Casein-derived bioactive peptides: biological effects, industrial uses, safety aspects and regulatory status.

Much research has been carried out on casein-derived bioactive peptides that are encrypted within the primary structures of intact casein. Casein peptides are not active within the parent protein but can be released and activated during enzymatic hydrolysis, microbial fermentation and during gastrointestinal digestion. Once absorbed, casein peptides have potential to exert numerous biological effects in the body. These bioactive effects are being exploited by the food industry. Important tasks for the production of functional foods containing bioactive peptides are to either enhance their bioavailability from their natural source or create novel foods via the addition and/or fortification of isolated or enriched fractions of bioactive peptides. In this review, selected biological effects of casein-derived bioactive peptides, their application in industry, in addition to safety aspects and regulations relating to the use of these peptides, will be discussed.

[1]  H. Gill,et al.  Immunoregulatory peptides in bovine milk , 2000, British Journal of Nutrition.

[2]  H. Korhonen,et al.  RELEASE OF BIOACTIVE PEPTIDES BY ENZYMATIC PROTEOLYSIS OF LACTOBACILLUS GGFERMENTED UHT MILK , 1997 .

[3]  R. Macdonald,et al.  A cell culture model to identify biologically active peptides generated by bacterial hydrolysis of casein. , 1994, Journal of dairy science.

[4]  H. Teschemacher Opioid receptor ligands derived from food proteins. , 2003, Current pharmaceutical design.

[5]  W. Verstraete,et al.  Bioavailability of angiotensin I converting enzyme inhibitory peptides , 2004, British Journal of Nutrition.

[6]  B. Björkstén,et al.  Development of immunoglobulin G and immunoglobulin E antibodies to cow’s milk proteins and ovalbumin after a temporary neonatal exposure to hydrolyzed and whole cow’s milk proteins , 1999, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[7]  J. Warthesen,et al.  Beta-casomorphins: analysis in cheese and susceptibility to proteolytic enzymes from Lactococcus lactis ssp. cremoris. , 1996, Journal of dairy science.

[8]  A. Guillot,et al.  Specificity of Milk Peptide Utilization byLactococcus lactis , 1998, Applied and Environmental Microbiology.

[9]  R. Xu Bioactive Peptides in Milk and their Biological and Health Implications , 1998 .

[10]  A. Dávalos,et al.  Antioxidant activity of peptides derived from egg white proteins by enzymatic hydrolysis. , 2004, Journal of food protection.

[11]  D. Rao,et al.  Antimutagenic activity of milk fermented by Streptococcus thermophilus and Lactobacillus bulgaricus. , 1990, Journal of dairy science.

[12]  Kiyoshi Matsumoto,et al.  Identification of ACE-inhibitory peptides in salt-free soy sauce that are transportable across caco-2 cell monolayers , 2008, Peptides.

[13]  S. Gould,et al.  Antimutagenicity of an acetone extract of yogurt. , 1995, Mutation research.

[14]  A. Signorile,et al.  Casein phosphopeptides influence calcium uptake by cultured human intestinal HT-29 tumor cells. , 2001, The Journal of nutrition.

[15]  W. Heird New Perspectives in Infant Nutrition , 1996 .

[16]  Peter Libby,et al.  Inflammation in Atherosclerosis : From Vascular Biology to Biomarker Discovery and Risk Prediction , 2007 .

[17]  N. Yamamoto,et al.  Purification and characterization of an antihypertensive peptide from a yogurt-like product fermented by Lactobacillus helveticus CPN4. , 1999, Journal of dairy science.

[18]  B. Kimball,et al.  Hydrolyzed Casein Reduces Browsing of Trees and Shrubs by White-tailed Deer , 2005 .

[19]  M. Jensen,et al.  Casein phosphopeptides improve zinc and calcium absorption from rice-based but not from whole-grain infant cereal. , 1997, Journal of pediatric gastroenterology and nutrition.

[20]  H. Otani,et al.  Inhibition of proliferative responses of mouse spleen lymphocytes and rabbit Peyer's patch cells by bovine milk caseins and their digests , 1995, Journal of Dairy Research.

[21]  H. Meisel,et al.  Biochemical properties of peptides encrypted in bovine milk proteins. , 2005, Current medicinal chemistry.

[22]  R. Fitzgerald,et al.  Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme , 2000, British Journal of Nutrition.

[23]  R. Hartmann,et al.  Food-derived peptides with biological activity: from research to food applications. , 2007, Current opinion in biotechnology.

