THE MOLECULAR NUTRITION OF AMINO ACIDS AND PROTEINS THE MOLECULAR NUTRITION OF AMINO ACIDS AND PROTEINS A Volume in the Molecular Nutrition Series Edited by DOMINIQUE DARDEVET Institut National de la Recherche Agronomique (INRA), Ceyrat, France AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright r 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, 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the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-802167-5 For Information on all Academic Press publications visit our website at http://www.elsevier.com/ Publisher: Nikki Levy Acquisition Editor: Megan Ball Editorial Project Manager: Karen Miller Production Project Manager: Caroline Johnson Designer: Victoria Pearson Typeset by MPS Limited, Chennai, India List of Contributors A Bruhat Unite´ de Nutrition Humaine, UMR 1019, INRA, Universite´ d’Auvergne, Centre INRA de ClermontFerrand-Theix, Saint Gene`s Champanelle, France J.M Argile´s Cancer Research Group, Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain M.J Bruins The Hague, The Netherlands S Busquets Cancer Research Group, Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain P.J Atherton MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Medicine, University of Nottingham, Nottingham, United Kingdom D Attaix Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, Saint Gene`s Champanelle, France J.W Carbone School of Health Sciences, Eastern Michigan University, Ypsilanti, MI, United States C Chaumontet UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Universite´ Paris-Saclay, Paris, France J Averous Unite´ de Nutrition Humaine, UMR 1019, INRA, Universite´ d’Auvergne, Centre INRA de ClermontFerrand-Theix, Saint Gene`s Champanelle, France Y.-W Chen Department of Integrative Systems Biology, George Washington University, Washington DC, USA; Center for Genetic Medicine Research, Children’s National Healthy System, Washington DC, USA D Azzout-Marniche UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Universite´ Paris Saclay, Paris, France M.D Barberio Center for Genetic Medicine Research, Children’s National Healthy System, Washington DC, USA G Chevrier Department of Medicine, Faculty of Medicine, Cardiology Axis of the Que´bec Heart and Lung Institute, Que´bec, QC, Canada; Institute of Nutrition and Functional Foods, Laval University, Que´bec, QC, Canada E Barreiro Pulmonology Department, Muscle and Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain; Centro de Investigacio´n en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain P Codogno INEM, Institut Necker Enfants-Malades, Paris, France; INSERM U1151-CNRS UMR 8253, Paris, France; Universite´ Paris Descartes, Paris, France L Combaret Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, Saint Gene`s Champanelle, France M.-S Beaudoin Department of Medicine, Faculty of Medicine, Cardiology Axis of the Que´bec Heart and Lung Institute, Que´bec, QC, Canada; Institute of Nutrition and Functional Foods, Laval University, Que´bec, QC, Canada G Courtney-Martin Faculty of Kinesiology & Physical Education, Department of Clinical Dietetics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada D Be´chet Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, Saint Gene`s Champanelle, France N Darcel UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Universite´ Paris-Saclay, Paris, France Y Boirie Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, ClermontFerrand, France; CHU Clermont-Ferrand, service de Nutrition Clinique, Clermont-Ferrand, France E.L Dillon Department of Internal Medicine, Division of Endocrinology and Metabolism, The University of Texas Medical Branch, Galveston, TX, United States C G Boudry INRA UR1341 ADNC, St-Gilles, France R Boutrou INRA, UMR 1253, Science et Technologie du lait et de l’œuf, Rennes, France ix Domingues-Faria Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, ClermontFerrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, France x LIST OF CONTRIBUTORS et du INRA, F Mariotti UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Universite´ Paris-Saclay, Paris, France P Fafournoux Unite´ de Nutrition Humaine, UMR 1019, INRA, Universite´ d’Auvergne, Centre INRA de ClermontFerrand-Theix, Saint Gene`s Champanelle, France A.