Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina
Digital
- Autores:
-
Paez-Lizcano, Silvia Catalina
Uceda-Castellanos, Leidy Marcela
- Tipo de recurso:
- Trabajo de grado de pregrado
- Fecha de publicación:
- 2023
- Institución:
- Universidad de Santander
- Repositorio:
- Repositorio Universidad de Santander
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.udes.edu.co:001/9264
- Palabra clave:
- Enfermedades Infecciosas
Theobroma cacao L
Doxorrubicina
Cardioprotección
Cardiomioblastos
Encapsulados polifenólicos
Theobroma cacao L
Doxorrubicin
Cardioprotection
Cardiomyoblasts
Polyphenolic encapsulates
- Rights
- openAccess
- License
- http://purl.org/coar/access_right/c_abf2
| id |
RUDES2_467363f2fbb9b3e869da8710c571fe7c |
|---|---|
| oai_identifier_str |
oai:repositorio.udes.edu.co:001/9264 |
| network_acronym_str |
RUDES2 |
| network_name_str |
Repositorio Universidad de Santander |
| repository_id_str |
|
| dc.title.spa.fl_str_mv |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| dc.title.translated.none.fl_str_mv |
Cardioprotective Potential of Polyphenolic Encapsulates of Theobroma cacao L. on an In Vitro Model of Cardiotoxicity Induced by Doxorubicin |
| title |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| spellingShingle |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina Enfermedades Infecciosas Theobroma cacao L Doxorrubicina Cardioprotección Cardiomioblastos Encapsulados polifenólicos Theobroma cacao L Doxorrubicin Cardioprotection Cardiomyoblasts Polyphenolic encapsulates |
| title_short |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| title_full |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| title_fullStr |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| title_full_unstemmed |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| title_sort |
Potencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por Doxorrubicina |
| dc.creator.fl_str_mv |
Paez-Lizcano, Silvia Catalina Uceda-Castellanos, Leidy Marcela |
| dc.contributor.advisor.none.fl_str_mv |
García-Sánchez, Liliana Torcoroma |
| dc.contributor.author.none.fl_str_mv |
Paez-Lizcano, Silvia Catalina Uceda-Castellanos, Leidy Marcela |
| dc.contributor.jury.none.fl_str_mv |
Hernández, Indira Paola Rueda-Forero, Nohora Juliana |
| dc.contributor.researchgroup.none.fl_str_mv |
Biotecnología Agroambiental y Salud - MICROBIOTA Manejo Clínico - CLINIUDES |
| dc.subject.decs.none.fl_str_mv |
Enfermedades Infecciosas |
| topic |
Enfermedades Infecciosas Theobroma cacao L Doxorrubicina Cardioprotección Cardiomioblastos Encapsulados polifenólicos Theobroma cacao L Doxorrubicin Cardioprotection Cardiomyoblasts Polyphenolic encapsulates |
| dc.subject.proposal.spa.fl_str_mv |
Theobroma cacao L Doxorrubicina Cardioprotección Cardiomioblastos Encapsulados polifenólicos |
| dc.subject.proposal.eng.fl_str_mv |
Theobroma cacao L Doxorrubicin Cardioprotection Cardiomyoblasts Polyphenolic encapsulates |
| description |
Digital |
| publishDate |
2023 |
| dc.date.accessioned.none.fl_str_mv |
2023-09-21T23:03:03Z |
| dc.date.available.none.fl_str_mv |
2023-09-21T23:03:03Z |
| dc.date.issued.none.fl_str_mv |
2023-07-19 |
| dc.type.none.fl_str_mv |
Trabajo de grado - Pregrado |
| dc.type.coar.none.fl_str_mv |
http://purl.org/coar/resource_type/c_7a1f |
| dc.type.coarversion.none.fl_str_mv |
http://purl.org/coar/version/c_71e4c1898caa6e32 |
| dc.type.content.none.fl_str_mv |
Text |
| dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/bachelorThesis |
| dc.type.redcol.none.fl_str_mv |
http://purl.org/redcol/resource_type/TP |
| dc.type.version.none.fl_str_mv |
info:eu-repo/semantics/submittedVersion |
| format |
http://purl.org/coar/resource_type/c_7a1f |
| status_str |
submittedVersion |
| dc.identifier.instname.none.fl_str_mv |
Universidad de Santander |
| dc.identifier.local.none.fl_str_mv |
T 33.23 P129p |
| dc.identifier.reponame.none.fl_str_mv |
Repositorio Digital Universidad de Santander |
| dc.identifier.repourl.none.fl_str_mv |
https://repositorio.udes.edu.co |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.udes.edu.co/handle/001/9264 |
| identifier_str_mv |
Universidad de Santander T 33.23 P129p Repositorio Digital Universidad de Santander |
| url |
https://repositorio.udes.edu.co https://repositorio.udes.edu.co/handle/001/9264 |
| dc.language.iso.none.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.none.fl_str_mv |
