Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad

ilustraciones, diagramas

Autores:: Lopez-Cano, Juan Guillermo

Tipo de recurso:

Fecha de publicación:: 2023

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
dc.title.translated.eng.fl_str_mv	Evaluation of the effect of Zanthoxylum martinicense extract over the expression of ApoE, LRP, GLAST y GLT-1 in an astrocyte model and 3x Tg-AD mice
title	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
spellingShingle	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad 570 - Biología::572 - Bioquímica 570 - Biología::573 - Sistemas fisiológicos específicos en animales, histología regional y fisiología en los animales 580 - Plantas::582 - Plantas destacadas por características vegetativas y flores 610 - Medicina y salud::615 - Farmacología y terapéutica 610 - Medicina y salud::616 - Enfermedades Medicina alternativa Alternative medicine Neuropathy Medicinal plant Neuropatía Plantas medicinales Alzheimer Zanthoxylum martinicense ApoE GLT-1 GLT1 GLAST Astrocitos Excitotoxicidad Glutamato Transportadores Alzheimer Zanthoxylum martinicense ApoE GLT-1 GLT1 GLAST Astrocytes Excitotoxicity Glutamate Transporters
title_short	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
title_full	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
title_fullStr	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
title_full_unstemmed	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
title_sort	Evaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-ad
dc.creator.fl_str_mv	Lopez-Cano, Juan Guillermo
dc.contributor.advisor.none.fl_str_mv	Arboleda Bustos, Gonzalo Humberto
dc.contributor.author.none.fl_str_mv	Lopez-Cano, Juan Guillermo
dc.contributor.financer.none.fl_str_mv	Colciencias
dc.contributor.researchgroup.spa.fl_str_mv	Grupo de Neurociencias-Universidad Nacional de Colombia Muerte Celular
dc.subject.ddc.spa.fl_str_mv	570 - Biología::572 - Bioquímica 570 - Biología::573 - Sistemas fisiológicos específicos en animales, histología regional y fisiología en los animales 580 - Plantas::582 - Plantas destacadas por características vegetativas y flores 610 - Medicina y salud::615 - Farmacología y terapéutica 610 - Medicina y salud::616 - Enfermedades
topic	570 - Biología::572 - Bioquímica 570 - Biología::573 - Sistemas fisiológicos específicos en animales, histología regional y fisiología en los animales 580 - Plantas::582 - Plantas destacadas por características vegetativas y flores 610 - Medicina y salud::615 - Farmacología y terapéutica 610 - Medicina y salud::616 - Enfermedades Medicina alternativa Alternative medicine Neuropathy Medicinal plant Neuropatía Plantas medicinales Alzheimer Zanthoxylum martinicense ApoE GLT-1 GLT1 GLAST Astrocitos Excitotoxicidad Glutamato Transportadores Alzheimer Zanthoxylum martinicense ApoE GLT-1 GLT1 GLAST Astrocytes Excitotoxicity Glutamate Transporters
dc.subject.decs.spa.fl_str_mv	Medicina alternativa
dc.subject.lemb.eng.fl_str_mv	Alternative medicine Neuropathy Medicinal plant
dc.subject.lemb.spa.fl_str_mv	Neuropatía Plantas medicinales
dc.subject.proposal.spa.fl_str_mv	Alzheimer Zanthoxylum martinicense ApoE GLT-1 GLT1 GLAST Astrocitos Excitotoxicidad Glutamato Transportadores
dc.subject.proposal.eng.fl_str_mv	Alzheimer Zanthoxylum martinicense ApoE GLT-1 GLT1 GLAST Astrocytes Excitotoxicity Glutamate Transporters
description	ilustraciones, diagramas
publishDate	2023
dc.date.accessioned.none.fl_str_mv	2023-07-31T14:23:20Z
dc.date.available.none.fl_str_mv	2023-07-31T14:23:20Z
dc.date.issued.none.fl_str_mv	2023-07-30
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TM
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/84372
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/84372 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