[24]  Y. Elitsur,et al.  Beta‐casomorphin (BCM) and human colonic lamina propria lymphocyte proliferation , 1991, Clinical and experimental immunology.

[25]  M. A. Lasunción,et al.  Bioavailability of the antihypertensive peptide LHLPLP : Transepithelial flux of HLPLP , 2008 .

[26]  Youling L. Xiong,et al.  Fractionation and characterisation for antioxidant activity of hydrolysed whey protein , 2004 .

[27]  E. Kostyra,et al.  Contents of agonistic and antagonistic opioid peptides in different cheese varieties. , 2009 .

[28]  G. Perdigón,et al.  Immunomodulating effects of peptidic fractions issued from milk fermented with Lactobacillus helveticus. , 2002, Journal of dairy science.

[29]  P. Jollès,et al.  Casein peptide release and passage to the blood in humans during digestion of milk or yogurt. , 1998, Biochimie.

[30]  D. Mollé,et al.  Peptides identified during Emmental cheese ripening: origin and proteolytic systems involved. , 2001, Journal of agricultural and food chemistry.

[31]  J. Kloek,et al.  Angiotensin converting enzyme inhibitory peptides from a lactotripeptide-enriched milk beverage are absorbed intact into the circulation. , 2007, The Journal of nutrition.

[32]  Haiyan Sun,et al.  Transepithelial Transport Characteristics of the Antihypertensive Peptide, Lys-Val-Leu-Pro-Val-Pro, in Human Intestinal Caco-2 Cell Monolayers , 2009, Bioscience, biotechnology, and biochemistry.

[33]  I. Losito,et al.  Antibacterial activities of peptides from the water-soluble extracts of Italian cheese varieties. , 2005, Journal of dairy science.

[34]  A. Iwaniak,et al.  Database of biologically active peptide sequences. , 1999, Die Nahrung.

[35]  S. Kaminogawa,et al.  Cytokine responses of human intestinal epithelial-like Caco-2 cells to the nonpathogenic bacterium Bacillus subtilis (natto). , 2003, International journal of food microbiology.

[36]  T. Tadros,et al.  Formation and stability of nano-emulsions. , 2004, Advances in colloid and interface science.

[37]  Michael Gardner INTESTINAL ASSIMILATION OF INTACT PEPTIDES AND PROTEINS FROM THE DIET‐A NEGLECTED FIELD? , 1984, Biological reviews of the Cambridge Philosophical Society.

[38]  D. Mcclements,et al.  Use of caseinophosphopeptides as natural antioxidants in oil-in-water emulsions. , 2003, Journal of agricultural and food chemistry.

[39]  P. Jollès,et al.  Immunostimulating substances from human casein. , 1981, Journal of immunopharmacology.

[40]  E. Decker,et al.  Endogenous skeletal muscle antioxidants. , 1994, Critical reviews in food science and nutrition.

[41]  B. Bernard,et al.  Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): VI. Effects of Lactobacillus helveticus-fermented Milk Powder on Fertility and Reproductive Performance of Rats , 2005, International journal of toxicology.

[42]  M. Leja,et al.  Antioxidant activity of fresh and dry herbs of some Lamiaceae species , 2005 .

[43]  P. Arhan,et al.  Mechanisms of absorption of caseinophosphopeptide bound iron. , 1999, The Journal of nutritional biochemistry.

[44]  A. Pihlanto,et al.  Food-derived bioactive peptides--opportunities for designing future foods. , 2003, Current pharmaceutical design.

[45]  A. Kilara,et al.  Peptides From Milk Proteins and Their Properties , 2003, Critical reviews in food science and nutrition.

[46]  H. Jang,et al.  Antioxidant capacity of caseinophosphopeptides prepared from sodium caseinate using Alcalase , 2007 .

[47]  R. Fitzgerald Potential Uses of Caseinophosphopeptides , 1998 .

[48]  M. Gobbetti,et al.  Bioactive peptides in dairy products: synthesis and interaction with proteolytic enzymes. , 2000 .

[49]  G. Grimble Mechanisms of peptide and amino acid transport and their regulation. , 2000, Nestle Nutrition workshop series. Clinical & performance programme.

[50]  T. Takano,et al.  Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. , 1996, The Journal of nutrition.

[51]  T. Saito,et al.  Isolation and structural analysis of antihypertensive peptides that exist naturally in Gouda cheese. , 2000, Journal of dairy science.