Organización Mundial de la Salud. Enfermedades cardiovasculares. (OMS). 2015. Available from: http://www.who.int/mediacentre/factsheets/fs317/es/ Enfermedades cardiovascular. WHO.int. https://www.who.int/es/health-topics/cardiovascular-diseases Departamento Nacional de Estadísticas (DANE). Defunciones no Fetales 2021 preliminar. Departamento Nacional de Estadísticas (DANE). 2021. https://www.dane.gov.co/index.php/estadisticas-por-tema/salud/nacimientos-y-defunciones/defunciones-no-fetales/defunciones-no-fetales-12/2022 Adão R, De Keulenaer G, Leite-Moreira A, Brás-Silva C. Cardiotoxicity associated with cancer therapy: Pathophysiology and prevention. Rev Port Cardiol. 2013;32(5). http://dx.doi.org/10.1016/j.repce.2012 Ajaykumar C. Overview on the side effects of doxorubicin. Npj Precision Oncology. IntechOpen; 2021. 10.5772/intechopen.94896 Brunton L, Lazo JS, Parker K. Goodman & gilman’s the pharmacological basis of therapeutics. 11th ed. Sanford L, Gilman A, editors. New York, NY: McGraw-Hill Medical; 2005. Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021;139(111708):111708. https://doi.org/10.1016/j.biopha.2021.111708 Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115(2):155–62 http://dx.doi.org/10.1159/000265166 Ferreira A, Matsubara L, Matsubara B. Anthracycline-induced cardiotoxicity. Cardiovasc Hematol Agents Med Chem. Betham Science. 2008;6(4):278–81. http://dx.doi.org/10.2174/187152508785909474 Hrdina R, Gersl V, Klimtová I, Simůnek T, Machácková J, Adamcová M. Anthracycline-induced cardiotoxicity. Acta Medica (Hradec Kralove). 2000;43(3):75–82. http://dx.doi.org/10.14712/18059694.2019.117 Lipshultz S. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. U.S. National Library of Medicine; 1991. https://do.org/10.1056/NEJM199103213241205 Tanai E, Frantz S. Pathophysiology of heart failure. Compr Physiol. 2015;6(1):187–214. http://dx.doi.org/10.1002/cphy.c140055 Armenian S. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. U.S. National Library of Medicine; 2017. https://doi.org/10.1200/JCO.2016.70.5400 Romero M, Vásquez E, Acero G, Huérfano L. Estimación de los costos directos de los eventos coronarios en Colombia. Rev Colomb Cardiol. 2018 [citado el 21 de junio de 2023];25(6):373–9. https://doi.org/10.1016/j.rccar.2018.05.010 Enfermedades cardiovasculares. WHO.int. Disponible en: https://www.who.int/es/health-topics/cardiovascular-diseases Bouayed J, Bohn T. Exogenous antioxidants-double-edged swords in cellular redoc state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid. Med. Cell. Longev. OXID MED CELL LONGEV. 2010;3(4):228–37. https://doi.org/10.4161/oxim.3.4.12858 Agrawal A. Pharmacological Activities of Flavonoids: A Review.IJPSN. 2011;4(2). https://doi.org/10.37285/ijpsn.2011.4.2.3 Cooper KA, Donovan JL, Waterhouse AL, Williamson G. Cocoa and health: a decade of research. nUTR. 2008;99:1–11. https://doi.org/10.1017/S0007114507795296 Arts IC, Hollman PC. Polyphenols and disease risk in epidemiologic studies. NUTR CLIN. 2005;317–25. https://doi.org/10.1093/ajcn/81.1.317S Global cocoa production 2022/23. Statista. https://www.statista.com/statistics/262620/globalcocoa-production Sesso H, Manson J. Effect of cocoa flavanol supplementation for the Prevention of Cardiovascular Disease Events: The Cocoa Supplement and Multivitamin Outcomes Study (Cosmos) randomized clinical trial. U.S. NL; 2022. https://doi.org/10.1093/ajcn/nqac055 Fivelman QL, Adagu IS, Warhurst DC. Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum. ASM. 2004;48(11):4097–102. https://doi.org/10.1128/aac.48.11.4097-4102.2004 Azeredo CMO, Soares MJ. Combination of the essential oil constituents citral, eugenol and thymol enhance their inhibitory effect on Crithidia fasciculata and Trypanosoma cruzi growth. Rev Bras Farmacogn. 2013;23(5):762–8. https://doi.org/10.1590/S0102-695X2013000500007 Shishir MRI, Xie L, Sun C, Zheng X, Chen W. Advances in micro and nano-encapsulation of bioactive compounds using biopolymer and lipid-based transporters. Trends Food Sci Technol. 2018;78:34–60. https://doi.org/10.1016/j.tifs.2018.05.018 Bolvar-Meja A. Burden of cardiovascular disease in Colombia. Rodriguez-Morales AJ, editor. Current Topics in Public Health. 2013. DOI 10.5772/53280 Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Frontiers; 2020 https://doi.org/10.3389/fcvm.2020.00026 Kalyanaraman B. Exploiting the tumor immune microenvironment and immunometabolism using mitochondria‐targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research. FASEB J. 2022;36(4). https://doi.org/10.1096/fj.202101862R Madonna R. Diagnóstico y prevención de la cardiotoxicidad inducida por fármacos antineoplásicos: de la imagen a las tecnologías «ómicas». Rev Esp Cardiol. 