Fawzy","year":"2015","journal-title":"Mol. Diagn. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13944","DOI":"10.1073\/pnas.0506654102","article-title":"miR-15 and miR-16 induce apoptosis by targeting BCL2","volume":"102","author":"Cimmino","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1002\/jmv.23758","article-title":"Immunopathogenesis of dengue hemorrhagic fever: Contribution to the study of human liver lesions","volume":"86","author":"Pagliari","year":"2014","journal-title":"J. Med. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"783","DOI":"10.4269\/ajtmh.18-0761","article-title":"Significance of autophagy in dengue virus infection: A brief review","volume":"100","author":"Acharya","year":"2019","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lu, Z.-Y., Cheng, M.-H., Yu, C.-Y., Lin, Y.-S., Yeh, T.-M., Chen, C.-L., Chen, C.-C., Wan, S.-W., and Chang, C.-P. (2020). Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249702"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.meegid.2018.12.033","article-title":"Vitamin D-mediated attenuation of miR-155 in human macrophages infected with dengue virus: Implications for the cytokine response","volume":"69","author":"Arboleda","year":"2019","journal-title":"Infect. Genet. Evol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s00705-011-0969-0","article-title":"The dengue virus nonstructural protein 1 (NS1) increases NF-\u03baB transcriptional activity in HepG2 cells","volume":"156","author":"Silva","year":"2011","journal-title":"Arch. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.celrep.2019.01.036","article-title":"Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism","volume":"26","author":"Glasner","year":"2019","journal-title":"Cell. Rep."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/6\/291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:42:24Z","timestamp":1760125344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/6\/291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,26]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["cimb45060291"],"URL":"https:\/\/doi.org\/10.3390\/cimb45060291","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,26]]}}}