[52]  Exendin-4, a GLP-1 receptor agonist, interacts with proteins and their products of digestion to suppress food intake in rats. , 2003, The Journal of nutrition.

[53]  D. Walsh,et al.  Hypotensive peptides from milk proteins. , 2004, The Journal of nutrition.

[54]  H. Meisel ACE-INHIBITORY ACTIVITIES IN MILK PRODUCTS , 1997 .

[55]  R. López-Fandiño,et al.  κ-Casein Macropeptides from Cheese Whey: Physicochemical, Biological, Nutritional, and Technological Features for Possible Uses , 2004 .

[56]  H. Meisel,et al.  Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins , 1996, FEBS letters.

[57]  Pei-yu Wang,et al.  Effect of milk tripeptides on blood pressure: a meta-analysis of randomized controlled trials. , 2008, Nutrition.

[58]  E. Seki,et al.  Val‐Tyr As A Natural Antihypertensive Dipeptide Can Be Absorbed Into The Human Circulatory Blood System , 2002, Clinical and experimental pharmacology & physiology.

[59]  E. Kostyra,et al.  Transport of bovine milk-derived opioid peptides across a Caco-2 monolayer , 2009 .

[60]  E. Metcalf,et al.  Salmonella typhi stimulation of human intestinal epithelial cells induces secretion of epithelial cell-derived interleukin-6 , 1997, Infection and immunity.

[61]  H. E. Berg,et al.  Heating milk: a study on mutagenicity. , 1990 .

[62]  Shoichiro Tsukita,et al.  Multifunctional strands in tight junctions , 2001, Nature Reviews Molecular Cell Biology.

[63]  P. Jollès,et al.  Casein, a prohormone with an immunomodulating role for the newborn? , 1988, Experientia.

[64]  I. Recio,et al.  Angiotensin converting enzyme inhibitory activity in commercial fermented products. Formation of peptides under simulated gastrointestinal digestion. , 2004, Journal of agricultural and food chemistry.

[65]  B. Berkhout,et al.  Antibacterial and antiviral effects of milk proteins and derivatives thereof. , 2003, Current pharmaceutical design.

[66]  S. Gauthier,et al.  Antihypertensive activity of casein-enriched milk fermented by Lactobacillus helveticus , 2002 .

[67]  F. Cai,et al.  Remineralization of Enamel Subsurface Lesions by Sugar-free Chewing Gum Containing Casein Phosphopeptide-Amorphous Calcium Phosphate , 2001, Journal of dental research.

[68]  P. Moughan,et al.  Bioactive peptides derived from food. , 2005, Journal of AOAC International.

[69]  H. Meisel,et al.  Food proteins as precursors of peptides modulating human cell activity (short communication). , 1998, Die Nahrung.

[70]  A. Clemente,et al.  Obtención y aplicaciones de hidrolizados protéicos , 2001 .

[71]  N. Yamamoto,et al.  Purification and characterization of angiotensin I-converting enzyme inhibitors from sour milk. , 1995, Journal of dairy science.

[72]  A. Ferraretto,et al.  Casein‐derived bioactive phosphopeptides: role of phosphorylation and primary structure in promoting calcium uptake by HT‐29 tumor cells , 2003, FEBS letters.

[73]  H. Otani,et al.  Inhibition of mitogen-induced proliferative responses of lymphocytes by bovine κ-caseinoglycopeptides having different carbohydrate chains , 1995, Journal of Dairy Research.

[74]  H. Meisel Overview on Milk Protein-derived Peptides , 1998 .

[75]  F. Yamauchi,et al.  Structural Analysis of Antioxidative Peptides from Soybean .beta.-Conglycinin , 1995 .

[76]  T. Suzuki,et al.  The effect of casein phosphopeptides on calcium absorption from calcium-fortified milk in growing rats , 2001, British Journal of Nutrition.

[77]  E. Seki,et al.  Absorption of Val-Tyr with in vitro angiotensin I-converting enzyme inhibitory activity into the circulating blood system of mild hypertensive subjects. , 2002, Biological & pharmaceutical bulletin.

[78]  M. Raida,et al.  Casocidin‐I: a casein‐αs2 derived peptide exhibits antibacterial activity , 1995 .

[79]  D. Kitts Antioxidant properties of casein-phosphopeptides , 2005 .

[80]  H. Teschemacher,et al.  Demonstration of β-casomorphin immunoreactive materials in in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans , 1985, Peptides.