-C Maurin Unite´ de Nutrition Humaine, UMR 1019, INRA, Universite´ d’Auvergne, Centre INRA de ClermontFerrand-Theix, Saint Gene`s Champanelle, France G Fromentin UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Universite´ Paris-Saclay, Paris, France C C Gaudichon UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Universite´ Paris-Saclay, Paris, France A.J Meijer Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands J Gea Pulmonology Department, Muscle and Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain; Centro de Investigacio´n en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain C Michel P Even UMR Physiologie de la Nutrition Comportement Alimentaire, AgroParisTech, Universite´ Paris-Saclay, Paris, France C Guillet Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, ClermontFerrand, France M.J Hubal Center for Genetic Medicine Research, Children’s National Healthy System, Washington DC, USA; Department of Exercise and Nutrition Sciences, George Washington University, Washington DC, USA C Jousse Unite´ de Nutrition Humaine, UMR 1019, INRA, Universite´ d’Auvergne, Centre INRA de ClermontFerrand-Theix, Saint Gene`s Champanelle, France I Knerr National Centre for Inherited Metabolic Disorders, Temple Street Children’s University Hospital, Dublin, Ireland K.V.K Koelfat Maastricht University Medical Center, Maastricht, The Netherlands I Le Hueărou-Luron INRA UR1341 ADNC, St-Gilles, France F.J Lo´pez-Soriano Cancer Research Group, Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain S Lorin Faculte´ de Pharmacie, Universite´ Paris-Saclay, Chaˆtenay-Malabry, France; INSERM UMR-S-1193, Chaˆtenay-Malabry, France A Marette Department of Medicine, Faculty of Medicine, Cardiology Axis of the Que´bec Heart and Lung Institute, Que´bec, QC, Canada; Institute of Nutrition and Functional Foods, Laval University, Que´bec, QC, Canada L.M Margolis Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, United States McGlory Exercise Metabolism Research Group, Department of Kinesiology, McMaster University, Hamilton, ON, Canada INRA UMR1280 PhAN, Nantes, France P Mitchell Department of Medicine, Faculty of Medicine, Cardiology Axis of the Que´bec Heart and Lung Institute, Que´bec, QC, Canada; Institute of Nutrition and Functional Foods, Laval University, Que´bec, QC, Canada S.M Pasiakos Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, United States S Pattingre IRCM, Institut de Recherche en Cance´rologie de Montpellier, Montpellier, France; INSERM, U1194, Montpellier, France; Universite´ de Montpellier, Montpellier, France; Institut re´gional du Cancer de Montpellier, Montpellier, France P.B Pencharz Department of Paediatrics and Nutritional Sciences (Emeritus), Senior Scientist Research Institute, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada S.M Phillips Exercise Metabolism Research Group, Department of Kinesiology, McMaster University, Hamilton, ON, Canada C Polge Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, Saint Gene`s Champanelle, France D Re´mond INRA, UMR 1019-Unite´ de Nutrition Humaine, St Gene`s-Champanelle, France I Savary-Auzeloux INRA, UMR 1019-Unite´ de Nutrition Humaine, St Gene`s-Champanelle, France K Smith MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Medicine, University of Nottingham, Nottingham, United Kingdom P.B Soeters Maastricht University Maastricht, The Netherlands D Medical Center, Taillandier Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, ClermontFerrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, Saint Gene`s Champanelle, France P.M Taylor Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom LIST OF CONTRIBUTORS D Tome´ UMR Physiologie de la Nutrition Comportement Alimentaire, AgroParisTech, Universite´ Paris-Saclay, Paris, France et du INRA, K Torii Torii Nutrient-Stasis Institute, Inc., Tokyo, Japan T Tsurugizawa Neurospin, Commissariat a` l’Energie Atomique et aux Energies Alternatives, Gif-sur-Yvette, France S Walrand Clermont Universite´, Universite´ d’Auvergne, Unite´ de Nutrition Humaine, Clermont-Ferrand, France; INRA, UMR 1019, UNH, CRNH Auvergne, ClermontFerrand, France xi P.J.M Weijs Department of Nutrition and Dietetics, Internal Medicine, VU University Medical Center; Department of Intensive Care Medicine, VU University Medical Center; Department of Nutrition and Dietetics, School of Sports and Nutrition, Amsterdam University of Applied Sciences, Amsterdam, The Netherlands D.J Wilkinson MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Medicine, University of Nottingham, Nottingham, United Kingdom Preface In this series on Molecular Nutrition, the editors of each book aim to disseminate important material pertaining to molecular nutrition in its broadest sense The coverage ranges from molecular aspects to whole organs, and the impact of nutrition or malnutrition on individuals and whole communities It includes concepts, policy, preclinical studies, and clinical investigations relating to molecular nutrition The subject areas include molecular mechanisms, polymorphisms, SNPs, genomic-wide analysis, genotypes, gene expression, genetic modifications, and many other aspects Information given in the Molecular Nutrition series relates to national, international, and global issues A major feature of the series that sets it apart from other texts is the initiative to bridge the transintellectual divide so that it is suitable for novices and experts alike It embraces traditional and nontraditional formats of nutritional sciences in different ways Each book in the series has both overviews and detailed and focused chapters Molecular Nutrition is designed for nutritionists, dieticians, educationalists, health experts, epidemiologists, and health-related professionals