{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T22:35:53Z","timestamp":1776206153115,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011223","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000}}],"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["311539\/2020-3"],"award-info":[{"award-number":["311539\/2020-3"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["306037\/2019-0"],"award-info":[{"award-number":["306037\/2019-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["E-26\/201.096\/2022"],"award-info":[{"award-number":["E-26\/201.096\/2022"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["E-26\/ 210.190\/2018"],"award-info":[{"award-number":["E-26\/ 210.190\/2018"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["U54MD007592"],"award-info":[{"award-number":["U54MD007592"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Chronic Chagas cardiomyopathy (CCC) is one of the leading causes of morbidity and mortality due to cardiovascular disorders in endemic areas of Chagas disease (CD), a neglected tropical illness caused by the protozoan parasite<jats:italic>Trypanosoma cruzi<\/jats:italic>. CCC is characterized by parasite persistence and inflammatory response in the heart tissue, which occur parallel to microRNA (miRNA) alterations. Here, we investigated the miRNA transcriptome profiling in the cardiac tissue of chronically<jats:italic>T<\/jats:italic>.<jats:italic>cruzi<\/jats:italic>-infected mice treated with a suboptimal dose of benznidazole (Bz), the immunomodulator pentoxifylline alone (PTX), or the combination of both (Bz+PTX), following the CCC onset. At 150 days post-infection, Bz, PTX, and Bz+PTX treatment regimens improved electrocardiographic alterations, reducing the percentage of mice afflicted by sinus arrhythmia and second-degree atrioventricular block (AVB2) when compared with the vehicle-treated animals. miRNA Transcriptome profiling revealed considerable changes in the differential expression of miRNAs in the Bz and Bz+PTX treatment groups compared with the control (infected, vehicle-treated) group. The latter showed pathways related to organismal abnormalities, cellular development, skeletal muscle development, cardiac enlargement, and fibrosis, likely associated with CCC. Bz-Treated mice exhibited 68 differentially expressed miRNAs related to signaling pathways like cell cycle, cell death and survival, tissue morphology, and connective tissue function. Finally, the Bz+PTX-treated group revealed 58 differentially expressed miRNAs associated with key signaling pathways related to cellular growth and proliferation, tissue development, cardiac fibrosis, damage, and necrosis\/cell death. The<jats:italic>T<\/jats:italic>.<jats:italic>cruzi<\/jats:italic>-induced upregulation of miR-146b-5p, previously shown in acutely infected mice and<jats:italic>in vitro T<\/jats:italic>.<jats:italic>cruzi<\/jats:italic>-infected cardiomyocytes, was reversed upon Bz and Bz+PTX treatment regimens when further experimentally validated. Our results further our understanding of molecular pathways related to CCC progression and evaluation of treatment response. Moreover, the differentially expressed miRNAs may serve as drug targets, associated molecular therapy, or biomarkers of treatment outcomes.<\/jats:p>","DOI":"10.1371\/journal.pntd.0011223","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T17:38:52Z","timestamp":1679938732000},"page":"e0011223","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Treatment with benznidazole and pentoxifylline regulates microRNA transcriptomic profile in a murine model of Chagas chronic cardiomyopathy"],"prefix":"10.1371","volume":"17","author":[{"given":"Priscila","family":"Silva Grij\u00f3 Farani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Iandra da Silva Ferreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khodeza","family":"Begum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glaucia","family":"Vilar-Pereira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabela Resende","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith A.","family":"Fern\u00e1ndez-Figueroa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto Alejandro","family":"Cardenas-Ovando","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor C.","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sourav","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseli","family":"Lannes-Vieira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5340-8697","authenticated-orcid":true,"given":"Otacilio Cruz","family":"Moreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"issue":"2","key":"pntd.0011223.ref001","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.idc.2012.03.002","article-title":"American trypanosomiasis (Chagas disease).","volume":"26","author":"A Rassi","year":"2012","journal-title":"Infect Dis Clin North Am"},{"key":"pntd.0011223.ref002","unstructured":"WHO. Chagas disease (American trypanosomiasis) 2021. Available from: https:\/\/www.who.int\/health-topics\/chagas-disease#."},{"issue":"10115","key":"pntd.0011223.ref003","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0140-6736(17)31612-4","article-title":"Chagas disease","volume":"391","author":"JA P\u00e9rez-Molina","year":"2018","journal-title":"The Lancet"},{"key":"pntd.0011223.ref004","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/978-3-030-44054-1_2","volume-title":"Chagas Disease: A Neglected Tropical Disease","author":"B Alarc\u00f3n de Noya","year":"2020"},{"key":"pntd.0011223.ref005","article-title":"Review of pharmacological options for the treatment of Chagas disease","author":"F Lascano","year":"2020","journal-title":"Br J Clin Pharmacol"},{"key":"pntd.0011223.ref006","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ejim.2017.05.001","article-title":"Chagas disease in Europe: A review for the internist in the globalized world","volume":"43","author":"S Antinori","year":"2017","journal-title":"Eur J Intern Med"},{"issue":"4","key":"pntd.0011223.ref007","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S1473-3099(13)70002-1","article-title":"Global economic burden of Chagas disease: a computational simulation model","volume":"13","author":"BY Lee","year":"2013","journal-title":"The Lancet Infectious diseases"},{"issue":"9723","key":"pntd.0011223.ref008","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/S0140-6736(10)60061-X","article-title":"Chagas disease","volume":"375","author":"A Rassi","year":"2010","journal-title":"The Lancet"},{"issue":"12","key":"pntd.0011223.ref009","first-page":"e169","article-title":"Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association","volume":"138","author":"MCP Nunes","year":"2018","journal-title":"Circulation"},{"issue":"26","key":"pntd.0011223.ref010","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1056\/NEJMct1014204","article-title":"Antitrypanosomal therapy for chronic Chagas\u2019 disease","volume":"364","author":"C. Bern","year":"2011","journal-title":"N Engl J Med"},{"key":"pntd.0011223.ref011","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/B978-0-12-801029-7.00029-0","volume-title":"American Trypanosomiasis Chagas Disease (Second Edition).","author":"A Rassi","year":"2017"},{"issue":"3","key":"pntd.0011223.ref012","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1590\/0074-02760160334","article-title":"Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial","volume":"112","author":"A Rassi","year":"2017","journal-title":"Mem Inst Oswaldo Cruz"},{"issue":"5","key":"pntd.0011223.ref013","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1590\/S0074-02762002000500002","article-title":"The impact of Chagas disease control in Latin America, a review","volume":"97","author":"JC Dias","year":"2002","journal-title":"Mem Inst Oswaldo Cruz"},{"issue":"10","key":"pntd.0011223.ref014","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1080\/17512433.2018.1509704","article-title":"Clinical and pharmacological profile of benznidazole for treatment of Chagas disease","volume":"11","author":"JM Kratz","year":"2018","journal-title":"Expert Rev Clin Pharmacol"},{"issue":"14","key":"pntd.0011223.ref015","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1056\/NEJMoa1507574","article-title":"Randomized Trial of Benznidazole for Chronic Chagas\u2019 Cardiomyopathy","volume":"373","author":"CA Morillo","year":"2015","journal-title":"N Engl J Med"},{"issue":"1","key":"pntd.0011223.ref016","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ijpddr.2015.12.001","article-title":"Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain","volume":"6","author":"AC Cevey","year":"2016","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"pntd.0011223.ref017","unstructured":"DNDi. BENDITA BEnznidazole New Doses Improved Treatment and Associations (BENDITA) 2019. Available from: https:\/\/www.dndial.org\/wp-content\/uploads\/2019\/03\/2page_BenditatStudyOverview_ENG.pdf."