[81]  A. Pihlanto Antioxidative peptides derived from milk proteins , 2006 .

[82]  Yasunori Nakamura,et al.  Effect of Powdered Fermented Milk with Lactobacillus helveticus on Subjects with High-Normal Blood Pressure or Mild Hypertension , 2005, Journal of the American College of Nutrition.

[83]  R. Korpela,et al.  Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement. , 2005, American journal of hypertension.

[84]  C. Boeriu,et al.  Caseins and casein hydrolysates. 1. Lipoxygenase inhibitory properties. , 2001, Journal of agricultural and food chemistry.

[85]  A. Pihlanto-Leppälä,et al.  Angiotensin I converting enzyme inhibitory peptides derived from bovine milk proteins , 1998 .

[86]  A. Nasi,et al.  Casein proteolysis in human milk: tracing the pattern of casein breakdown and the formation of potential bioactive peptides. , 2004, The Journal of dairy research.

[87]  H. Meisel,et al.  Chemical characterization of bioactive peptides from in vivo digests of casein , 1989, Journal of Dairy Research.

[88]  T. Nishimura,et al.  Antioxidant activity of peptides obtained from porcine myofibrillar proteins by protease treatment. , 2003, Journal of agricultural and food chemistry.

[89]  A. Pihlanto-Leppälä,et al.  Milk-derived bioactive peptides: formation and prospects for health promotion. , 2003 .

[90]  H. Meisel Bioactive peptides from milk proteins : a perspective for consumers and producers , 2001 .

[91]  S. Parrot,et al.  In vitro study on digestion of peptides in Emmental cheese: analytical evaluation and influence on angiotensin I converting enzyme inhibitory peptides. , 2003, Die Nahrung.

[92]  H. Gill,et al.  Modulation of immune function by a modified bovine whey protein concentrate , 1999, Immunology and cell biology.

[93]  Y. Watanabe,et al.  Induction of apoptosis in HL-60 cells by skimmed milk digested with a proteolytic enzyme from the yeast Saccharomyces cerevisiae. , 1999, Journal of bioscience and bioengineering.

[94]  Y. Hata,et al.  A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. , 1996, The American journal of clinical nutrition.

[95]  N. Yamamoto,et al.  Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme. , 1995, Journal of dairy science.

[96]  E. Brody,et al.  Biological activities of bovine glycomacropeptide , 2000, British Journal of Nutrition.

[97]  G. M. Gray,et al.  Protein digestion and absorption. , 1971, Gastroenterology.

[98]  I. López-Expósito,et al.  Protective effect of milk peptides: antibacterial and antitumor properties. , 2008, Advances in experimental medicine and biology.

[99]  H. Teschemacher,et al.  Milk protein-derived opioid receptor ligands. , 1997, Biopolymers.

[100]  A. Alegría,et al.  Antioxidant effect of casein phosphopeptides compared with fruit beverages supplemented with skimmed milk against H2O2-induced oxidative stress in Caco-2 cells , 2008 .

[101]  R. Chand,et al.  Fermented milk containing ACE-inhibitory peptides reduces blood pressure in middle aged hypertensive subjects , 2004 .

[102]  D. Jonker,et al.  Safety evaluation of an IPP tripeptide-containing milk protein hydrolysate. , 2009, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[103]  Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): V. A 13-Week Toxicity Study of Tripeptides-Containing Casein Hydrolysate in Male and Female Rats , 2005, International journal of toxicology.

[104]  P. Cuatrecasas,et al.  Analgesic activity of intracerebroventricular administration of morphiceptin and β-casomorphins: Correlation with the morphine (μ) receptor binding affinity , 1982 .

[105]  P. Fürst,et al.  Proteins, peptides and amino acids in enteral nutrition. , 2000 .

[106]  M. Bedoni,et al.  Casein phosphopeptide promotion of calcium uptake in HT‐29 cells − relationship between biological activity and supramolecular structure , 2007, The FEBS journal.

[107]  H. Otani,et al.  Immunomodificatory effect of dietary bovine kappa-caseinoglycopeptide on serum antibody levels and proliferative responses of lymphocytes in mice , 1998 .

[108]  R. Korpela,et al.  A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. , 2003, The American journal of clinical nutrition.

[109]  H. Otani,et al.  Stimulatory Effects of Casein Phosphopeptide (CPP-III) on mRNA Expression of Cytokines in Caco-2 Cells , 2004, Bioscience, biotechnology, and biochemistry.

