Mitochondria-targeted phenolic antioxidants induce ROS-protective pathways in primary human skin fibroblasts

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Teixeira, J (Author) Other; Basit, F (Author) Other; Willems, PHGM (Author) Other; Wagenaars, JA (Author) Other; van de Westerlo, E (Author) Other; Amorim, R (Author) Other; Fernando Cagide (Author) FCUP; Benfeito, S (Author) Other; Oliveira, C (Author) Other; Fernanda Borges (Author) FCUP; Oliveira, PJ (Author) Other; Koopman, WJH (Author) Other

Journal

Title: Free Radical Biology and Medicine

Vol. 163

Pages: 314-324

ISSN: 0891-5849

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 16 Citations

Other information

Authenticus ID: P-00T-99C

DOI: 10.1016/j.freeradbiomed.2020.12.023

Abstract (EN): Phytochemical antioxidants like gallic and caffeic acid are constituents of the normal human diet that display beneficial health effects, potentially via activating stress response pathways. Using primary human skin fibroblasts (PHSFs) as a model, we here investigated whether such pathways were induced by novel mitochondriatargeted variants of gallic acid (AntiOxBEN(2)) and caffeic acid (AntiOxCIN(4)). Both molecules reduced cell viability with similar kinetics and potency (72 h incubation, IC50 similar to 23 mu M). At a relatively high but non-toxic concentration (12.5 mu M), AntiOxBEN(2) and AntiOxCIN(4) increased ROS levels (at 24 h), followed by a decline (at 72 h). Further analysis at the 72 h timepoint demonstrated that AntiOxBEN(2) and AntiOxCIN(4) did not alter mitochondrial membrane potential (Delta psi), but increased cellular glutathione (GSH) levels, mitochondrial NAD(P) H autofluorescence, and mitochondrial superoxide dismutase 2 (SOD2) protein levels. In contrast, cytosolic SOD1 protein levels were not affected. AntiOxBEN(2) and AntiOxCIN(4) both stimulated the gene expression of Nuclear factor erythroid 2-related factor 2 (NRF2; a master regulator of the cellular antioxidant response toward oxidative stress). AntiOxBEN2 and ANtiOxCIN4 differentially affected the gene expression of the antioxidants Heme oxygenase 1 (HMOX1) and NAD(P)H dehydrogenase (quinone) 1 (NQO1). Both antioxidants did not protect from cell death induced by GSH depletion and AntiOxBEN(2) (but not AntiOxCIN(4)) antagonized hydrogen peroxide-induced cell death. We conclude that AntiOxBEN(2) and AntiOxCIN(4) increase ROS levels, which stimulates NRF2 expression and, as a consequence, SOD2 and GSH levels. This highlights that AntiOxBEN(2) and AntiOxCIN(4) can act as prooxidants thereby activating endogenous ROS-protective pathways.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11