},{"key":"pntd.0011223.ref018","article-title":"New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial","author":"F Torrico","year":"2021","journal-title":"The Lancet Infectious Diseases"},{"issue":"1","key":"pntd.0011223.ref019","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1186\/s13063-020-4226-2","article-title":"Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized Phase II non-inferiority clinical trial","volume":"21","author":"D Molina-Morant","year":"2020","journal-title":"Trials"},{"issue":"12","key":"pntd.0011223.ref020","doi-asserted-by":"crossref","first-page":"e052897","DOI":"10.1136\/bmjopen-2021-052897","article-title":"New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia","volume":"11","author":"C Alonso-Vega","year":"2021","journal-title":"BMJ Open"},{"issue":"8","key":"pntd.0011223.ref021","doi-asserted-by":"crossref","first-page":"e0008529","DOI":"10.1371\/journal.pntd.0008529","article-title":"Fixed vs adjusted-dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: A systematic review and meta-analysis","volume":"14","author":"A Ciapponi","year":"2020","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0011223.ref022","doi-asserted-by":"crossref","first-page":"e000365","DOI":"10.1136\/openhrt-2015-000365","article-title":"Pentoxifylline for vascular health: a brief review of the literature","volume":"3","author":"MF McCarty","year":"2016","journal-title":"Open Heart"},{"key":"pntd.0011223.ref023","year":"2021","journal-title":"PubChem. Pentoxifylline"},{"issue":"7","key":"pntd.0011223.ref024","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1182\/blood.V84.7.2234.2234","article-title":"Pentoxifylline inhibits integrin-mediated adherence of interleukin-2- activated human peripheral blood lymphocytes to human umbilical vein endothelial cells, matrix components, and cultured tumor cells","volume":"84","author":"NL Kovach","year":"1994","journal-title":"Blood"},{"issue":"3","key":"pntd.0011223.ref025","doi-asserted-by":"crossref","first-page":"e0003659","DOI":"10.1371\/journal.pntd.0003659","article-title":"Pentoxifylline reverses chronic experimental Chagasic cardiomyopathy in association with repositioning of abnormal CD8+ T-cell response","volume":"9","author":"IR Pereira","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"issue":"7","key":"pntd.0011223.ref026","doi-asserted-by":"crossref","first-page":"4297","DOI":"10.1128\/AAC.02123-15","article-title":"Combination Chemotherapy with Suboptimal Doses of Benznidazole and Pentoxifylline Sustains Partial Reversion of Experimental Chagas\u2019 Heart Disease","volume":"60","author":"G Vilar-Pereira","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"pntd.0011223.ref027","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nbt0607-631","article-title":"MicroRNA gets down to business","volume":"25","author":"GS Mack","year":"2007","journal-title":"Nat Biotechnol"},{"issue":"2","key":"pntd.0011223.ref028","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: target recognition and regulatory functions","volume":"136","author":"DP Bartel","year":"2009","journal-title":"Cell"},{"issue":"2","key":"pntd.0011223.ref029","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nri2252","article-title":"Micromanagement of the immune system by microRNAs","volume":"8","author":"HF Lodish","year":"2008","journal-title":"Nature Reviews Immunology"},{"issue":"9","key":"pntd.0011223.ref030","doi-asserted-by":"crossref","first-page":"15891","DOI":"10.3390\/ijms150915891","article-title":"Small engine, big power: microRNAs as regulators of cardiac diseases and regeneration","volume":"15","author":"D Joladarashi","year":"2014","journal-title":"Int J Mol Sci"},{"key":"pntd.0011223.ref031","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev-phyto-073009-114457","article-title":"Role