[110]  A. Fuglsang,et al.  Characterization of New Milk-derived Inhibitors of Angiotensin Converting Enzyme In Vitro and In Vivo , 2003, Journal of enzyme inhibition and medicinal chemistry.

[111]  Yasunori Nakamura,et al.  Casein Hydrolysate Containing the Antihypertensive Tripeptides Val-Pro-Pro and Ile-Pro-Pro Improves Vascular Endothelial Function Independent of Blood Pressure–Lowering Effects: Contribution of the Inhibitory Action of Angiotensin-Converting Enzyme , 2007, Hypertension Research.

[112]  T. Honda,et al.  Caseinpbospbopeptides (CPP) in Feces of Rats Fed Casein Diet. , 1992, Bioscience, biotechnology, and biochemistry.

[113]  Y. Mine,et al.  Immunoenhancing effects of bovine glycomacropeptide and its derivatives on the proliferative response and phagocytic activities of human macrophagelike cells, U937. , 2004, Journal of agricultural and food chemistry.

[114]  H. Ueshima,et al.  Randomized controlled trial of sour milk on blood pressure in borderline hypertensive men. , 2004, American journal of hypertension.

[115]  M. Phelan,et al.  Potential bioactive effects of casein hydrolysates on human cultured cells. , 2009 .

[116]  S. Arai,et al.  Transepithelial Transport of the Bioactive Tripeptide, Val-Pro-Pro, in Human Intestinal Caco-2 Cell Monolayers , 2002, Bioscience, biotechnology, and biochemistry.

[117]  K. Nokihara,et al.  Antioxidant activity of designed peptides based on the antioxidative peptide isolated from digests of a soybean protein , 1996 .

[118]  K. Igarashi,et al.  Reduction of Paraquat-induced Oxidative Stress in Rats by Dietary Soy Peptide , 2003, Bioscience, biotechnology, and biochemistry.

[119]  Yasunori Nakamura,et al.  Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): III. Single- and/or Repeated-Dose Toxicity of Tripeptides-Containing Lactobacillus helveticus-Fermented Milk Powder and Casein Hydrolysate in Rats , 2005, International journal of toxicology.

[120]  P. Minkiewicz,et al.  Identification of peptides obtained via hydrolysis of bovine casein by chymosin using HPLC and mass spectrometry. , 2000 .

[121]  S. Kaminogawa,et al.  DNA-Synthesis Stimulating Peptides from Human β-Casein , 1989 .

[122]  H. Isoda,et al.  Inhibition by lactoferrin and kappa-casein glycomacropeptide of binding of Cholera toxin to its receptor. , 1992, Bioscience, biotechnology, and biochemistry.

[123]  G. Duchateau,et al.  The angiotensin converting enzyme inhibitory tripeptides Ile-Pro-Pro and Val-Pro-Pro show increasing permeabilities with increasing physiological relevance of absorption models , 2008, Peptides.

[124]  C. Genot,et al.  $\beta$-Caseinophosphopeptide (f1-25) confers on $\beta$-casein tryptic hydrolysate an antioxidant activity during iron/ascorbate-induced oxidation of liposomes , 2004 .

[125]  J. Ni,et al.  Value-added utilization of yak milk casein for the production of angiotensin-I-converting enzyme inhibitory peptides , 2007 .

[126]  H. Ukeda,et al.  Isolation and characterization of free radical scavenging activities peptides derived from casein. , 2000, The Journal of nutritional biochemistry.

[127]  U. Bütikofer,et al.  Occurrence of the angiotensin-converting enzyme inhibiting tripeptides Val-Pro-Pro and Ile-Pro-Pro in different cheese varieties of Swiss origin. , 2008, Journal of dairy science.

[128]  J. Schrezenmeir,et al.  Effects of bioactive substances in milk on mineral and trace element metabolism with special reference to casein phosphopeptides , 2000, British Journal of Nutrition.

[129]  S. Kapila,et al.  Biofunctional Properties of Bioactive Peptides of Milk Origin , 2008 .

[130]  M. Dent,et al.  A 90-day subchronic toxicity study and reproductive toxicity studies on ACE-inhibiting lactotripeptide. , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[131]  R. Macdonald,et al.  Antiproliferative effects of yogurt fractions obtained by membrane dialysis on cultured mammalian intestinal cells. , 1997, Journal of dairy science.

[132]  G. Anderson,et al.  Dietary peptides induce satiety via cholecystokinin-A and peripheral opioid receptors in rats. , 2002, The Journal of nutrition.

