Milk-derived bioactive peptides exhibit antioxidant activity through the Keap1-Nrf2 signaling pathway

Bioactive peptides are relevant nutritional factors that exhibit many functions including antioxidant, anti-hypertensive, 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-8-K) with sequences present in milk proteinswere examined for their antioxidant properties. The compounds show moderate free radical scavenging activityin the ABTS 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 tran-scription factor Nrf2 from the cytosol to nucleus. This activation triggers the overexpression of the antioxidantenzymes Trx1, TrxR1, GR, NQO1 and SOD1. Furthermore, molecular modeling shows that K-8-K is able to hinderthe interaction of Nrf2 with Keap1. The reported results show that the antioxidant action in cells of thesebioactive peptides is mostly due to the activation of Keap1-Nrf2 signaling pathway