such as chemists It is also suitable for students, graduates, postgraduates, researchers, lecturers, teachers, and professors Contributors are national or international experts, many of whom are from world-renowned institutions or universities It is intended to be an authoritative text covering nutrition at the molecular level V.R Preedy Series Editor xiii C H A P T E R Bioactive Peptides Derived From Food Proteins D Re´mond1, I Savary-Auzeloux1 and R Boutrou2 INRA, UMR 1019-Unite´ de Nutrition Humaine, St Gene`s-Champanelle, France INRA, UMR 1253, Science et Technologie du lait et de l’œuf, Rennes, France The value of dietary proteins is classically assessed using amino acid composition and protein digestibility (Leser, 2013) However, other parameters, such as their digestion rate (Dangin et al., 2002) or their potential to release bioactive peptides during digestion (Kitts and Weiler, 2003), would be of interest to fully describe dietary proteins value The term bioactive peptide was mentioned for the first time by Mellander and Isaksson in 1950 (Mellander, 1950) who observed that casein phosphorylated peptides were favoring calcium binding in bones of children suffering from rachitis In 1979, Zioudrou et al (1979) showed an opioid effect of peptides derived from gluten hydrolysis Since then, a large spectrum of studies has been devoted to bioactive peptides (also called functional peptides) and their potential beneficial effect on human health and metabolism, with effects on digestive, immune, cardiovascular, and nervous systems Many bioactive peptides have been discovered in foods from both animal or plant origin Actually the largest part of the investigation has been carried out on milk proteins (Nagpal et al., 2011; Boutrou et al., 2015) Bioactive peptides generally correspond to molecules with fewer than 20 amino acids (down to two), but several bigger molecules, such as caseinomacropeptide, have been equally identified as bioactive peptides Inactive within their precursor proteins, bioactive peptides have to be released by proteolysis in order to become functional Any food protein source can provide bioactive peptides Apart from milk and milk products, bioactive peptides have also been isolated from hydrolysates of proteins from egg, fish, cereals, and legumes These peptides can be produced directly in the food by the action of endogenous proteases in various food technological processing, such as milk fermentation, or meat ripening and cooking, but also can be already present in the ingested food (eg, glutathione, carnosine, or peptides produced during food processing implying fermentations) They can also be generated in vitro by the use of exogenous proteases In this last case, the peptides should be resistant as much as possible to intestinal digestion to be able to trigger a biological effect However, most bioactive peptides are formed during digestion in the body In this chapter, we present the main biological activities attributed to peptides derived from food proteins, the mechanisms by which they are produced in the digestive tract, and potentially absorbed across its wall/barrier 1.1 PHYSIOLOGICAL EFFECTS OF FOOD-DERIVED PEPTIDES Impact on the digestive tract Once released in the digestive tract, peptides derived from food proteins can act on digestive processes (secretions and transit) or modulate nutrients absorption (Shimizu, 2004) a Regulation of digestion The potential involvement of food-derived peptides on the regulation of digestive processes can be explained partially and indirectly via the secretion of a gut hormone, cholecystokinin (CCK), known to stimulate biliary and pancreatic secretion, and inhibit gastric secretion of enzymes Furthermore, this hormone increases intestinal motility, inhibits gastric emptying, and is considered as a strong anorexigenic The Molecular Nutrition of Amino Acids and Proteins DOI: http://dx.doi.org/10.1016/B978-0-12-802167-5.00001-3 © 2016 Elsevier Inc All rights reserved BIOACTIVE PEPTIDES DERIVED FROM FOOD PROTEINS gut hormone Casein, ovalbumin, soya, meat, and gluten enzymatic hydrolysates have been shown to stimulate CCK secretion in perfused rat intestine (Cuber et al., 1990), isolated intestinal cells (Nishi et al., 2001), or tumorous intestinal cells (Nemoz-Gaillard et al., 1998), showing a direct action of some compounds issued from these hydrolysates Some of the corresponding bioactive peptides have been identified For instance, the caseinomacropeptide (obtained through hydrolysis of κ-casein by gastric proteinases) or the derived peptides were shown to stimulate CCK (Yvon et al., 1994) and pancreatic secretions (Pedersen et al., 2000) and to inhibit gastric acid secretion (Yvon et al., 1994) Furthermore, CCK antagonists have also been shown to inhibit the satietogenic effect of CCK induced by a casein meal (Froetschel et al., 2001) In soy hydrolysate, the 51À63 fragment of β-conglycinin, presenting a high affinity for intestinal brush border cells, has also been shown