{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T02:45:17Z","timestamp":1784601917561,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of National Education, Ministry of Industry, Commerce and Tourism and ICETEX, call for scientific ecosystem \u2013 Scientific Colombia. Francisco Jos\u00e9 de Caldas Fund","award":["RC-FP44842-212-2018"],"award-info":[{"award-number":["RC-FP44842-212-2018"]}]},{"name":"the Vicerrector\u00eda de Investigaciones\u2014Universidad de Santander UDES","award":["001-18"],"award-info":[{"award-number":["001-18"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>In the late phase of Trypanosoma cruzi infection, parasite persistence and an exaggerated immune response accompanied by oxidative stress play a crucial role in the genesis of Chronic Chagasic Cardiomyopathy (CCC). Current treatments (Benznidazole (BNZ) and Nifurtimox) can effect only the elimination of the parasite, but are ineffective for late stage treatment and for preventing heart damage and disease progression. In vivo trypanocidal and cardioprotective activity has been reported for Lippia alba essential oils (EOs), ascribed to their two major terpenes, limonene and caryophyllene oxide. To investigate the role of antioxidant and immunomodulatory mechanisms behind these properties, chronic-T. cruzi-infected rats were treated with oral synergistic mixtures of the aforementioned EOs. For this purpose, the EOs were optimized through limonene-enrichment fractioning and by the addition of exogenous caryophyllene oxide (LIMOX) and used alone or in combined therapy with subtherapeutic doses of BNZ (LIMOXBNZ). Clinical, toxicity, inflammatory, oxidative, and parasitological (qPCR) parameters were assessed in cardiac tissue. These therapies demonstrated meaningful antioxidant and immunomodulatory activity on markers involved in CCC pathogenesis (IFN-\u03b3, TNF-\u03b1, IL-4, IL-10, and iNOS), which could explain their significant trypanocidal properties and their noteworthy role in preventing, and even reversing, the progression of cardiac damage in chronic Chagas disease.<\/jats:p>","DOI":"10.3390\/antiox10111851","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T02:55:17Z","timestamp":1637636117000},"page":"1851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Immunomodulation and Antioxidant Activities as Possible Trypanocidal and Cardioprotective Mechanisms of Major Terpenes from Lippia alba Essential Oils in an Experimental Model of Chronic Chagas Disease"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1961-6844","authenticated-orcid":false,"given":"Denerieth Ximena","family":"Espinel-Mesa","sequence":"first","affiliation":[{"name":"Infectious Diseases Postgraduate Program, Instituto de Investigaci\u00f3n Masira, Universidad de Santander, Bucaramanga 680006, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Isabel","family":"Gonz\u00e1lez Rugeles","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Epidemiology Group, School of Microbiology, Universidad Industrial de Santander, Bucaramanga 680002, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio C\u00e9sar","family":"Mantilla Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Pathology Department, School of Medicine, Universidad Industrial de Santander, Bucaramanga 680002, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-932X","authenticated-orcid":false,"given":"Elena E.","family":"Stashenko","sequence":"additional","affiliation":[{"name":"National Research Center for the Agroindustrialization of Tropical Aromatic and Medicinal Plant Species\u2014CENIVAM, Universidad Industrial de Santander, Bucaramanga 680002, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Andr\u00e9s","family":"Villegas-Lanau","sequence":"additional","affiliation":[{"name":"Neurosciences Group of Antioquia, Brain Bank, Universidad de Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Jaime","family":"Quimbaya Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Infectious Diseases Postgraduate Program, Instituto de Investigaci\u00f3n Masira, Universidad de Santander, Bucaramanga 680006, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9054-9328","authenticated-orcid":false,"given":"Liliana Torcoroma","family":"Garc\u00eda S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Infectious Diseases Postgraduate Program, Instituto de Investigaci\u00f3n Masira, Universidad de Santander, Bucaramanga 680006, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1161\/CIR.0000000000000599","article-title":"American Heart Association rheumatic fever, endocarditis and Kawasaki disease committee of the council on cardiovascular disease in the young; council on cardiovascular and stroke nursing; and stroke council, Chagas cardiomyopathy: An update of current clinical knowledge and management: A scientific statement from the American Heart Association","volume":"138","author":"Nunes","year":"2018","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1051\/parasite\/2014012","article-title":"Chagas disease in the 21st century: A public health success or an emerging threat?","volume":"21","author":"Bonney","year":"2014","journal-title":"Parasite"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11886-019-1095-y","article-title":"Chagas cardiomyopathy in Latin America review","volume":"21","author":"Vieira","year":"2019","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bartsch, S.M., Avelis, C.M., Asti, L., Hertenstein, D.L., Ndeffo-Mbah, M., Galvani, A., and Lee, B.Y. (2018). The economic value of identifying and treating Chagas disease patients earlier and the impact on Trypanosoma cruzi transmission. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006809"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Paiva, C.N., Medei, E., and Bozza, M.T. (2018). ROS and Trypanosoma cruzi: Fuel to infection, poison to the heart. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1006928"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.4269\/ajtmh.16-0761","article-title":"Experimental and clinical treatment of Chagas disease: A review","volume":"97","author":"Sales","year":"2017","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_7","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":"Morillo","year":"2015","journal-title":"N. Eng. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Moreno, \u00c9.M., Leal, S.M., Stashenko, E.E., and Garc\u00eda, L.T. (2018). Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide). BMC Complement. Altern. Med., 18.","DOI":"10.1186\/s12906-018-2293-7"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Quintero, W.L., Moreno, E.M., Pinto, S.M.L., Sanabria, S.M., Stashenko, E.E., and Garc\u00eda, L.T. (2021). Immunomodulatory, trypanocide, and antioxidant properties of essential oil fractions of Lippia alba (Verbenaceae). BMC Complement. Med. Ther., 21.","DOI":"10.1186\/s12906-021-03347-6"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113553","DOI":"10.1016\/j.indcrop.2021.113553","article-title":"In vivo protection against chagasic cardiomyopathy progression using trypanocidal fractions from Lippia alba (Verbenaceae) essential oils","volume":"167","author":"Stashenko","year":"2021","journal-title":"Ind. Crop. Prod."},{"key":"ref_11","unstructured":"Jennings, W.G., and Shibamoto, T. (1980). Qualitative Analysis of Flavor and Fragrance Volatiles by Glass Capillary Gas Chromatography, Academic Press."},{"key":"ref_12","first-page":"389","article-title":"Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi","volume":"4","author":"Brener","year":"1962","journal-title":"Rev. Inst. Med. Trop. S\u00e3o Paulo"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open-source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Molina-Berr\u00edos, A., Campos-Estrada, C., Henr\u00edquez, N., Fa\u00fandez, M., Torres, G., Castillo, C., Escanilla, S., Kemmerling, U., Morello, A., and L\u00f3pez-Mu\u00f1oz, R.A. (2013). Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: Evidence of a 15-epi-lipoxin a4-mediated effect. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002173"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.ajpath.2014.12.023","article-title":"Autoimmune pathogenesis of Chagas heart disease: Looking back, looking ahead","volume":"185","author":"Bonney","year":"2015","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_16","first-page":"1102","article-title":"Disfun\u00e7\u00e3o microvascular coronariana: \u00bfIsso realmente importa na doen\u00e7a de Chagas?","volume":"115","year":"2021","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Angulo, H., Marques, J., Mendoza, I., Villegas, M., Mijares, A., Giron\u00e8s, N., and Fresno, M. (2017). Differential cytokine profiling in Chagasic patients according to their arrhythmogenic-status. BMC Infect. Dis., 17.","DOI":"10.1186\/s12879-017-2324-x"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1590\/S0001-37652005000400009","article-title":"An overview of chagasic cardiomyopathy: Pathogenic importance of oxidative stress","volume":"77","author":"Zacks","year":"2005","journal-title":"An. Acad. Bras. Ci\u00eancias"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1146\/annurev-pathol-020117-043711","article-title":"Pathology and pathogenesis of Chagas heart disease","volume":"14","author":"Bonney","year":"2019","journal-title":"Annu. Rev. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.3389\/fimmu.2018.02791","article-title":"Disease tolerance and pathogen resistance genes may underlie Trypanosoma cruzi persistence and differential progression to Chagas disease cardiomyopathy","volume":"9","author":"Chevillard","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s40588-018-0081-2","article-title":"Pathogenesis of chronic Chagas disease: Macrophages, mitochondria, and oxidative stress","volume":"5","author":"Lopez","year":"2018","journal-title":"Curr. Clin. Microbiol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jsb.2010.10.007","article-title":"Structures of a key interaction protein from the Trypanosoma brucei editosome in complex with single domain antibodies","volume":"174","author":"Wu","year":"2011","journal-title":"J. Struct. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1084\/jem.194.8.1123","article-title":"Reprogramming of the macrophage transcriptome in response to interferon-and Mycobacterium tuberculosis: Signaling roles of Nitric Oxide Synthase-2 and phagocyte oxidase","volume":"194","author":"Ehrt","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s10741-013-9393-8","article-title":"Could interferon-gamma be a therapeutic target for treating heart failure?","volume":"19","author":"Levick","year":"2014","journal-title":"Heart Fail. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e23773","DOI":"10.1097\/MD.0000000000023773","article-title":"Metabolic and immunological evaluation of patients with indeterminate and cardiac forms of Chagas disease","volume":"99","author":"Rocha","year":"2020","journal-title":"Med. Baltim."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sousa, G.R., Gomes, J.A.S., Fares, R.C.G., de Dam\u00e1sio, M.P.S., Chaves, A.T., Ferreira, K.S., Nunes, M.C.P., Medeiros, N.I., Valente, V.A.A., and Correa-Oliveira, R. (2014). Plasma cytokine expression is associated with cardiac morbidity in Chagas disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087082"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Freyberg, Z., and Harvill, E.T. (2017). Pathogen manipulation of host metabolism: A common strategy for immune evasion. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006669"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5771","DOI":"10.4049\/jimmunol.180.9.5771","article-title":"IL-10: The master regulator of immunity to infection","volume":"180","author":"Couper","year":"2008","journal-title":"J. Immun."},{"key":"ref_29","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":"Pinazo","year":"2015","journal-title":"Mem. Inst. Oswaldo Cruz."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.it.2018.02.007","article-title":"Origin and immunological functions of spleen stromal cells","volume":"39","author":"Golub","year":"2018","journal-title":"Trends Immun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Alvarez, G., Bertocchi, G., Pengue, C., Cesar, G., Eiro, M.D.C., Lococo, B., Viotti, R., Natale, M.A., Castro Eiro, M.D., and Cambiazzo, S.S. (2019). Impaired frequencies and function of platelets and tissue remodeling in chronic Chagas disease. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0218260"},{"key":"ref_32","first-page":"323","article-title":"Linfocitos at\u00edpicos en dengue: Papel en el diagn\u00f3stico y pron\u00f3stico de la enfermedad. Revisi\u00f3n sistem\u00e1tica de la literatura","volume":"10","year":"2012","journal-title":"Rev. Cienc. Salud"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/11\/1851\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:33:58Z","timestamp":1760168038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/11\/1851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,22]]},"references-count":32,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["antiox10111851"],"URL":"https:\/\/doi.org\/10.3390\/antiox10111851","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,22]]}}}