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In Frontiers in Aging Neuroscience (Vol. 11). Frontiers Media S.A. https://doi.org/10.3389/fnagi.2019.00059 McConnell, H. L., & Mishra, A. (2022). Cells of the Blood-brain Barrier: an Overview of the Neurovascular Unit in Health and Disease. Methods in Molecular Biology (Clifton, N.J.), 2492, 3. https://doi.org/10.1007/978-1-0716-2289-6_1 Muñoz-Cabrera, J. M. (2015). Efecto del Bexaroteno sobre la plasticidad en la sinapsis comisural CA3-CA1 en un modelo murino de enfermedad de Alzheimer. Universidad Nacional de Colombia Muñoz-Cabrera, J. M., Sandoval-Hernández, A. G., Niño, A., Báez, T., Bustos-Rangel, A., Cardona-Gómez, G. P., Múnera, A., & Arboleda, G. (2019). Bexarotene therapy ameliorates behavioral deficits and induces functional and molecular changes in very-old Triple Transgenic Mice model of Alzheimer´s disease. PLOS ONE, 14(10), e0223578. https://doi.org/10.1371/JOURNAL.PONE.0223578 Namjoshi, D. 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Amyloid-ß peptides inhibit the expression of AQP4 and glutamate transporter EAAC1 in insulin-treated C6 glioma cells. Toxicology Reports, 7, 1083–1089. https://doi.org/10.1016/j.toxrep.2020.08.032 Peng, M., Ling, X., Song, R., Gao, X., Liang, Z., Fang, F., & Cang, J. (2019). Upregulation of GLT-1 via PI3K/Akt Pathway Contributes to Neuroprotection Induced by Dexmedetomidine. Frontiers in Neurology, 10(SEP). https://doi.org/10.3389/FNEUR.2019.01041 Pérez Silva, A. (2023). Evaluación del potencial terapéutico del extracto vegetal Zanthoxylum martinicense asociado a la actividad agonista de LXR en el modelo murino de enfermedad de Alzheimer (3xTg-AD). Universidad Nacional de Colombia. https://repositorio.unal.edu.co/handle/unal/83985 Prada, S. I., Takeuchi, Y., & Ariza, Y. (2014). Costo monetario del tratamiento de la enfermedad de Alzheimer en Colombia Monetary cost of treatment for Alzheimer’s disease in Colombia Artículo original. Acta Neurol Colomb, 30(4), 247–255. Rebec, G. V. (2013). Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington’s Disease. Antioxidants & Redox Signaling, 19(17), 2115. https://doi.org/10.1089/ARS.2013.5387 Rezaee, N., Fernando, W. M. A. D. B., Hone, E., Sohrabi, H. R., Johnson, S. K., Gunzburg, S., & Martins, R. N. (2021). Potential of Sorghum Polyphenols to Prevent and Treat Alzheimer’s Disease: A Review Article. Frontiers in Aging Neuroscience, 13, 603. https://doi.org/10.3389/FNAGI.2021.729949/BIBTEX Rodríguez-Arellano, J. J., Parpura, V., Zorec, R., & Verkhratsky, A. (2016). Astrocytes in physiological aging and Alzheimer’s disease. In Neuroscience (Vol. 323, pp. 170–182). Elsevier Ltd. https://doi.org/10.1016/j.neuroscience.2015.01.007 Rodríguez-Giraldo, M., González-Reyes, R. E., Ramírez-Guerrero, S., Bonilla-Trilleras, C. E., Guardo-Maya, S., & Nava-Mesa, M. O. (2022). Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments. 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The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting. Journal of Comparative Neurology, 524(18), 3865–3895. https://doi.org/10.1002/CNE.24040 Wood, O. W. G., Yeung, J. H. Y., Faull, R. L. M., & Kwakowsky, A. (2022). EAAT2 as a therapeutic research target in Alzheimer’s disease: A systematic review. Frontiers in Neuroscience, 16, 952096. https://doi.org/10.3389/fnins.2022.952096 Zhang, X., Lao, K., Qiu, Z., Rahman, M. S., Zhang, Y., & Gou, X. (2019). Potential Astrocytic Receptors and Transporters in the Pathogenesis of Alzheimer’s Disease. Journal of Alzheimer’s Disease : JAD, 67(4), 1109–1122. https://doi.org/10.3233/JAD-181084 Ruiz González, J. (2021). Evaluación del potencial terapéutico de un extracto de raíz de Zanthoxylum caribaeum en un modelo triple transgénico de Enfermedad de Alzheimer. Universidad Nacional de Colombia Caicedo Díaz, J. (2021). Evaluación del potencial terapéutico de agonistas sintéticos y naturales de LXR (GW3965 y Nectandra reticulata) en el modelo murino 3xTg-AD de la enfermedad de Alzheimer. Universidad Nacional de Colombia. Prillaman, M. (2022). Alzheimer's drug slows mental decline in trial-but is it a breakthrough?. Nature