2017;70(7):576–82. https://doi.org/10.1016/j.recesp.2016.12.032 Velásquez C. Cardiotoxicidad inducida por la quimioterapia desde las bases Moleculares Hasta la Perspectiva Clínica. https://doi.org/10.1016/j.rccar.2015.10.002 Agudelo C, Acevedo S, Carrillo-Hormaza L, Galeano E, Osorio E. Chemometric classification of Colombian cacao crops: Effects of different genotypes and origins in different years of harvest on levels of flavonoid and methylxanthine metabolites in raw cacao beans. Molecules. 2022;27(7):2068. https://doi.org/10.3390/molecules27072068 Nair P, Cocoa KP. Theobroma cacao L. In The Agronomy and Economy of Important Tree Crops of the Developing World. Amsterdam, The Netherlands: Elsevier; 2010. Veres B. Anti-inflammatory role of natural polyphenols and their degradation products. En: Fernandez R, editor. Severe Sepsis and Septic Shock - Understanding a Serious Killer. Londres, Inglaterra: InTech; 2012. Chen W-C, Hsieh S-R, Chiu C-H, Hsu B-D, Liou Y-M. Molecular identification for epigallocatechin-3-gallate-mediated antioxidant intervention on the H2O2-induced oxidative stress in H9C2 rat cardiomyoblasts - journal of biomedical science. BioMed Central; 2014. https://doi.org/10.1186/1423-0127-21-56 Andújar I, Recio MC, Giner RM, Ríos JL. Cocoa polyphenols and their potential benefits for human health. Oxid Med Cell Longev. 2012;2012:906252. https://doi.org/10.1155/2012/906252 Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev. 1998;56(11):317–33. https://doi.org/10.1111/j.1753-4887.1998.tb01670.x Ariyarathna I. Microencapsulation stabilizes curcumin for efficient delivery in food applications. Elsevier; 2016. https://doi.org/10.1016/j.fpsl.2016.10.005 Miller KB, Stuart DA, Smith NL, Lee CY, McHale NL, Flanagan JA, et al. Antioxidant activity and polyphenol and procyanidin contents of selected commercially available cocoa-containing and chocolate products in the United States. J Agric Food Chem. http://dx.doi.org/10.1021/jf060290o Ottaviani JI, Carrasquedo F, Keen CL, Lazarus SA, Schmitz HH, Fraga CG. Influence of flavan-3-ols and procyanidins on UVC-mediated formation of 8-oxo-7,8-dihydro-2’-deoxyguanosine in isolated DNA. Arch Biochem Biophys. 2002;406(2):203–8. http://dx.doi.org/10.1016/s0003-9861(02)00455-1 García OJ, Angélica B, Sandoval P, Juan A, Fajardo GB. Innovación tecnológica en cacao andino Producto 7. Informe con la caracterización de extractos de flavonoides y pruebas de encapsulación realizadas. Fontagro.org. [cited 2023 Jun 20]. https://www.fontagro.org/new/uploads/productos/16109_-_Producto_7.pdf Rahayu Y, Triwahyuni I, Kusumawardani B, Sari D. The cytotoxic and proliferative activity of cocoa pod husk extract (Theobroma cacao L.) on periodontal ligament fibroblasts. Odonto Dent J. 2022;9(1):46. http://dx.doi.org/10.30659/odj.9.1.46-52 Kaźmierczak-Barańska J, Karwowski B, Adamus-Grabicka A, Boguszewska K. Two faces of vitamin C-antioxidative and Pro-Oxidative Agent. U.S. National Library of Medicine; 2020. 12:1501. https://doi.org/10.3390/nu12051501 Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82(4):513–23. https://doi.org/10.1016/j.fitote.2011.01.018 Rietjens I, Boersma M, Haan L de, Spenkelink B, Awad H, Cnubben N, et al. The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids. Environ Toxicol Pharmacol. 2002;11(3–4):321–33. http://dx.doi.org/10.1016/s1382-6689(02)00003-0 |
| dc.rights.accessrights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| dc.rights.coar.none.fl_str_mv |
http://purl.org/coar/access_right/c_abf2 |
| dc.rights.license.none.fl_str_mv |
Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0) |
| dc.rights.uri.none.fl_str_mv |
https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| rights_invalid_str_mv |
http://purl.org/coar/access_right/c_abf2 Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.format.extent.none.fl_str_mv |
32 p |
| dc.format.mimetype.none.fl_str_mv |
application/pdf image/png |
| dc.publisher.none.fl_str_mv |
Universidad de Santander |
| dc.publisher.branch.none.fl_str_mv |
Bucaramanga |
| dc.publisher.faculty.none.fl_str_mv |
Facultad de Ciencias Naturales |
| dc.publisher.place.none.fl_str_mv |
Bucaramanga, Colombia |
| dc.publisher.program.none.fl_str_mv |
Microbiología Industrial |
| publisher.none.fl_str_mv |
Universidad de Santander |
| institution |
Universidad de Santander |
| bitstream.url.fl_str_mv |