[133]  Karaki Hideaki,et al.  Antihypertensive effect of tryptic hydrolysate of milk casein in spontaneously hypertensive rats. , 1990 .

[134]  H. Otani,et al.  Antimutagenic activity of whole casein on the pepper-induced mutagenicity to streptomycin-dependent strain SD 510 of Salmonella typhimurium TA 98 , 1988, Journal of Dairy Research.

[135]  F. Tani,et al.  Opioid antagonist peptides derived from κ-casein , 1989, Journal of Dairy Research.

[136]  G. Folkers β-casomorphins and related peptides: Recent developments: V. Brantl and H. Teschemacher (Eds.), Verlag Chemie, Weinheim, New York, 1994, ISBN 3-527-30038-4, SFr 164.-. , 1994 .

[137]  H. Meisel,et al.  Bioactive Sequences in Milk Proteins , 1989 .

[138]  I. Lebrun,et al.  Biochemical and Pharmacological Aspects of Two Bradykinin-Potentiating Peptides Obtained from Tryptic Hydrolysis of Casein , 2003, Journal of protein chemistry.

[139]  E. Farnworth Handbook of Fermented Functional Foods , 2003 .

[140]  Greet Vanhoof,et al.  Proline motifs in peptides and their biological processing , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[141]  D. Kitts,et al.  Calcium-enriched casein phosphopeptide stimulates release of IL-6 cytokine in human epithelial intestinal cell line , 2005, Journal of Dairy Research.

[142]  P. Arhan,et al.  Bioavailability of caseinophosphopeptide-bound iron. , 2002, The Journal of laboratory and clinical medicine.

[143]  R. Vachet,et al.  Antioxidant mechanisms of enzymatic hydrolysates of beta-lactoglobulin in food lipid dispersions. , 2006, Journal of agricultural and food chemistry.

[144]  M. Kaczmarski,et al.  Transport of μ-opioid receptor agonists and antagonist peptides across Caco-2 monolayer , 2008, Peptides.

[145]  Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): IX. Evaluation of the Mutagenic Potential of Synthesized L-Valyl-L-prolyl-L-proline in the Salmonella-Escherichia coli/Microsome, Incorporation Assay , 2005, International journal of toxicology.

[146]  B. Bechinger,et al.  Structure and Functions of Channel-Forming Peptides: Magainins, Cecropins, Melittin and Alamethicin , 1997, The Journal of Membrane Biology.

[147]  Eric A. Decker,et al.  Antioxidant Activity of Proteins and Peptides , 2008, Critical reviews in food science and nutrition.

[148]  S. Jois,et al.  Transport of angiotensin peptides across the Caco-2 monolayer , 2004, Peptides.

[149]  S. Dashper,et al.  Kappacin, a Novel Antibacterial Peptide from Bovine Milk , 2001, Antimicrobial Agents and Chemotherapy.

[150]  D W Cushman,et al.  Enzymes of the renin-angiotensin system and their inhibitors. , 1982, Annual review of biochemistry.

[151]  F. Ren,et al.  Effect of yak milk casein hydrolysate on TH1/TH2 cytokines production by murine spleen lymphocytes in vitro. , 2007, Journal of agricultural and food chemistry.

[152]  G. Bray,et al.  β-Casomorphins Stimulate and Enterostatin Inhibits the Intake of Dietary Fat in Rats , 1998, Peptides.

[153]  R. Fitzgerald,et al.  Bioactive peptides and lactic fermentations , 2006 .

[154]  P. Jollès,et al.  Characterization of an antithrombotic peptide from α-casein in newborn plasma after milk ingestion , 1995, British Journal of Nutrition.

[155]  M. V. van Boekel,et al.  Antimutagenic effects of casein and its digestion products. , 1993, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[156]  M. Hansen,et al.  The Effect of Casein Phosphopetides on Zinc and Calcium Absorption from High Phytate Infant Diets Assessed in Rat Pups and Caco-2 Cells , 1996, Pediatric Research.

[157]  Yasunori Nakamura,et al.  Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): IV. Assessment of the Repeated-Dose Toxicological Potential of Synthesized L-Valyl-L-prolyl-L-proline in Male and Female Rats and Dogs , 2005, International journal of toxicology.

[158]  J. Awaya,et al.  Angiotensin I-Converting Enzyme Inhibitory Activity of the C-Terminal Hexapeptide of αs1-Casein , 1987 .