of small RNAs in host-microbe interactions","volume":"48","author":"S Katiyar-Agarwal","year":"2010","journal-title":"Annu Rev Phytopathol"},{"key":"pntd.0011223.ref032","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev.micro.112408.134243","article-title":"Viruses, microRNAs, and host interactions","volume":"64","author":"RL Skalsky","year":"2010","journal-title":"Annu Rev Microbiol"},{"issue":"11","key":"pntd.0011223.ref033","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.pt.2011.07.001","article-title":"Apicomplexan parasites and subversion of the host cell microRNA pathway","volume":"27","author":"MA Hakimi","year":"2011","journal-title":"Trends Parasitol"},{"issue":"6","key":"pntd.0011223.ref034","doi-asserted-by":"crossref","first-page":"742","DOI":"10.4161\/rna.20018","article-title":"The mammalian microRNA response to bacterial infections","volume":"9","author":"A Eulalio","year":"2012","journal-title":"RNA Biol"},{"issue":"3","key":"pntd.0011223.ref035","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ijcard.2014.05.019","article-title":"MicroRNAs miR-1, miR-133a, miR-133b, miR-208a and miR-208b are dysregulated in Chronic Chagas disease Cardiomyopathy","volume":"175","author":"LR Ferreira","year":"2014","journal-title":"Int J Cardiol"},{"issue":"12","key":"pntd.0011223.ref036","doi-asserted-by":"crossref","first-page":"e0008889","DOI":"10.1371\/journal.pntd.0008889","article-title":"miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy","volume":"14","author":"L Laugier","year":"2020","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0011223.ref037","doi-asserted-by":"crossref","first-page":"428","DOI":"10.3389\/fimmu.2015.00428","article-title":"Differential Expression of microRNAs in Thymic Epithelial Cells from Trypanosoma cruzi Acutely Infected Mice: Putative Role in Thymic Atrophy.","volume":"6","author":"L Linhares-Lacerda","year":"2015","journal-title":"Front Immunol"},{"issue":"6","key":"pntd.0011223.ref038","doi-asserted-by":"crossref","first-page":"e0003828","DOI":"10.1371\/journal.pntd.0003828","article-title":"MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes.","volume":"9","author":"IC Navarro","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0011223.ref039","article-title":"MicroRNA-155 Deficiency Exacerbates Trypanosoma cruzi Infection","author":"BK Jha","year":"2020","journal-title":"Infect Immun"},{"issue":"4","key":"pntd.0011223.ref040","doi-asserted-by":"crossref","first-page":"e1002645","DOI":"10.1371\/journal.ppat.1002645","article-title":"CD8+ T-cells expressing interferon gamma or perforin play antagonistic roles in heart injury in experimental Trypanosoma cruzi-elicited cardiomyopathy","volume":"8","author":"JC Silverio","year":"2012","journal-title":"PLoS Pathog"},{"issue":"3","key":"pntd.0011223.ref041","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1590\/0074-0276140033","article-title":"Severity of chronic experimental Chagas\u2019 heart disease parallels tumour necrosis factor and nitric oxide levels in the serum: models of mild and severe disease","volume":"109","author":"IR Pereira","year":"2014","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"pntd.0011223.ref042","doi-asserted-by":"crossref","first-page":"798078","DOI":"10.1155\/2014\/798078","article-title":"Tumor necrosis factor is a therapeutic target for immunological unbalance and cardiac abnormalities in chronic experimental Chagas\u2019 heart disease","volume":"2014","author":"IR Pereira","year":"2014","journal-title":"Mediators Inflamm"},{"issue":"4","key":"pntd.0011223.ref043","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":"KJ Livak","year":"2001","journal-title":"Methods"},{"issue":"6","key":"pntd.0011223.ref044","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"TD Schmittgen","year":"2008","journal-title":"Nat Protoc"},{"issue":"4","key":"pntd.0011223.ref045","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"A Kramer","year":"2014","journal-title":"Bioinformatics"},{"issue":"3","key":"pntd.0011223.ref046","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1161\/01.CIR.0000079174.13444.9C","article-title":"Prognostic value of QT interval