Evaluación del efecto de metabolitos de Cannabis sativa y Piper nigrum sobre la expresión y señalización celular de GPR55 y PINK1 en modelos de glioblastoma multiforme

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dc.contributor.advisorArboleda Bustos, Gonzalo Humberto
dc.contributor.advisorMarín Loaiza, Juan Camilo
dc.contributor.authorTurizo Smith, Andres David
dc.contributor.cvlacTurizo Smith, Andres David [0000071294]
dc.contributor.orcidTurizo Smith, Andres David [0000000303584008]
dc.contributor.projectmemberKaren Lizzette Velasquez Mendez
dc.contributor.projectmemberJean Carlos Martinez Perez
dc.contributor.projectmemberLuis Alejandro García Rairán
dc.contributor.projectmemberJaime Arias Guatibonza
dc.contributor.projectmemberNicolás Montoya Moreno,
dc.contributor.projectmemberJosefa Antonia Rodríguez García,
dc.contributor.researchgateTurizo Smith, Andres David [Andres-D-Turizo-Smith]
dc.contributor.researchgroupGiffun-Grupo de Investigación en Fitoquímica y Farmacognosia de la Universidad Nacional de Colombia
dc.contributor.researchgroupMuerte Celular
dc.date.accessioned2026-02-20T12:55:26Z
dc.date.available2026-02-20T12:55:26Z
dc.date.issued2025
dc.descriptionilustraciones a color, diagramasspa
dc.description.abstractEl glioblastoma multiforme (GB) es un tumor astrocítico maligno que se caracteriza por un crecimiento rápido, gran invasividad y alta vascularización. A pesar de los avances en las técnicas quirúrgicas y en el desarrollo de nuevos protocolos en radio y quimioterapia, el pronóstico de los pacientes que padecen esta neoplasia sigue siendo precario. En algunos estudios epidemiológicos, la proteína PINK1 se ha vinculado a una reducción del riesgo de ciertos tipos de cáncer en pacientes con enfermedades neurodegenerativas y viceversa. Esta proteína interactúa en varios niveles con el eje de señalización oncogénicas PI3-quinasa/AKT/mTOR y controla funciones mitocondriales y metabólicas críticas que regulan la supervivencia en cáncer, la resistencia al estrés y el ciclo celular. Por otro lado, se ha informado que GPR55 y su ligando endógeno L-α-lisofosfatidilinositol (LPI) desempeñan un papel en varios tipos de cánceres. Se ha descrito un efecto potenciador de la proliferación de GPR55 en varias líneas de células cancerosas y se ha encontrado que el LPI está elevado en pacientes con cáncer; este aumento de la expresión del receptor se ha correlacionado con la agresividad tumoral y el aumento de la activación de la cascada de la cinasa ERK. El objetivo de este trabajo fue establecer, mediante una serie de ensayos y análisis in silico e in vitro, la acción de los metabolitos presentes en Cannabis sativa y Piper nigrum sobre las proteínas GPR55 y PINK1; y determinar su efecto citotóxico y las vías de señalización relacionadas, en líneas celulares y muestras de pacientes con GB. (Texto tomado de la fuente)spa
dc.description.abstractGlioblastoma multiforme is a malignant astrocytic tumor characterized by rapid growth, extensive invasiveness and high vascularity. Despite advances in surgical techniques and in the development of new protocols in radio- and chemotherapy, the prognosis for patients suffering from this malignancy remains poor. In some epidemiological studies, the PINK1 protein has been linked to a reduction in the risk of certain types of cancer in patients with neurodegenerative diseases and vice versa. This protein interacts at various levels with the PI3-kinase / AKT / mTOR oncogenic signaling axis and controls critical mitochondrial and metabolic functions that regulate cancer survival, stress resistance, and the cell cycle. On the other hand, GPR55 and its endogenous ligand L-α-lysophosphatidylinositol (LPI) have been reported to play a role in various types of cancers. A proliferation-enhancing effect of GPR55 has been described in several cancer cell lines and LPI has been found to be elevated in cancer patients; this increase in receptor expression has been correlated with tumor aggressiveness and increased activation of the ERK kinase cascade. The objective of this work was to establish, through a series of in silico and in vitro tests and analyses, the action of the metabolites present in Cannabis sativa and Piper nigrum on the GPR55 and PINK1 proteins; and determine its effect on cell lines and GB patient samples.eng