https://repositorio.udes.edu.co/bitstreams/c899d9f5-6731-4cf0-b67e-f0bfcdaa0cb9/download https://repositorio.udes.edu.co/bitstreams/e0c7c346-8674-47fb-b4fa-69c6b500dd06/download https://repositorio.udes.edu.co/bitstreams/2aab37e7-acd5-4bc1-9c8c-9b1a62f56b1c/download https://repositorio.udes.edu.co/bitstreams/2fb0145c-b89d-46b7-9274-195c82ab4258/download https://repositorio.udes.edu.co/bitstreams/8ab6c456-0a0e-4b35-a148-bb1353d24f87/download https://repositorio.udes.edu.co/bitstreams/27d50373-b4c5-48b6-9411-5d3c78747724/download https://repositorio.udes.edu.co/bitstreams/66f7bec2-a9d0-4c71-881e-68782e94a473/download https://repositorio.udes.edu.co/bitstreams/3ba40e7f-31e0-443c-8299-fa2257718e23/download https://repositorio.udes.edu.co/bitstreams/75de3fb4-aa16-4503-b9fa-0635594310ad/download https://repositorio.udes.edu.co/bitstreams/fd068d43-0cbb-48fc-b900-396d5a6f0db1/download https://repositorio.udes.edu.co/bitstreams/06bd3432-cd1b-469c-9b40-94d248016390/download https://repositorio.udes.edu.co/bitstreams/7c775b69-52b2-485f-bfd4-56e3a0c0bdcd/download https://repositorio.udes.edu.co/bitstreams/e2f8e284-98cd-4a96-9590-16df276fd919/download https://repositorio.udes.edu.co/bitstreams/ab71ed09-1bcb-4ec6-b96c-8e18b4a10220/download https://repositorio.udes.edu.co/bitstreams/4f89d3fa-cd8b-480e-9975-d23557690bd8/download https://repositorio.udes.edu.co/bitstreams/f54c4fde-bf0f-4b2a-b48d-d732f9f83c66/download https://repositorio.udes.edu.co/bitstreams/ffc24f71-e331-42c7-a289-1206784e4160/download https://repositorio.udes.edu.co/bitstreams/2366b094-7b0b-476c-93ed-ba57db918b4f/download https://repositorio.udes.edu.co/bitstreams/776247fe-2515-4851-bad6-a1e1324864c1/download https://repositorio.udes.edu.co/bitstreams/f9dd2a34-0a14-46cd-b2ee-c960cd531f00/download https://repositorio.udes.edu.co/bitstreams/78f76506-b687-4dd0-b4ec-f901fc29e0e1/download https://repositorio.udes.edu.co/bitstreams/df66af3a-5d59-4941-804c-df3b73165a3e/download https://repositorio.udes.edu.co/bitstreams/2341badf-578c-4189-b1d3-f816fcc07527/download https://repositorio.udes.edu.co/bitstreams/3ab18225-0379-4eb5-9ed0-dd88635891f5/download https://repositorio.udes.edu.co/bitstreams/5af6a4da-d357-4ea2-a7c5-9f70312930b8/download |
| bitstream.checksum.fl_str_mv |
a4e6b1891fd505b75703c409cc053ec1 d114a08ce1a8a90f0249852af3bdc948 964c990d679a65b4d81c4c78048bcf65 69c16ddfe327d9281c8572733ee673b4 2f19e271a27ae0139a9018dc4d950249 e8948542512efdfe64476ad662b13fbd 8c6fc12c421f33a1cd89e4643d36df37 9083672df9483098cae2ca0386f9bdfd 565ad8bb1feaf8e6885a8dead1f6d0a1 e28eb7b87795b8548fea804b3e695f73 73a5432e0b76442b22b026844140d683 93a4736144fe08d26d46dde17805ec62 31323c2ec88852fb3e6d06d3e95d9b6f d67eff27cbe0a607bdee3e4944d5d836 cfc1cd0018470faaa483ddf5ca4163a7 f6b4986771e98b257cf12290dc346ef8 3d8c3a396c05de83f5e01566a8101181 d27ed3e1bc18daeaa339fb49466048a3 184ab525b784733f0b726b1d660bda4e a1e86e4b89fcafcf249aad2fa7d0a27a 7edd67009a31e18d142885f0dd8eb60f 4bf36615c4ab54a2aa72433587cb9bba 0b0f1bcbf698487ee1effecb02f68da6 bb7f11e4cf3944b078647b45e4b8492c aa42cdf99d893a69da8fffdd4be1d6a8 |
| bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 |
| repository.name.fl_str_mv |
Repositorio Universidad de Santander |
| repository.mail.fl_str_mv |
soporte@metabiblioteca.com |
| _version_ |
1808490943698960384 |
| spelling |
García-Sánchez, Liliana Torcoroma96bab1e9-3d27-4151-ac58-352a07fc5f2b-1Paez-Lizcano, Silvia Catalina2e361c38-3555-4da1-b112-822cd4b40d33-1Uceda-Castellanos, Leidy Marcelac9d21ec2-2cdd-4a3b-bacb-7d23e71a3eb4-1Hernández, Indira Paolae7527a84-82e6-40ba-8c58-4de3f6288260-1Rueda-Forero, Nohora Julianac3af6947-0599-4b60-aead-3f4ae65719b1-1Biotecnología Agroambiental y Salud - MICROBIOTAManejo Clínico - CLINIUDES2023-09-21T23:03:03Z2023-09-21T23:03:03Z2023-07-19DigitalAntecedentes: El cáncer es considerado un desafío global de salud pública y una de las principales causas de muerte, a nivel global. Los tratamientos convencionales se basan en el uso de quimioterápicos como Doxorrubicina (Dox), que ocasionan gran variedad de efectos adversos, principalmente de tipo cardiotóxico. Así, es importante el estudio de terapias complementarias con capacidad cardioprotectora. Al respecto, polifenoles derivados de Theobroma cacao L han sido descritos como potentes antioxidantes, antiinflamatorios y cardioprotectores. Métodos: Extractos polifenólicos de semillas de clones de T. cacao L [CCN51 (A16-160) e ICS-95 (ICS-95)] fueron deshidratados mediante spray dryer y liofilización respectivamente; y encapsulados en goma arábiga al 16%. Ensayos de citotoxicidad de los encapsulados y de interacción farmacológica, en combinación con Dox, fueron realizados sobre células de miocardioblastos murinos H9c2. Técnicas de microscopía óptica y de fluorescencia fueron usadas para estimar los efectos sobre la integridad celular, el potencial de membrana mitocondrial y el estrés oxidativo. Resultados: Las terapias individuales con encapsulados