parameters for mortality risk stratification in Chagas\u2019 disease: results of a long-term follow-up study","volume":"108","author":"G Salles","year":"2003","journal-title":"Circulation"},{"key":"pntd.0011223.ref047","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3389\/fcvm.2015.00026","article-title":"Long QT Syndrome: An Emerging Role for Inflammation and Immunity.","volume":"2","author":"PE Lazzerini","year":"2015","journal-title":"Front Cardiovasc Med"},{"issue":"1","key":"pntd.0011223.ref048","doi-asserted-by":"crossref","first-page":"17990","DOI":"10.1038\/s41598-017-18080-9","article-title":"Integration of miRNA and gene expression profiles suggest a role for miRNAs in the pathobiological processes of acute Trypanosoma cruzi infection","volume":"7","author":"LRP Ferreira","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"pntd.0011223.ref049","doi-asserted-by":"crossref","first-page":"e0244710","DOI":"10.1371\/journal.pone.0244710","article-title":"Memory impairment in chronic experimental Chagas disease: Benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue.","volume":"16","author":"G Vilar-Pereira","year":"2021","journal-title":"PLOS ONE"},{"issue":"7","key":"pntd.0011223.ref050","doi-asserted-by":"crossref","first-page":"e0007602","DOI":"10.1371\/journal.pntd.0007602","article-title":"TGF-\u03b2 inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas\u2019 heart disease","volume":"13","author":"RR Ferreira","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0011223.ref051","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1590\/0037-8682-0184-2018","article-title":"Electrocardiogram in Chagas disease","volume":"51","author":"BOdF Brito","year":"2018","journal-title":"Revista da Sociedade Brasileira de Medicina Tropical"},{"issue":"1","key":"pntd.0011223.ref052","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s12974-017-0952-0","article-title":"Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu","volume":"14","author":"AA Silva","year":"2017","journal-title":"J Neuroinflammation."},{"issue":"1","key":"pntd.0011223.ref053","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/s12920-021-01134-3","article-title":"Comprehensive analysis of miRNA-mRNA regulatory network and potential drugs in chronic chagasic cardiomyopathy across human and mouse","volume":"14","author":"J Wu","year":"2021","journal-title":"BMC Med Genomics"},{"issue":"7","key":"pntd.0011223.ref054","article-title":"Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease.","volume":"22","author":"CKV Nonaka","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"12","key":"pntd.0011223.ref055","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1016\/j.biochi.2012.08.018","article-title":"MicroRNA-467b targets LPL gene in RAW 264.7 macrophages and attenuates lipid accumulation and proinflammatory cytokine secretion","volume":"94","author":"GP Tian","year":"2012","journal-title":"Biochimie"},{"key":"pntd.0011223.ref056","article-title":"MiR-467b alleviates lipopolysaccharide-induced inflammation through targeting STAT1 in chondrogenic ATDC5 cells","author":"F Jin","year":"2021","journal-title":"International journal of immunogenetics"},{"key":"pntd.0011223.ref057","doi-asserted-by":"crossref","first-page":"683230","DOI":"10.1155\/2014\/683230","article-title":"Chagas disease cardiomyopathy: immunopathology and genetics","volume":"2014","author":"E Cunha-Neto","year":"2014","journal-title":"Mediators Inflamm"},{"key":"pntd.0011223.ref058","doi-asserted-by":"crossref","first-page":"8523","DOI":"10.1038\/ncomms9523","article-title":"miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program","volume":"6","author":"S Su","year":"2015","journal-title":"Nat Commun"},{"key":"pntd.0011223.ref059","doi-asserted-by":"crossref","first-page":"16262","DOI":"10.1038\/srep16262","article-title":"Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD-induced obesity by inhibiting PTEN","volume":"5","author":"J Ji","year":"2015","journal-title":"Sci Rep"},{"key":"pntd.0011223.ref060","doi-asserted-by":"crossref","first-page":"7016","DOI":"10.12659\/MSM.916361","article-title":"Inhibition of microRNA-141-3p Reduces Hypoxia-Induced Apoptosis in H9c2 Rat Cardiomyocytes by Activating