to induce an increase of CCK secretion and hence indirectly impact on appetite control (Nishi et al., 2003) Again, this latter effect is blunted by administration of a CCK antagonist (Nishi et al., 2003) A similar effect was reported for the tripeptide RIY that is released from the rapeseed napin Food-derived peptides could also modulate the gastric emptying rate and intestinal food transit via an activation of the opioid receptors that are present in the intestine Indeed it was shown in rats that β-casomorphins (obtained from αS1- and β-casein) slow down gastric emptying, this effect being blunted by treatment with naloxone, an opioid antagonist (Daniel et al., 1990) In addition, some food-derived peptides could also interact with intestinal barrier function whose role is to selectively allow the absorption of nutrients and ions while preventing the influx of microorganisms from the intestinal lumen (Martinez-Augustin et al., 2014) For example, the β-casein fragment (94À123) evidenced in yogurts is able to specifically stimulate MUC2 production, a crucial factor of intestinal protection (Plaisancie et al., 2013, 2015) b Modulation of nutrients uptake This mainly concerns the capacity of some peptides, such as caseinophosphopeptides (CPPs), to favor the uptake of micronutrients, such as minerals CPPs are obtained from casein by trypsin or chymotrypsin hydrolysis (Sato et al., 1991) They have been detected in the human stomach and duodenum after milk ingestion (Chabance et al., 1998) Although primary sequences of these CPPs greatly differ, they all share a phosphorylated seryl-cluster (SpSpSpEE) (Silva and Malcata, 2005) where 30% of the phosphate ions from milk are bound These sites, negatively charged, are one of the sites of minerals binding (Meisel, 1998), especially for calcium This latter property was first demonstrated in the 1950s by Mellander and Isaksson who showed that casein phosphorylated peptides (via their ability to fix milk calcium; Sato et al., 1986) had a beneficial effect on calcium uptake by bones of rachitic children Phosphorylation and mineral binding prevent CPPs from intestinal peptidases hydrolysis until they reach epithelial cells, where minerals are released by phosphatase activity (Boutrou et al., 2010) However, subsequent calcium absorption was not improved when associated with CPPs (Teucher et al., 2006) Other ions such as iron, zinc, copper, and magnesium can also bind to CPPs (FitzGerald, 1998) The type of bound cation deeply modifies the intestinal enzyme action; for example the coordination of bound copper to CPP inhibits the action of both phosphatase and peptidases (Boutrou et al., 2010) Egg yolks represent another source of phosphopeptides (phosvitin) with calcium-binding capacity (Choi et al., 2005) And, aside from phosphopeptides, some calcium-binding peptides have been evidenced in whey and wheat proteins hydrolysates (Zhao et al., 2014; Liu et al., 2013) Immunomodulation The immunomodulatory activities (proliferation, activity, antibody synthesis, and cytokines production/ regulation) of peptides issued from milk and soy proteins have mainly been described in vitro, on lymphocytes and macrophages (Singh et al., 2014; Chakrabarti et al., 2014) Peptides derived from milk β-and α-casein as well as α-lactalbumin, have been proven efficient to stimulate lymphocytes proliferation in vitro (Kayser and Meisel, 1996; Coste et al., 1992) and to increase the resistance of mice to Klebsiella pneumonia infection (Fiat et al., 1993) Caseinomacropeptide from κ-casein presents similar properties on proliferation and phagocytic activities in human macrophage-like cells (Li and Mine, 2004) The underlying mechanisms responsible for these immunomodulatory activities are not known The μ opioid receptors, that are present in lymphocytes, could be involved in the stimulation of the immunoreactivity (Kayser and Meisel, 1996) Antimicrobial effect Antimicrobial peptides have been identified mainly from milk protein hydrolysates (Walther and Sieber, 2011; Clare et al., 2003) More precisely, lactoferricins (derived from lactoferrin) (Wakabayashi et al., 2003) and casein fragments were proven efficient to exhibit bactericidal activity (Lahov and Regelson, 1996) Bactericidal I GENERAL AND INTRODUCTORY ASPECTS 1.1 PHYSIOLOGICAL EFFECTS OF FOOD-DERIVED PEPTIDES activity of lactoferricidins results from a direct interaction of the peptide (sequences 17À41 and 20À30) with the bacterial membrane, by increasing its permeability Their action covers a relatively wide spectrum of microbes (gram bacteria, some yeasts and mushrooms) (Tomita et al., 1994) Caseinomacropeptide has also been shown to inhibit the binding of actinomyces and streptococci to enterocytes (Neeser et al., 1988) Although less studied, peptides from other food-proteins seem to present antimicrobial properties: pepsin hydrolysates from bovine hemoglobin (Nedjar-Arroume et al., 2006), hydrolysates from sarcoplasmic proteins (Jang et al., 2008), or peptides issued