de T. cacao L demostraron muy baja toxicidad sobre células H9c2 (CC50 A16-160=4.709 ± 2,0 µg/mL; CC50 ICS-95=1.916 ± 4,0 µg/mL), en comparación con Dox (CC50 10,3 ± 0,6 µg/mL). No obstante, su uso combinado con Dox presentó comportamiento sinergístico sobre H9c2, incrementando la toxicidad del quimioterapéutico [Dox+A16-160 (∑CIF= 0,4 ± 0,14) y Dox+ICS-95 (∑CIF= 0,5 ± 0,12)], a pesar de disminuir hasta cuatro veces su CC50. Igualmente, la mezcla de encapsulados de cacao con Dox incrementó la perturbación del potencial de membrana mitocondrial y el aumento de estrés oxidativo, sobre las células cardiacas. Conclusión: Los extractos polifenólicos de T. cacao L demostraron ser seguros sobre las células estudiadas, sin embargo, estudios posteriores de interacción farmacológica con Dox deben realizarse usando menores concentraciones, considerando su potencial antioxidante y cardioprotector.Background: Cancer is considered a global public health challenge and one of the leading causes of death, worldwide. Conventional treatments are based on the use of chemotherapy drugs such as Doxorubicin (Dox), which cause a wide variety of adverse effects, mainly cardiotoxic. Thus, it is important to study complementary therapies with cardioprotective capacity. In this regard, polyphenols derived from Theobroma cacao L have been described as potent antioxidants, anti-inflammatory and cardioprotective. Methods: Polyphenolic extracts from seeds of T. cacao L clones [CCN51 (A16-160) and ICS-95 (ICS-95)] were dehydrated by spray dryer and lyophilization, respectively; and encapsulated in 16% gum arabic. Cytotoxicity of the studied encapsulates as well as drug interaction assays, in combination with Dox, were performed on H9c2 murine myocardioblast cells. Light and fluorescence microscopy techniques were used to estimate effects on cell integrity, mitochondrial membrane potential and oxidative stress. Results: Individual therapies with T. cacao L encapsulates showed very low citotoxicity on H9c2 cells (CC50 A16-160=4,709 ± 2.0 µg/mL; CC50 ICS-95=1,916 ± 4.0 µg/mL), compared to Dox (CC50 10.3 ± 0.6 µg/mL). However, its combined use with Dox presented synergistic behavior on H9c2, increasing the toxicity of the chemotherapeutic [Dox+A16-160 (∑CIF= 0.4 ± 0.14) and Dox+ISC-95 (∑CIF= 0.5 ± 0.12)], despite decreasing up to four times its CC50 value. Likewise, the mixture of cocoa encapsulates with Dox increased the perturbation of mitochondrial membrane potential and increased oxidative stress, on cardiac cells. Conclusion: The polyphenolic extracts of T. cacao L proved to be safe on the cells studied; however, further studies of pharmacological interaction with Dox should be carried out using lower concentrations, considering its antioxidant and cardioprotective potential.PregradoMicrobiólogo IndustrialTecnologías y Biotecnologías Aplicadas en el Agroambiente, Salud e Industria32 papplication/pdfimage/pngUniversidad de SantanderT 33.23 P129pRepositorio Digital Universidad de Santanderhttps://repositorio.udes.edu.cohttps://repositorio.udes.edu.co/handle/001/9264spaUniversidad de SantanderBucaramangaFacultad de Ciencias NaturalesBucaramanga, ColombiaMicrobiología IndustrialOrganización Mundial de la Salud. Enfermedades cardiovasculares. (OMS). 2015. Available from: http://www.who.int/mediacentre/factsheets/fs317/es/Enfermedades cardiovascular. WHO.int. https://www.who.int/es/health-topics/cardiovascular-diseasesDepartamento Nacional de Estadísticas (DANE). Defunciones no Fetales 2021 preliminar. Departamento Nacional de Estadísticas (DANE). 2021. https://www.dane.gov.co/index.php/estadisticas-por-tema/salud/nacimientos-y-defunciones/defunciones-no-fetales/defunciones-no-fetales-12/2022Adão R, De Keulenaer G, Leite-Moreira A, Brás-Silva C. Cardiotoxicity associated with cancer therapy: Pathophysiology and prevention. Rev Port Cardiol. 2013;32(5). http://dx.doi.org/10.1016/j.repce.2012Ajaykumar C. Overview on the side effects of doxorubicin. Npj Precision Oncology. IntechOpen; 2021. 10.5772/intechopen.94896Brunton L, Lazo JS, Parker K. Goodman & gilman’s the pharmacological basis of therapeutics. 11th ed. Sanford L, Gilman A, editors. New York, NY: McGraw-Hill Medical; 2005.Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021;139(111708):111708. https://doi.org/10.1016/j.biopha.2021.111708Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115(2):155–62 http://dx.doi.org/10.1159/000265166Ferreira A, Matsubara L, Matsubara B. Anthracycline-induced cardiotoxicity. Cardiovasc Hematol Agents Med Chem. Betham Science. 