[159]  L. Juneja,et al.  Antioxidant properties of casein calcium peptides and their effects on lipid oxidation in beef homogenates. , 2005, Journal of agricultural and food chemistry.

[160]  C. Boeriu,et al.  Caseins and casein hydrolysates. 2. Antioxidative properties and relevance to lipoxygenase inhibition. , 2001, Journal of agricultural and food chemistry.

[161]  Hannu Korhonen,et al.  Bioactive peptides: Production and functionality , 2006 .

[162]  M. Romero,et al.  Expression cloning of a mammalian proton-coupled oligopeptide transporter , 1994, Nature.

[163]  R. Korpela,et al.  Effect of long-term intake of milk products on blood pressure in hypertensive rats , 2002, Journal of Dairy Research.

[164]  E. Reynolds,et al.  The Prevention of Sub-surface Demineralization of Bovine Enamel and Change in Plaque Composition by Casein in an Intra-oral Model , 1987, Journal of dental research.

[165]  N. Yamamoto,et al.  Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus CP790. , 1994, Journal of dairy science.

[166]  R. Korpela,et al.  Long-term intake of milk peptides attenuates development of hypertension in spontaneously hypertensive rats. , 2001, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[167]  U. Bütikofer,et al.  Quantification of the angiotensin-converting enzyme-inhibiting tripeptides Val-Pro-Pro and Ile-Pro-Pro in hard, semi-hard and soft cheeses , 2007 .

[168]  R. Fitzgerald,et al.  Biofunctional peptides from milk proteins: mineral binding and cytomodulatory effects. , 2003, Current pharmaceutical design.

[169]  S. Fairweather-Tait,et al.  Calcium absorption is not increased by caseinophosphopeptides. , 2006, The American journal of clinical nutrition.

[170]  D. Miller,et al.  Calcium, zinc, and iron bioavailabilities from a commercial human milk fortifier: a comparison study. , 2004, Journal of dairy science.

[171]  Fereidoon Shahidi,et al.  Nutraceutical Proteins and Peptides in Health and Disease , 2005 .

[172]  B. Bartolomé,et al.  ACE-inhibitory and radical-scavenging activity of peptides derived from beta-lactoglobulin f(19-25). Interactions with ascorbic acid. , 2007, Journal of agricultural and food chemistry.

[173]  H. Stark,et al.  Derivatives of β-casomorphins with high analgesic potency , 1984, Peptides.

[174]  H. Meisel Biochemical properties of regulatory peptides derived from milk proteins. , 1997, Biopolymers.

[175]  A. Pihlanto-Leppälä,et al.  Opioid peptides produced by in-vitro proteolysis of bovine caseins , 1994 .

[176]  W. Regelson,et al.  Antibacterial and immunostimulating casein-derived substances from milk: casecidin, isracidin peptides. , 1996, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[177]  B. Kimball,et al.  Avoidance of hydrolyzed casein by mice , 2008, Physiology & Behavior.

[178]  H. Swaisgood,et al.  Biodefense properties of milk: the role of antimicrobial proteins and peptides. , 2003, Current pharmaceutical design.

[179]  Boldyrev Aa,et al.  EFFECT OF HISTIDINE-CONTAINING DIPEPTIDES ON ISOLATED HEART UNDER ISCHEMIA/REPERFUSION , 1997 .

[180]  M. Hayes,et al.  Casein-Derived Antimicrobial Peptides Generated by Lactobacillus acidophilus DPC6026 , 2006, Applied and Environmental Microbiology.

[181]  D. Kitts Bioactive substances in food: identification and potential uses. , 1994, Canadian journal of physiology and pharmacology.

[182]  K. Nokihara,et al.  Antioxidative Properties of Histidine-Containing Peptides Designed from Peptide Fragments Found in the Digests of a Soybean Protein. , 1998, Journal of agricultural and food chemistry.

[183]  E. Decker,et al.  Antioxidant mechanisms of caseinophosphopeptides and casein hydrolysates and their application in ground beef. , 2004, Journal of agricultural and food chemistry.

[184]  W. Bockelmann,et al.  Bioactive peptides encrypted in milk proteins: proteolytic activation and thropho-functional properties , 1999, Antonie van Leeuwenhoek.

[185]  H. Otani,et al.  Stimulatory Effect of a Dietary Casein Phosphopeptide Preparation on the Mucosal IgA Response of Mice to Orally Ingested Lipopolysaccharide from Salmonella typhimurium , 2003, Bioscience, biotechnology and biochemistry.