the RP105-Dependent PI3K\/AKT Signaling Pathway","volume":"25","author":"Q Qin","year":"2019","journal-title":"Medical science monitor: international medical journal of experimental and clinical research"},{"key":"pntd.0011223.ref061","first-page":"7","article-title":"Mitogen-Activated Protein Kinase (MAPK) Pathway: Role in Immune Evasion by Trypanosomatids.","author":"M Soares-Silva","year":"2016","journal-title":"Frontiers in Microbiology"},{"issue":"1","key":"pntd.0011223.ref062","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1755-1536-5-15","article-title":"Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease","volume":"5","author":"D Fan","year":"2012","journal-title":"Fibrogenesis Tissue Repair"},{"issue":"3","key":"pntd.0011223.ref063","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1086\/653481","article-title":"Gene expression changes associated with myocarditis and fibrosis in hearts of mice with chronic chagasic cardiomyopathy","volume":"202","author":"MB Soares","year":"2010","journal-title":"J Infect Dis"},{"key":"pntd.0011223.ref064","doi-asserted-by":"crossref","first-page":"692655","DOI":"10.3389\/fcimb.2021.692655","article-title":"Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy.","volume":"11","author":"PSG Farani","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"pntd.0011223.ref065","article-title":"Antitrypanosomal Therapy for Chronic Chagas\u2019 Disease","author":"C. Bern","year":"2011","journal-title":"The New England Journal of Medicine"},{"issue":"6\u20137","key":"pntd.0011223.ref066","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.molimm.2010.12.021","article-title":"Benznidazole treatment attenuates liver NF-kappaB activity and MAPK in a cecal ligation and puncture model of sepsis","volume":"48","author":"MT Ronco","year":"2011","journal-title":"Mol Immunol"},{"key":"pntd.0011223.ref067","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.taap.2016.11.015","article-title":"Benznidazole, the trypanocidal drug used for Chagas disease, induces hepatic NRF2 activation and attenuates the inflammatory response in a murine model of sepsis","volume":"315","author":"F Lambertucci","year":"2017","journal-title":"Toxicol Appl Pharmacol"},{"issue":"7","key":"pntd.0011223.ref068","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s004360000357","article-title":"Treatment with benznidazole and its immunomodulating effects on Trypanosoma cruzi-infected rats","volume":"87","author":"E Piaggio","year":"2001","journal-title":"Parasitol Res"},{"issue":"2","key":"pntd.0011223.ref069","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1046\/j.1365-2249.1999.01053.x","article-title":"Benznidazole, a drug employed in the treatment of Chagas\u2019 disease, down-regulates the synthesis of nitrite and cytokines by murine stimulated macrophages","volume":"118","author":"S Revelli","year":"1999","journal-title":"Clinical and experimental immunology"},{"issue":"11","key":"pntd.0011223.ref070","first-page":"2335","article-title":"Chloroquine attenuates LPS-mediated macrophage activation through miR-669n-regulated SENP6 protein translation","volume":"7","author":"Y Long","year":"2015","journal-title":"American journal of translational research"},{"issue":"1","key":"pntd.0011223.ref071","first-page":"1535","article-title":"MicroRNA-509-3p inhibits cancer cell proliferation and migration by targeting the mitogen-activated protein kinase kinase kinase 8 oncogene in renal cell carcinoma","volume":"12","author":"Z Su","year":"2015","journal-title":"Molecular medicine reports"},{"key":"pntd.0011223.ref072","doi-asserted-by":"crossref","first-page":"2058738418786656","DOI":"10.1177\/2058738418786656","article-title":"miR-149-5p inhibits cell growth by regulating TWEAK\/Fn14\/PI3K\/AKT pathway and predicts favorable survival in human osteosarcoma","volume":"32","author":"RD Xu","year":"2018","journal-title":"International journal of immunopathology and pharmacology"},{"issue":"12","key":"pntd.0011223.ref073","doi-asserted-by":"crossref","first-page":"22874","DOI":"10.1002\/jcp.28850","article-title":"miR-497a-5p attenuates lipopolysaccharide-induced inflammatory injury by targeting IRAK2","volume":"234","author":"S