from barley and soybean (McClean et al., 2014) Impact on the cardiovascular system a Antithrombotic effect During blood clotting, fibrinogen binding to its platelet receptor induces platelets aggregation Analogies between peptide sequences from κ-casein and from the C-terminal peptide of the γ chain of fibrinogen lead to a competition between casein peptides and fibrinogen for platelet receptors, causing the antithrombotic property of peptides issued from κ-casein (Jolles et al., 1986) This is also true for a lactotrasferrin peptide, whose antithrombotic effect has been demonstrated in vivo (Drouet et al., 1990) b Antihypertensive effect Antihypertensive peptides act by inhibiting the angiotensin-converting enzyme (ACE), a key step in the cascade of events involved in the regulation of blood pressure The first inhibitors of ACE have been identified in snake venom (Ondetti et al., 1971) The capacity of peptides to bind to ACE and inhibit its activity lies in their C-terminal tripeptide sequence, often rich in proline, branched chain, aromatic, and basic amino acids (FitzGerald and Meisel, 2000) Various peptides, from to 10 amino acids residues, presenting these characteristics have been identified Many of them come from hydrolysis of milk proteins, such as casein αS1 (Maruyama et al., 1987) and β (Maruyama et al., 1985), as well as muscle proteins (Vercruysse et al., 2005) The antihypertensive activity of these peptides has been demonstrated in vivo on hypertensive rats with a reduced systolic blood pressure and a lower ACE activity (Masuda et al., 1996; Nakamura et al., 1996) and in humans (Seppo et al., 2003) Peptides presenting similar properties have also been isolated from various food proteins (nonexhaustive list): fish (Yokoyama et al., 1992), egg (ovalbumin) (Fujita et al., 1995), and several vegetable proteins like soya (Yang et al., 2004), rapeseed (Marczak et al., 2003), or pea (Pedroche et al., 2002) Impact on the nervous system Because some food-derived peptides can present similar opioid activities as the enkephalins and endorphins released by brain and pituitary gland, they have been called exorphins (Zioudrou et al., 1979) They have been detected in hydrolysates from wheat gluten, casein α (Zioudrou et al., 1979), casein β (Brantl et al., 1979), and lactalbumin (Yoshikawa et al., 1986) Usually, food-derived opioid peptides present the following N-terminal sequence: YXF or YX1X2F The tyrosine residue in the N-terminal position and the presence of another aromatic amino acid in the 3rd or 4th position favor the interaction of the peptide with μ receptors at the brain level The absence of this sequence leads to no biological effect (Chang et al., 1981) Antiopioid effects also exist among the food-derived peptides; they derive from casein κ and are called casoxins (Chiba et al., 1989) Some food-derived peptides could have anxiolytic activity Indeed, it was shown that by binding to a benzodiazepine receptor, a α-casein fragment decreased anxiousness and improved sleep quality in animals subject to a slight chronic stress (Guesdon et al., 2006; Miclo et al., 2001) Antiproliferative activity Some peptides from animal or vegetable origins have been proven efficient in preventing initiation, promotion, or progression of cancer both in vivo and in vitro (de Mejia and Dia, 2010) It was, for instance, shown that a pentapeptide isolated from rice possesses cancer growth inhibitory properties on colon, breast, lung, and liver cancer cells (Kannan et al., 2010) Anti-inflammatory and antioxidant activity Food-derived peptides having anti-inflammatory activity have been evidenced in different animal- or plant-derived foods In vitro approaches showed that this effect is mediated by an inhibition of the NF-κB signaling (Majumder et al., 2013), or the c-Jun N-terminal kinase pathway (Aihara et al., 2009) For instance, the bioactive peptide lactoferricin, released from bovine lactoferrin through hydrolysis, demonstrated an anti-inflammatory effect on human cartilage and synovial cells (Yan et al., 2013) In vivo, casein hydrolysates were shown to decrease inflammation in animal models of arthritis (Hatori et al., 2008), corn gluten hydrolysates decreased inflammation in animal models of inflammatory bowel disease (Mochizuki et al., 2010), and fish protein hydrolysate reduced inflammatory markers in high fat-fed mice (Bjorndal et al., 2013) In vivo evidence of such an effect in humans are lacking, however a meta-analysis of the literature suggests I GENERAL AND INTRODUCTORY ASPECTS ... methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher... present, and they would still remain far below the upper level of intake, despite the scarcity of data This is the rationale for the utilization of the wording “safe level of intake” by the FAO/WHO/... provides the body with free amino acids when dietary protein and/ or energy requirements are not met These amino acids can be used as either an energy source or for the synthesis of proteins essential