dc.description.degreelevelDoctorado
dc.description.degreenameDoctor en Oncología
dc.description.methodsEl presente estudio adoptó un enfoque de investigación traslacional que integró herramientas computacionales (in silico) y experimentales (in vitro e in vivo). La metodología se desarrolló en cuatro fases principales: Análisis In Silico: Se realizaron simulaciones de acoplamiento molecular (docking) para evaluar la afinidad de unión de fitocannabinoides de Cannabis sativa y alcaloides de Piper nigrum sobre los modelos estructurales de los receptores GPR55 y la proteína PINK1 (obtenidos de AlphaFold), utilizando los softwares AutoDock Vina y ECR. Modelos Celulares: Se emplearon líneas celulares de glioblastoma multiforme humano (U87 y T98G) y cultivos primarios de Glioblastoma. Se evaluó la viabilidad celular mediante el ensayo de MTT, WST y la liberación de Lactato Deshidrogenasa (LDH) tras el tratamiento con los compuestos seleccionados. Análisis Molecular y de Señalización: Se determinó la expresión génica y proteica mediante RT-qPCR e Inmunofluorescencia, analizando PINK1 y la señalización mediada por GPR55 bajo condiciones de estrés mitocondrial. Validación en Muestras Clínicas: Se realizó un estudio descriptivo retrospectivo mediante inmunohistoquímica (IHC) en tejidos de pacientes con glioblastoma del distrito y el Hospital El Tunal, correlacionando la expresión de los biomarcadores con los hallazgos experimentales.
dc.description.notesEste proyecto quedo de segundo lugar en el II congreso del grupo de alternativas terapéuticas en cáncer (GAT), de la universidad javeriana del 2023, Primer lugar a nivel nacional por parte de la Agencia Distrital para la Educación Superior, la Ciencia y la Tecnología (ATENEA) por un monto de USD 62.000, en la convocatoria de Cannabis medicinal del 2023, y se presento gracias a una de las 41 becas a nivel mundial de la European Association Of Cancer Research (EACR) en su congreso anual en lisboa, Portugal en junio 2025.spa
dc.description.sponsorshipEste proyecto de investigación fue financiado por la Agencia Distrital para la Educación Superior, la Ciencia y la Tecnología (ATENEA) de Bogotá, Colombia, bajo el contrato número 396-2023. El apoyo se otorgó en el marco de la convocatoria para la 'Cooperación para la gestión y ejecución de proyectos de investigación en cannabis medicinal', contando con un financiamiento de USD 62,000 para el desarrollo de los estudios in silico e in vitro sobre glioblastoma multiforme. La investigación contó con el apoyo financiero y técnico de la Universidad Nacional de Colombia - Sede Bogotá, a través de sus programas internos de fomento a la investigación y el acceso a la infraestructura del Grupo de Fitoquímica y Farmacognosia de la Universidad Nacional de Colombia (GIFFUN) y el Instituto de Genética de la Universidad Nacional (IGUN) y los laboratorios de la Facultad de Medicina. El trabajo se desarrolló en colaboración con el Instituto Nacional de Cancerología (INC) y el Hospital El Tunal (Subred Sur, Bogotá), entidades que facilitaron el acceso a muestras de pacientes y datos clínicos esenciales para los estudios de inmunohistoquímica. Asimismo, se contó con el apoyo técnico y donación de insumos de laboratorios externos como Bio-Molecular Diagnostica Ltd., Laboratorio Inmunotech, y Microgen Ltd. LABG&M (provisión de Suero Fetal Bovino colombiano)
dc.description.technicalinfoAnálisis Estadístico: Se utilizó el software GraphPad Prism (v.9 ) para el análisis de varianza (ANOVA) y pruebas de significancia estadística de los datos experimentales de viabilidad celular y expresión génica." Análisis de Imágenes: "Para la cuantificación de inmunofluorescencia y análisis de Western Blot, se empleó el software ImageJ (NIH) / FIJI, permitiendo la densitometría de bandas y normalización de proteínas. Software y Metodología: Se realizaron simulaciones de acoplamiento molecular (docking) utilizando las estructuras de las proteínas PINK1 y GPR55 obtenidas de la base de datos AlphaFold. Los ligandos, que incluyeron metabolitos de Cannabis sativa y Piper nigrum, fueron optimizados mediante el campo de fuerza MMFF94. Para el cálculo de las afinidades de unión y la identificación de interacciones ligando-receptor, se emplearon los programas AutoDock y Vina. Adicionalmente, se utilizaron funciones de puntuación como Vinardo y el sistema de ranking de consenso exponencial (ECR) para validar la consistencia de los resultados.spa