Guo","year":"2019","journal-title":"Journal of cellular physiology"},{"issue":"5","key":"pntd.0011223.ref074","doi-asserted-by":"crossref","first-page":"e1644","DOI":"10.1371\/journal.pntd.0001644","article-title":"Inducible nitric oxide synthase in heart tissue and nitric oxide in serum of Trypanosoma cruzi-infected rhesus monkeys: association with heart injury","volume":"6","author":"CM Carvalho","year":"2012","journal-title":"PLoS Negl Trop Dis"},{"issue":"2","key":"pntd.0011223.ref075","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/eurjhf\/hfn040","article-title":"Immunological mechanisms of pentoxifylline in chronic heart failure","volume":"11","author":"SM Shaw","year":"2009","journal-title":"Eur J Heart Fail"},{"issue":"1","key":"pntd.0011223.ref076","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1038\/s41598-022-05493-4","article-title":"Modulation of miR-145-5p and miR-146b-5p levels is linked to reduced parasite load in H9C2 Trypanosoma cruzi infected cardiomyoblasts","volume":"12","author":"PSG Farani","year":"2022","journal-title":"Sci Rep"},{"key":"pntd.0011223.ref077","first-page":"737","article-title":"Differential regulation of microRNA-146a and microRNA-146b-5p in human retinal pigment epithelial cells by interleukin-1\u03b2, tumor necrosis factor-\u03b1, and interferon-\u03b3","volume":"19","author":"RK Kutty","year":"2013","journal-title":"Molecular vision"},{"issue":"4","key":"pntd.0011223.ref078","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1152\/physiolgenomics.00133.2016","article-title":"MiR-146a\/b: a family with shared seeds and different roots","volume":"49","author":"MR Paterson","year":"2017","journal-title":"Physiol Genomics"},{"issue":"Suppl 1","key":"pntd.0011223.ref079","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1590\/S0074-02762009000900032","article-title":"Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy","volume":"104","author":"E Cunha-Neto","year":"2009","journal-title":"Mem Inst Oswaldo Cruz"},{"issue":"6","key":"pntd.0011223.ref080","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.4049\/jimmunol.167.6.3422","article-title":"Trypanocidal drug benznidazole impairs lipopolysaccharide induction of macrophage nitric oxide synthase gene transcription through inhibition of NF-kappaB activation","volume":"167","author":"E Piaggio","year":"2001","journal-title":"J Immunol"},{"issue":"1","key":"pntd.0011223.ref081","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/vms3.204","article-title":"Effects of pentoxifylline on whole blood IL-2 and IFN-gamma gene expression in normal dogs","volume":"6","author":"E Kummari","year":"2020","journal-title":"Veterinary medicine and science"},{"issue":"4","key":"pntd.0011223.ref082","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/00042560-199512000-00004","article-title":"Inhibition of cytotoxicity and cytokine release of CD8+ HIV-specific cytotoxic T lymphocytes by pentoxifylline","volume":"10","author":"M Heinkelein","year":"1995","journal-title":"J Acquir Immune Defic Syndr Hum Retrovirol"},{"issue":"3","key":"pntd.0011223.ref083","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1590\/0074-02760140435","article-title":"Biomarkers of therapeutic responses in chronic Chagas disease: state of the art and future perspectives","volume":"110","author":"MJ Pinazo","year":"2015","journal-title":"Mem Inst Oswaldo Cruz"},{"issue":"7","key":"pntd.0011223.ref084","doi-asserted-by":"crossref","first-page":"165758","DOI":"10.1016\/j.bbadis.2020.165758","article-title":"State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response","volume":"1866","author":"N Cortes-Serra","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0011223","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011223","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T03:56:43Z","timestamp":1729137403000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011223"}},"subtitle":[],"editor":[{"given":"Armando","family":"Jardim","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,27]]},"references-count":84,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0011223","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0011223","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,27]]}}}