2008;6(4):278–81. http://dx.doi.org/10.2174/187152508785909474Hrdina R, Gersl V, Klimtová I, Simůnek T, Machácková J, Adamcová M. Anthracycline-induced cardiotoxicity. Acta Medica (Hradec Kralove). 2000;43(3):75–82. http://dx.doi.org/10.14712/18059694.2019.117Lipshultz S. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. U.S. National Library of Medicine; 1991. https://do.org/10.1056/NEJM199103213241205Tanai E, Frantz S. Pathophysiology of heart failure. Compr Physiol. 2015;6(1):187–214. http://dx.doi.org/10.1002/cphy.c140055Armenian S. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. U.S. National Library of Medicine; 2017. https://doi.org/10.1200/JCO.2016.70.5400Romero M, Vásquez E, Acero G, Huérfano L. Estimación de los costos directos de los eventos coronarios en Colombia. Rev Colomb Cardiol. 2018 [citado el 21 de junio de 2023];25(6):373–9. https://doi.org/10.1016/j.rccar.2018.05.010Enfermedades cardiovasculares. WHO.int. Disponible en: https://www.who.int/es/health-topics/cardiovascular-diseasesBouayed J, Bohn T. Exogenous antioxidants-double-edged swords in cellular redoc state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid. Med. Cell. Longev. OXID MED CELL LONGEV. 2010;3(4):228–37. https://doi.org/10.4161/oxim.3.4.12858Agrawal A. Pharmacological Activities of Flavonoids: A Review.IJPSN. 2011;4(2). https://doi.org/10.37285/ijpsn.2011.4.2.3Cooper KA, Donovan JL, Waterhouse AL, Williamson G. Cocoa and health: a decade of research. nUTR. 2008;99:1–11. https://doi.org/10.1017/S0007114507795296Arts IC, Hollman PC. Polyphenols and disease risk in epidemiologic studies. NUTR CLIN. 2005;317–25. https://doi.org/10.1093/ajcn/81.1.317SGlobal cocoa production 2022/23. Statista. https://www.statista.com/statistics/262620/globalcocoa-productionSesso H, Manson J. Effect of cocoa flavanol supplementation for the Prevention of Cardiovascular Disease Events: The Cocoa Supplement and Multivitamin Outcomes Study (Cosmos) randomized clinical trial. U.S. NL; 2022. https://doi.org/10.1093/ajcn/nqac055Fivelman QL, Adagu IS, Warhurst DC. Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum. ASM. 2004;48(11):4097–102. https://doi.org/10.1128/aac.48.11.4097-4102.2004Azeredo CMO, Soares MJ. Combination of the essential oil constituents citral, eugenol and thymol enhance their inhibitory effect on Crithidia fasciculata and Trypanosoma cruzi growth. Rev Bras Farmacogn. 2013;23(5):762–8. https://doi.org/10.1590/S0102-695X2013000500007Shishir MRI, Xie L, Sun C, Zheng X, Chen W. Advances in micro and nano-encapsulation of bioactive compounds using biopolymer and lipid-based transporters. Trends Food Sci Technol. 2018;78:34–60. https://doi.org/10.1016/j.tifs.2018.05.018Bolvar-Meja A. Burden of cardiovascular disease in Colombia. Rodriguez-Morales AJ, editor. Current Topics in Public Health. 2013. DOI 10.5772/53280Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Frontiers; 2020 https://doi.org/10.3389/fcvm.2020.00026Kalyanaraman B. Exploiting the tumor immune microenvironment and immunometabolism using mitochondria‐targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research. FASEB J. 2022;36(4). https://doi.org/10.1096/fj.202101862RMadonna R. Diagnóstico y prevención de la cardiotoxicidad inducida por fármacos antineoplásicos: de la imagen a las tecnologías «ómicas». Rev Esp Cardiol. 2017;70(7):576–82. https://doi.org/10.1016/j.recesp.2016.12.032Velásquez C. Cardiotoxicidad inducida por la quimioterapia desde las bases Moleculares Hasta la Perspectiva Clínica. https://doi.org/10.1016/j.rccar.2015.10.002Agudelo C, Acevedo S, Carrillo-Hormaza L, Galeano E, Osorio E. Chemometric classification of Colombian cacao crops: Effects of different genotypes and origins in different years of harvest on levels of flavonoid and methylxanthine metabolites in raw cacao beans. Molecules. 2022;27(7):2068. https://doi.org/10.3390/molecules27072068Nair P, Cocoa KP. Theobroma cacao L. In The Agronomy and Economy of Important Tree Crops of the Developing World. Amsterdam, The Netherlands: Elsevier; 2010.Veres B. Anti-inflammatory role of natural polyphenols and their degradation products. En: Fernandez R, editor. Severe Sepsis and Septic Shock - Understanding a Serious Killer. Londres, Inglaterra: InTech; 2012.Chen W-C, Hsieh S-R, Chiu C-H, Hsu B-D, Liou Y-M. Molecular identification for epigallocatechin-3-gallate-mediated antioxidant intervention on the H2O2-induced oxidative stress in H9C2 rat cardiomyoblasts - journal of biomedical science. BioMed Central; 2014. https://doi.org/10.1186/1423-0127-21-56Andújar I, Recio MC, Giner RM, Ríos JL. Cocoa polyphenols and their potential benefits for human health. Oxid Med Cell Longev. 