dc.rights.coar.fl_str_mv	http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv	Atribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rights.uri.spa.fl_str_mv	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.accessrights.spa.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	Atribución-NoComercial-SinDerivadas 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv	openAccess
dc.format.extent.spa.fl_str_mv	xxii, 98 páginas
dc.format.mimetype.spa.fl_str_mv	application/pdf
dc.publisher.spa.fl_str_mv	Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv	Bogotá - Medicina - Maestría en Neurociencias
dc.publisher.faculty.spa.fl_str_mv	Facultad de Medicina
dc.publisher.place.spa.fl_str_mv	Bogotá,Colombia
dc.publisher.branch.spa.fl_str_mv	Universidad Nacional de Colombia - Sede Bogotá
institution	Universidad Nacional de Colombia
bitstream.url.fl_str_mv	https://repositorio.unal.edu.co/bitstream/unal/84372/1/license.txt https://repositorio.unal.edu.co/bitstream/unal/84372/2/71786951.2023.pdf
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repository.name.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
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spelling	Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Arboleda Bustos, Gonzalo Humberto8d01100986b4e816de54bb4d3f52f1f0Lopez-Cano, Juan Guillermoae135867404dbed1cd4cc96ab553974bColcienciasGrupo de Neurociencias-Universidad Nacional de ColombiaMuerte Celular2023-07-31T14:23:20Z2023-07-31T14:23:20Z2023-07-30https://repositorio.unal.edu.co/handle/unal/84372Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramasEl aumento no regulado de la excitación neuronal y del ingreso de calcio a la célula, conocido como excitotoxicidad y causado por un exceso de glutamato (ya sea en tiempo de permanencia y/o en concentración) en la hendidura sináptica, o por acúmulos de Aβ en el espacio extracelular en contextos de Alzheimer, ha sido considerado como uno de los posibles mecanismos moleculares que derivan en la muerte de neuronas del hipocampo en el desarrollo de la enfermedad de Alzheimer (EA). Los extractos vegetales presentan características químicas estructurales que amplían el espectro de ligandos o compuestos con actividad neuroprotectora, y dada esa diversidad química han ganado importancia en la búsqueda de alternativas terapéuticas a enfermedades neurodegenerativas como la EA convirtiéndolos en sustancias privilegiadas multidiana. En este trabajo se evaluó el efecto de un extracto etanólico de raíz de Zanthoxylum martinicense sobre la expresión de las proteínas astrocitarias responsables de la regulación del glutamato en la hendidura sináptica, adicionalmente se evaluó el cambio en otras proteínas de interés en contextos de la EA dada la actividad agonista LXRβ de este extracto demostrada previamente en nuestro grupo de investigación. Mediante técnicas de inmunología y de cuantificación de proteínas totales, se evaluó el cambio en la expresión de las proteínas LRP, APOE (que tienen un rol protagónico en la homeostasis de Aβ en el sistema nervioso central) y de los transportadores de glutamato GLAST (EAAT1) y GLT-1 (EAAT2), en cultivos in vitro de la línea U87-MG empleado como modelo de astrocitos y en un modelo in vivo de ratones 3xTg-AD que fueron tratados con el extracto de Zanthoxylum martinicense. El resultado muestra que el tratamiento con este extracto específicamente tiene un efecto dosis dependiente en el aumento de la expresión de las proteínas ya mencionadas excepto LRP. El aumento en la expresión de APOE, GLAST y GLT1 tiene un potencial efecto neuroprotector por la posible mejora de la remoción de Aβ y en el incremento en la eficiencia de la retoma del glutamato sináptico evitando eventos de excitotoxidad, y puede pensarse que sean una parte del sustento molecular que soporta la recuperación de la memoria espacial en ratones 3xTg-AD tratados con el extracto. (Texto tomado de la fuente)The dysregulated increase of neuronal excitation and calcium entry into the neuron, known as excitotoxicity, after a glutamate