dc.description.technicalinfoMolecular Modeling and Docking: Molecular docking studies were performed to evaluate the binding affinity of Cannabis sativa and Piper nigrum ligands on the structural models of GPR55 and PINK1. AutoDock Vina (o tu software específico) and PyMOL software were used for the visualization and analysis of protein-ligand interactions and the calculation of binding free energies. Software and Methodology: Molecular docking simulations were performed using the structures of PINK1 and GPR55 proteins obtained from the AlphaFold database. Ligands, including metabolites from Cannabis sativa and Piper nigrum, were optimized using the MMFF94 force field. AutoDock and Vina software were employed to calculate binding affinities and identify ligand-receptor interactions. Additionally, Vinardo scoring functions and the exponential consensus ranking (ECR) system were used to validate the consistency of the findings.eng
dc.format.extent198 páginas
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad Nacional de Colombia
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/89612
dc.language.isospa
dc.publisherUniversidad Nacional de Colombia
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotá
dc.publisher.facultyFacultad de Medicina
dc.publisher.placeBogotá, Colombia
dc.publisher.programBogotá - Medicina - Doctorado en Oncología
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc610 - Medicina y salud
dc.subject.ddc540 - Química y ciencias afines
dc.subject.ddc570 - Biología
dc.subject.ddc580 - Plantas
dc.subject.decsCannabaceaespa
dc.subject.decsCannabaceaeeng
dc.subject.decsNeoplasias Neuroepitelialesspa
dc.subject.decsNeoplasms, Neuroepithelialeng
dc.subject.decsAstrocitomaspa
dc.subject.decsAstrocytomaeng
dc.subject.decsNeoplasiasspa
dc.subject.decsNeoplasmseng
dc.subject.decsPlantas Medicinalesspa
dc.subject.decsPlants, Medicinaleng
dc.subject.decsExtractos Vegetalesspa
dc.subject.decsPlant Extractseng
dc.subject.proposalGPR55spa
dc.subject.proposalPINK1spa
dc.subject.proposalGlioblastoma multiformespa
dc.subject.proposalCáncerspa
dc.subject.proposalCannabis sativaspa
dc.subject.proposalPiper nigrumeng
dc.subject.proposalGlioblastoma Multiformespa
dc.titleEvaluación del efecto de metabolitos de Cannabis sativa y Piper nigrum sobre la expresión y señalización celular de GPR55 y PINK1 en modelos de glioblastoma multiformespa
dc.title.translatedEvaluation of the effect of metabolites from Cannabis sativa and Piper nigrum on the expression and cellular signaling of GPR55 and PINK1 in glioblastoma multiforme modelseng
dc.typeTrabajo de grado - Doctorado
dc.type.coarhttp://purl.org/coar/resource_type/c_db06
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentDataPaper
dc.type.contentText
dc.type.contentOther
dc.type.driverinfo:eu-repo/semantics/doctoralThesis
dc.type.redcolhttp://purl.org/redcol/resource_type/TD
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dcterms.audience.professionaldevelopmentInvestigadores
dcterms.audience.professionaldevelopmentEstudiantes
dcterms.audience.professionaldevelopmentMaestros
dcterms.audience.professionaldevelopmentEspecializada
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2
oaire.awardtitle"Evaluación del efecto de metabolitos de Cannabis sativa y Piper nigrum sobre modelos de glioblastoma", financiado por la Agencia Distrital para la Educación Superior, La Ciencia y la Tecnología – Atenea, bajo el contrato No. 396 de 2023, de la Convocatoria Cooperación para la gestión y ejecución de proyectos de investigación en cannabis medicinal
oaire.fundernameAgencia Distrital para la Educación Superior, la Ciencia y la Tecnología (ATENEA)

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Doctorado en Oncología