Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis
| Autor: | Abdellah Ezzanad, José Manuel Botubol-Ares, Samuel Domínguez-García, Felipe Escobar-Montaño, Mónica Díez-Salguero, Ricardo Gómez-Oliva, Carmen Castro, Carolina de los Reyes, Pedro Nunez-Abades, Rosa Durán-Patrón, Noelia Geribaldi-Doldán, Antonio J. Macías-Sánchez, Rosario Hernández-Galán |
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| Přispěvatelé: | Universidad de Sevilla. Departamento de Fisiología, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Biomedicina, Biotecnología y Salud Pública, Química Orgánica |
| Rok vydání: | 2021 |
| Předmět: |
TGF alpha
Neurogenesis 01 natural sciences Mice 03 medical and health sciences chemistry.chemical_compound Neural Stem Cells In vivo Phorbol Esters Drug Discovery Animals Progenitor cell Cell Proliferation 030304 developmental biology 0303 health sciences biology Euphorbia resinifera Transforming Growth Factor alpha biology.organism_classification In vitro 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry chemistry Lipophilicity Phorbol Molecular Medicine |
| Zdroj: | idUS. Depósito de Investigación de la Universidad de Sevilla instname J. Med. Chem. 2021, 64, 6070−6084 RODIN: Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz Universidad de Cádiz RODIN. Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz |
| Popis: | A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a targeted UHPLC-HRMS screening of the latex of Euphorbia resinifera. Two new 12-deoxy-16-hydroxyphorbol 13,16-diesters were isolated, and their structures were deduced using two-dimensional NMR spectroscopy and NOE experiments. The ability of natural and synthetic compounds to stimulate transforming growth factor alpha (TFG alpha) release, to increase neural progenitor cell proliferation, and to stimulate neurogenesis was evaluated. All compounds that facilitated TGF alpha release promoted neural progenitor cell proliferation. The presence of two acyloxy moieties on the tigliane skeleton led to higher levels of activity, which decreased when a free hydroxyl group was at C-12. Remarkably, the compound bearing isobutyryloxy groups was the most potent on the TGF alpha assay and at inducing neural progenitor cell proliferation in vitro, also leading to enhanced neurogenesis in vivo when administered intranasally to mice. This work was supported by the Spanish Ministerio de Ciencia, Innovacion y Universidades (grant nos RTI2018-099908-BC21 and RTI2018-099908-B-C22 MICINN/FEDER granted to CC and RHG, respectively) and Consejeria de Economia, Conocimiento, Empresas y Universidades Junta de Andalucia (grant no FEDER-ANDALUCIA sol2018-00106647-tra). We thank the "Servicio de experimentacion y produccion animal (SEPA) de la Universidad de Cadiz" as well as the "Servicios Centrales de apoyo a la investigacion en Ciencias de la Salud (SCICS) de la Universidad de Cadiz" and "Servicios centrales de Ciencia Cadiz". |
| Databáze: | OpenAIRE |
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