excess in the synaptic cleft or because of the Aβ aggregates in the extracellular matrix in Alzheimer’s disease (AD), has been considered as one of the possible molecular mechanisms driving neurodegeneration in the hippocampus during progression of AD. Vegetable extracts exhibit structural chemical features that enlarge the spectrum of ligands or compounds with neuroprotective capacity. According to this chemical diversity, they have emerged as protagonists in the search for therapeutic alternatives to neurodegenerative diseases like Alzheimer, and make them privileged multitarget compounds. In this research, we tested the effect of an ethanolic Zanthoxylum martinicense root’s extract on the expression of astrocytic proteins responsible for glutamate reuptake in the synaptic cleft. Additionally, because previous research in our lab demonstrated an LXRβ agonist activity of the extract, we evaluate the change in additional proteins related to AD. By using immunology tools and total protein quantification procedures, we probed changes in the expression of LRP, APOE (with a main role in the Aβ homeostasis in the central nervous system) and for the astrocytic glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2), in cultures of U87-MG cell line used as an astrocytic model, and in an in-vivo model of 3xTg-AD mice that were treated with the Zanthoxylum martinicense extract. Our results show that the treatment with this extract has a dose-dependent effect in the upregulation of the above-mentioned proteins, except LRP. The APOE, GLT1, and GLAST upregulation has a potential neuroprotective effect, due to their potential increased in Aβ removal and increased reuptake of synaptic glutamate, therefore avoiding excitotoxicity. We speculate that these effects are a constitutive part of the molecular substrate that supports the spatial memory recovery of 3xTg-AD treated with the extract.MaestríaMagister en NeurocienciasMuerte CelularAlzheimerextractos vegetalesastrocitosexcitotoxicidadglutamatoxxii, 98 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en NeurocienciasFacultad de MedicinaBogotá,ColombiaUniversidad Nacional de Colombia - Sede Bogotá570 - Biología::572 - Bioquímica570 - Biología::573 - Sistemas fisiológicos específicos en animales, histología regional y fisiología en los animales580 - Plantas::582 - Plantas destacadas por características vegetativas y flores610 - Medicina y salud::615 - Farmacología y terapéutica610 - Medicina y salud::616 - EnfermedadesMedicina alternativaAlternative medicineNeuropathyMedicinal plantNeuropatíaPlantas medicinalesAlzheimerZanthoxylum martinicenseApoEGLT-1GLT1GLASTAstrocitosExcitotoxicidadGlutamatoTransportadoresAlzheimerZanthoxylum martinicenseApoEGLT-1GLT1GLASTAstrocytesExcitotoxicityGlutamateTransportersEvaluación del efecto del extracto de zanthoxylum martinicense sobre la expresión de apoe, lrp, glast y glt-1 en modelo de astrocitos y en ratones 3x tg-adEvaluation of the effect of Zanthoxylum martinicense extract over the expression of ApoE, LRP, GLAST y GLT-1 in an astrocyte model and 3x Tg-AD miceTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMAlmad, A., & Maragakis, N. 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NatureBioprospección del potencial terapéutico de extractos vegetales de las familias laurácea y rutácea asociados a la actividad farmacológica de LXR en un modelo murino de enfermedad de Alzheimer y análisis computacionalColcienciasEstudiantesInvestigadoresMaestrosMedios de comunicaciónPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84372/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL71786951.2023.pdf71786951.2023.pdfTesis de Maestría en Neurocienciasapplication/pdf2832137https://repositorio.unal.edu.co/bitstream/unal/84372/2/71786951.2023.pdfec1777795b9e383813e4545095d883dfMD52unal/84372oai:repositorio.unal.edu.co:unal/843722023-07-31 09:28:29.449Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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