Milk-derived bioactive peptides exhibit antioxidant activity through the Keapl-Nrf2 signaling pathway

Bioactive peptides are relevant nutritional factors that exhibit many functions including antioxidant, antihypertensive, anticancer and antimicrobial properties. In this paper, four synthetic peptides ARHPHPHLSFM (A-11-M), AVPYPQR (A-7-R), NPYVPR (N-6-R) and KVLPVPEK (K-B-K) with sequences present in milk proteins were examined for their antioxidant properties. The compounds show moderate free radical scavenging activity in the ARTS and crocin assays (A-7-R and N-6-R) and lipid peroxidation inhibition in Caco-2 cells (N-6-R and K-8-K). All peptides, in particular K-8-K, activate the Keap1-Nrf2 system by allowing the translocation of the transcription factor Nrf2 from the cytosol to nucleus. This activation triggers the overexpression of the antioxidant enzymes Trx1, TrxR1, GR, NQO1 and SOD1. Furthermore, molecular modeling shows that K-8-K is able to hinder the interaction of Nrf2 with Keap1. The reported results show that the antioxidant action in cells of these bioactive peptides is mostly due to the activation of Keap1-Nrf2 signaling pathway.