**1. Introduction**

In order to increase the shelf life and improve the flavour, fermentation is a process used for many years in a wide variety of food matrices such as soy, milk, meat and vegetables. Due to the presence of health-promoting compounds, fermented foods are considered important components of the human diet [1]. In fact, this type of food processing not only improves the organoleptic properties of the food matrix, but it can also increase the availability of various constituents, which can exert positive e ffects after consumption [2]. Among these compounds, bioactive peptides are inactive in the primary structure of proteins and can be released from them by fermenting bacteria-mediated proteolysis [3]. Many microorganisms are utilized in this process and it is well known that di fferent fermenting strains can generate various patterns of bioactive peptides [4–6]. In particular, for dairy

products, *Streptococcus thermophilus*, *Lactobacillus delbrueckii* subsp. *bulgaricus* and *Bifidobacterium* spp are usually employed [2,7]. Bioactive peptides generated from milk can originate both from whey proteins (β-lactoglobulin, α-lactalbumin, serum albumin, immunoglobulins, lactoferrin and protease-peptone fractions) and from caseins ( α-, β- and κ-casein) [8–10]. Bioactive peptides are studied for their various beneficial activities, for example anti-hypertensive, anti-microbial, opioid and antioxidant [4,11–14]. The antioxidant activity of bioactive peptides can depend on their amino acid composition and position in the sequence [15]. Moreover, these compounds can exert their antioxidant activity in cell environment through activation of specific pathways [16,17]. Oxidants and electrophiles are well known molecules recognized to determine the disruption of Keap1/Nrf2 interaction [16,18,19]. However, new series of other compounds are now emerging, such as the bioactive peptides, that with specific protein-protein interactions are able to activate nuclear factor erythroid 2-related factor 2 (Nrf2). The latter, after dissociation from Kelch-like ECH-associated protein 1 (Keap1), migrates to the nucleus where interacts with the antioxidant response element (ARE), activating a large number of genes expressing antioxidant enzymes. Nrf2 translocation is one of the key events required for the regulation of Keap1/Nrf2 pathway and it is considered an evidence of the activation of the system. [20,21]

As reported in the present paper, peptide fractions from fermented milk were isolated and tested for their antioxidant properties. From the most active fractions, sequences of the most abundant peptides were identified and then synthesized. Finally, these compounds were analyzed for their antioxidant activity in vitro and in a cellular model.

This work aimed to understand the mechanism of action of fermented milk-derived peptides in the protection from oxidative stress. In particular, the interaction of these peptides with Keap1/Nrf2 pathway, the main molecular pathway involved in the protection of cells from oxidative stress conditions, was taken into account.