[186]  H. Meisel,et al.  Estimation of calcium-binding constants of casein phosphopeptides by capillary zone electrophoresis , 1998 .

[187]  Tadataka Yamada,et al.  Textbook of Gastroenterology , 1995 .

[188]  A. Pihlanto-Leppälä,et al.  Milk protein-derived bioactive peptides : Novel opportunities for health promotion : Dairy nutrition for a healthy future , 2001 .

[189]  P. Ferranti,et al.  Production of Angiotensin-I-Converting-Enzyme-Inhibitory Peptides in Fermented Milks Started by Lactobacillus delbrueckiisubsp. bulgaricus SS1 and Lactococcus lactissubsp. cremoris FT4 , 2000, Applied and Environmental Microbiology.

[190]  N. Yamamoto,et al.  Purification and characterization of an endopeptidase that has an important role in the carboxyl terminal processing of antihypertensive peptides in Lactobacillus helveticus CM4 , 2004, Letters in applied microbiology.

[191]  M. Saxelin,et al.  Suppression of lymphocyte proliferation in vitro by bovine caseins hydrolyzed with Lactobacillus casei GG-derived enzymes. , 1996, The Journal of allergy and clinical immunology.

[192]  M. Jensen,et al.  Effect of casein phosphopeptides on zinc and calcium absorption from bread meals. , 1997, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[193]  Y. Osajima,et al.  Antihypertensive effects of angiotensin fragments in SHR. , 1995, Bioscience, biotechnology, and biochemistry.

[194]  William Francis Ganong,et al.  Review of Medical Physiology , 1969 .

[195]  Sofia V. Silva,et al.  Caseins as source of bioactive peptides , 2005 .

[196]  M. Shimizu Food‐derived peptides and intestinal functions , 2007, Current pharmaceutical design.

[197]  W. Klee,et al.  Opioid activities and structures of alpha-casein-derived exorphins. , 1983, Biochemistry.

[198]  H. Meisel,et al.  Biologically active peptides in milk proteins , 1989, Zeitschrift fur Ernahrungswissenschaft.

[199]  J. Carrero,et al.  Absorption of calcium from milks enriched with fructo-oligosaccharides, caseinophosphopeptides, tricalcium phosphate, and milk solids. , 2006, The American journal of clinical nutrition.

[200]  S. Blondelle,et al.  Combinatorial libraries: a tool to design antimicrobial and antifungal peptide analogues having lytic specificities for structure-activity relationship studies. , 2000, Biopolymers.

[201]  D. Tomé,et al.  Opiate activity and transepithelial passage of intact beta-casomorphins in rabbit ileum. , 1987, The American journal of physiology.

[202]  R. Fitzgerald,et al.  Opioid peptides encrypted in intact milk protein sequences , 2000, British Journal of Nutrition.

[203]  Chris J. Fone,et al.  Increased remineralization of tooth enamel by milk containing added casein phosphopeptide-amorphous calcium phosphate , 2006, Journal of Dairy Research.

[204]  H. Meisel,et al.  Milk proteins: precursors of bioactive peptides , 1990 .

[205]  W. Shen,et al.  C) Means to enhance penetration , 1992 .

[206]  C. Lamberg-Allardt,et al.  Effects of bioactive peptides isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-lysine-proline (LKP) on gene expression of osteoblasts differentiated from human mesenchymal stem cells. , 2007, The British journal of nutrition.

[207]  R. P. Ross,et al.  Antimicrobial activity of two peptides casecidin 15 and 17, found naturally in bovine colostrum , 2009, Journal of applied microbiology.

[208]  A. Pihlanto-Leppälä,et al.  A new type of ripened, low-fat cheese with bioactive properties , 2001 .

[209]  V. Ganapathy,et al.  Protein Digestion and Assimilation , 2009 .

[210]  W. Michalski,et al.  Isolation and characterisation of a novel antibacterial peptide from bovine αS1-casein , 2006 .

[211]  R. Borchardt,et al.  Effect of Size and Charge on the Passive Diffusion of Peptides Across Caco-2 Cell Monolayers via the Paracellular Pathway , 1997, Pharmaceutical Research.

[212]  R. Di Cagno,et al.  Latent Bioactive Peptides in Milk Proteins: Proteolytic Activation and Significance in Dairy Processing , 2002, Critical reviews in food science and nutrition.