Autor(es):
Teixeira, José ; Oliveira, Catarina ; Cagide, Fernando ; Amorim, Ricardo ; Garrido, Jorge ; Borges, Fernanda ; Oliveira, Paulo J.
Data: 2018
Identificador Persistente: https://hdl.handle.net/10316/107712
Origem: Estudo Geral - Universidade de Coimbra
Projeto/bolsa:
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/PT;
Assunto(s): Gallic acid; mitochondriotropic antioxidant; oxidative stress; mitochondrial dysfunction; mitochondrial permeability transition pore; Animals; Antioxidants; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Gallic Acid; Hep G2 Cells; Humans; Male; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Molecular Structure; Rats; Rats, Wistar; Structure-Activity Relationship; Drug Discovery
Descrição
Pharmacological interventions targeting mitochondria present several barriers for a complete efficacy. Therefore, a new mitochondriotropic antioxidant (AntiOxBEN3) based on the dietary antioxidant gallic acid was developed. AntiOxBEN3 accumulated several thousand-fold inside isolated rat liver mitochondria, without causing disruption of the oxidative phosphorylation apparatus, as seen by the unchanged respiratory control ratio, phosphorylation efficiency, and transmembrane electric potential. AntiOxBEN3 showed also limited toxicity on human hepatocarcinoma cells. Moreover, AntiOxBEN3 presented robust iron-chelation and antioxidant properties in both isolated liver mitochondria and cultured rat and human cell lines. Along with its low toxicity profile and high antioxidant activity, AntiOxBEN3 strongly inhibited the calcium-dependent mitochondrial permeability transition pore (mPTP) opening. From our data, AntiOxBEN3 can be considered as a lead compound for the development of a new class of mPTP inhibitors and be used as mPTP de-sensitiser for basic research or clinical applications or emerge as a therapeutic application in mitochondria dysfunction-related disorders.
This project was supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE [Grants POCI-01–0145- FEDER-007440, POCI-01–0145-FEDER-016659, UID/QUI/00081/2013/ POCI-01–0145-FEDER-006980, PTDC/DTP-FTO/2433/2014, and NORTE-01–0145-FEDER-000028]. J Teixeira, C Oliveira, and F. Cagide were supported by grants from FCT, POPH, FEDER/ COMPETE, and Norte2020. Ricardo Amorim is recipient of a Ph.D. fellowship from the FCT [SFRH/BD/131070/2017].