2012;2012:906252. https://doi.org/10.1155/2012/906252Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev. 1998;56(11):317–33. https://doi.org/10.1111/j.1753-4887.1998.tb01670.xAriyarathna I. Microencapsulation stabilizes curcumin for efficient delivery in food applications. Elsevier; 2016. https://doi.org/10.1016/j.fpsl.2016.10.005Miller KB, Stuart DA, Smith NL, Lee CY, McHale NL, Flanagan JA, et al. Antioxidant activity and polyphenol and procyanidin contents of selected commercially available cocoa-containing and chocolate products in the United States. J Agric Food Chem. http://dx.doi.org/10.1021/jf060290oOttaviani JI, Carrasquedo F, Keen CL, Lazarus SA, Schmitz HH, Fraga CG. Influence of flavan-3-ols and procyanidins on UVC-mediated formation of 8-oxo-7,8-dihydro-2’-deoxyguanosine in isolated DNA. Arch Biochem Biophys. 2002;406(2):203–8. http://dx.doi.org/10.1016/s0003-9861(02)00455-1García OJ, Angélica B, Sandoval P, Juan A, Fajardo GB. Innovación tecnológica en cacao andino Producto 7. Informe con la caracterización de extractos de flavonoides y pruebas de encapsulación realizadas. Fontagro.org. [cited 2023 Jun 20]. https://www.fontagro.org/new/uploads/productos/16109_-_Producto_7.pdfRahayu Y, Triwahyuni I, Kusumawardani B, Sari D. The cytotoxic and proliferative activity of cocoa pod husk extract (Theobroma cacao L.) on periodontal ligament fibroblasts. Odonto Dent J. 2022;9(1):46. http://dx.doi.org/10.30659/odj.9.1.46-52Kaźmierczak-Barańska J, Karwowski B, Adamus-Grabicka A, Boguszewska K. Two faces of vitamin C-antioxidative and Pro-Oxidative Agent. U.S. National Library of Medicine; 2020. 12:1501. https://doi.org/10.3390/nu12051501Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82(4):513–23. https://doi.org/10.1016/j.fitote.2011.01.018Rietjens I, Boersma M, Haan L de, Spenkelink B, Awad H, Cnubben N, et al. The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids. Environ Toxicol Pharmacol. 2002;11(3–4):321–33. http://dx.doi.org/10.1016/s1382-6689(02)00003-0Derechos Reservados - Universidad de Santander, 2023. Al consultar y hacer uso de este recurso, está aceptando las condiciones de uso establecidas por los autores.info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)https://creativecommons.org/licenses/by-nc-nd/4.0/Enfermedades InfecciosasTheobroma cacao LDoxorrubicinaCardioprotecciónCardiomioblastosEncapsulados polifenólicosTheobroma cacao LDoxorrubicinCardioprotectionCardiomyoblastsPolyphenolic encapsulatesPotencial Cardioprotector de Encapsulados Polifenólicos de Theobroma cacao L. Sobre un Modelo In Vitro de Cardiotoxicidad Inducido por DoxorrubicinaCardioprotective Potential of Polyphenolic Encapsulates of Theobroma cacao L. on an In Vitro Model of Cardiotoxicity Induced by DoxorubicinTrabajo de grado - Pregradohttp://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/version/c_71e4c1898caa6e32Textinfo:eu-repo/semantics/bachelorThesishttp://purl.org/redcol/resource_type/TPinfo:eu-repo/semantics/submittedVersionTodas las AudienciasPublicationORIGINALLabel.pngLabel.pngimage/png63530https://repositorio.udes.edu.co/bitstreams/c899d9f5-6731-4cf0-b67e-f0bfcdaa0cb9/downloada4e6b1891fd505b75703c409cc053ec1MD519Potencial_Cardioprotector_de_Encapsulados_Polifenólicos_de_Theobroma_cacao_L._Sobre_un_Modelo_In_Vitro_de_Cardiotoxicidad_Inducido_por_Doxorrubicina.pdfPotencial_Cardioprotector_de_Encapsulados_Polifenólicos_de_Theobroma_cacao_L._Sobre_un_Modelo_In_Vitro_de_Cardiotoxicidad_Inducido_por_Doxorrubicina.pdfapplication/pdf893123https://repositorio.udes.edu.co/bitstreams/e0c7c346-8674-47fb-b4fa-69c6b500dd06/downloadd114a08ce1a8a90f0249852af3bdc948MD514Informe Turnitin Paez et al. 2023. FINAL (1).pdfInforme Turnitin Paez et al. 2023. FINAL (1).pdfapplication/pdf923626https://repositorio.udes.edu.co/bitstreams/2aab37e7-acd5-4bc1-9c8c-9b1a62f56b1c/download964c990d679a65b4d81c4c78048bcf65MD511FIG 1.pngFIG 1.pngimage/png30139https://repositorio.udes.edu.co/bitstreams/2fb0145c-b89d-46b7-9274-195c82ab4258/download69c16ddfe327d9281c8572733ee673b4MD52FIG 2.pngFIG 2.pngimage/png27090https://repositorio.udes.edu.co/bitstreams/8ab6c456-0a0e-4b35-a148-bb1353d24f87/download2f19e271a27ae0139a9018dc4d950249MD53image.pngimage.pngimage/png232751https://repositorio.udes.edu.co/bitstreams/27d50373-b4c5-48b6-9411-5d3c78747724/downloade8948542512efdfe64476ad662b13fbdMD54image (1).pngimage (1).pngimage/png110527https://repositorio.udes.edu.co/bitstreams/66f7bec2-a9d0-4c71-881e-68782e94a473/download8c6fc12c421f33a1cd89e4643d36df37MD55image (2).pngimage (2).pngimage/png10889667https://repositorio.udes.edu.co/bitstreams/3ba40e7f-31e0-443c-8299-fa2257718e23/download9083672df9483098cae2ca0386f9bdfdMD56Acta de Sustentación.pdfActa de Sustentación.pdfapplication/pdf499376https://repositorio.udes.edu.co/bitstreams/75de3fb4-aa16-4503-b9fa-0635594310ad/download565ad8bb1feaf8e6885a8dead1f6d0a1MD517Cesión de Derechos_y_Confidencialidad.pdfCesión de Derechos_y_Confidencialidad.pdfapplication/pdf270845https://repositorio.udes.edu.co/bitstreams/fd068d43-0cbb-48fc-b900-396d5a6f0db1/downloade28eb7b87795b8548fea804b3e695f73MD520LICENSElicense.txtlicense.txttext/plain; charset=utf-815543https://repositorio.udes.edu.co/bitstreams/06bd3432-cd1b-469c-9b40-94d248016390/download73a5432e0b76442b22b026844140d683MD58THUMBNAILLabel.png.jpgLabel.png.jpgGenerated Thumbnailimage/jpeg11560https://repositorio.udes.edu.co/bitstreams/7c775b69-52b2-485f-bfd4-56e3a0c0bdcd/download93a4736144fe08d26d46dde17805ec62MD521Potencial_Cardioprotector_de_Encapsulados_Polifenólicos_de_Theobroma_cacao_L._Sobre_un_Modelo_In_Vitro_de_Cardiotoxicidad_Inducido_por_Doxorrubicina.pdf.jpgPotencial_Cardioprotector_de_Encapsulados_Polifenólicos_de_Theobroma_cacao_L._Sobre_un_Modelo_In_Vitro_de_Cardiotoxicidad_Inducido_por_Doxorrubicina.pdf.jpgGenerated Thumbnailimage/jpeg10953https://repositorio.udes.edu.co/bitstreams/e2f8e284-98cd-4a96-9590-16df276fd919/download31323c2ec88852fb3e6d06d3e95d9b6fMD523Informe Turnitin Paez et al. 2023. FINAL (1).pdf.jpgInforme Turnitin Paez et al. 2023. FINAL (1).pdf.jpgGenerated Thumbnailimage/jpeg8976https://repositorio.udes.edu.co/bitstreams/ab71ed09-1bcb-4ec6-b96c-8e18b4a10220/downloadd67eff27cbe0a607bdee3e4944d5d836MD525FIG 1.png.jpgFIG 1.png.jpgGenerated Thumbnailimage/jpeg5944https://repositorio.udes.edu.co/bitstreams/4f89d3fa-cd8b-480e-9975-d23557690bd8/downloadcfc1cd0018470faaa483ddf5ca4163a7MD526FIG 2.png.jpgFIG 2.png.jpgGenerated Thumbnailimage/jpeg4512https://repositorio.udes.edu.co/bitstreams/f54c4fde-bf0f-4b2a-b48d-d732f9f83c66/downloadf6b4986771e98b257cf12290dc346ef8MD527image.png.jpgimage.png.jpgGenerated Thumbnailimage/jpeg8509https://repositorio.udes.edu.co/bitstreams/ffc24f71-e331-42c7-a289-1206784e4160/download3d8c3a396c05de83f5e01566a8101181MD528image (1).png.jpgimage (1).png.jpgGenerated Thumbnailimage/jpeg7680https://repositorio.udes.edu.co/bitstreams/2366b094-7b0b-476c-93ed-ba57db918b4f/downloadd27ed3e1bc18daeaa339fb49466048a3MD529image (2).png.jpgimage (2).png.jpgGenerated Thumbnailimage/jpeg17238https://repositorio.udes.edu.co/bitstreams/776247fe-2515-4851-bad6-a1e1324864c1/download184ab525b784733f0b726b1d660bda4eMD530Acta de Sustentación.pdf.jpgActa de Sustentación.pdf.jpgGenerated Thumbnailimage/jpeg16526https://repositorio.udes.edu.co/bitstreams/f9dd2a34-0a14-46cd-b2ee-c960cd531f00/downloada1e86e4b89fcafcf249aad2fa7d0a27aMD532Cesión de Derechos_y_Confidencialidad.pdf.jpgCesión de Derechos_y_Confidencialidad.pdf.jpgGenerated Thumbnailimage/jpeg11205https://repositorio.udes.edu.co/bitstreams/78f76506-b687-4dd0-b4ec-f901fc29e0e1/download7edd67009a31e18d142885f0dd8eb60fMD534TEXTPotencial_Cardioprotector_de_Encapsulados_Polifenólicos_de_Theobroma_cacao_L._Sobre_un_Modelo_In_Vitro_de_Cardiotoxicidad_Inducido_por_Doxorrubicina.pdf.txtPotencial_Cardioprotector_de_Encapsulados_Polifenólicos_de_Theobroma_cacao_L._Sobre_un_Modelo_In_Vitro_de_Cardiotoxicidad_Inducido_por_Doxorrubicina.pdf.txtExtracted texttext/plain52179https://repositorio.udes.edu.co/bitstreams/df66af3a-5d59-4941-804c-df3b73165a3e/download4bf36615c4ab54a2aa72433587cb9bbaMD522Informe Turnitin Paez et al. 2023. FINAL (1).pdf.txtInforme Turnitin Paez et al. 2023. FINAL (1).pdf.txtExtracted texttext/plain56586https://repositorio.udes.edu.co/bitstreams/2341badf-578c-4189-b1d3-f816fcc07527/download0b0f1bcbf698487ee1effecb02f68da6MD524Acta de Sustentación.pdf.txtActa de Sustentación.pdf.txtExtracted texttext/plain2417https://repositorio.udes.edu.co/bitstreams/3ab18225-0379-4eb5-9ed0-dd88635891f5/downloadbb7f11e4cf3944b078647b45e4b8492cMD531Cesión de Derechos_y_Confidencialidad.pdf.txtCesión de Derechos_y_Confidencialidad.pdf.txtExtracted texttext/plain15https://repositorio.udes.edu.co/bitstreams/5af6a4da-d357-4ea2-a7c5-9f70312930b8/downloadaa42cdf99d893a69da8fffdd4be1d6a8MD533001/9264oai:repositorio.udes.edu.co:001/92642023-09-22 03:03:00.039https://creativecommons.org/licenses/by-nc-nd/4.0/Derechos Reservados - Universidad de Santander, 2023. Al consultar y hacer uso de este recurso, está aceptando las condiciones de uso establecidas por los autores.https://repositorio.udes.edu.coRepositorio Universidad de Santandersoporte@metabiblioteca.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 |