Are intact peptides absorbed from the healthy gut in the adult human?

Nutrition Research Reviews

Volumn 27, Issue 2, 2014, Pages 308-329

  Miner Williams, Warren M ^a   Stevens, Bruce R ^b   Moughan, Paul J ^a  

^a MASSEY UNIVERSITY   (New Zealand)

^b UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Absorption; Bioactive peptides; Gastrointestinal tract; Lactotripeptides; Opioids; PepT1 H+ peptide co transporter

Indexed keywords

AMINO ACID DERIVATIVE; ANTIGEN; DIPEPTIDE; OLIGOPEPTIDE; PEPTIDE DERIVATIVE; PEPTIDE TRANSPORTER 1; TRIPEPTIDE; PROTEIN INTAKE;

ADULTHOOD; AMINO ACID TRANSPORT; BASOLATERAL MEMBRANE; CYTOSOL; ENDOTHELIUM; GASTROINTESTINAL ABSORPTION; HUMAN; HYDROLYSIS; INTESTINE CELL; MACROMOLECULE; NONHUMAN; PROTEIN INTAKE; REVIEW; ADULT; CYTOLOGY; INTESTINE ABSORPTION; INTESTINE MUCOSA; METABOLISM; PHYSIOLOGY; PORTAL VEIN;

ADULT; DIETARY PROTEINS; HUMANS; INTESTINAL ABSORPTION; INTESTINAL MUCOSA; OLIGOPEPTIDES; PORTAL SYSTEM;

EID: 84921856057     PISSN: 09544224     EISSN: 14752700     Source Type: Journal    
DOI: 10.1017/S0954422414000225     Document Type: Review

References (313)

1. Bajaj-Elliott M & Sanderson IR (2004) Structure and function of the gastrointestinal mucosa. In Oral Tolerance: The Responce of the Intestinal Mucosa to Dietary Antigens, pp. 1-13 [O Morteau, editor]. New York: Kluwer Academic/Plenum Publishers.
2. Sanderson IR & Walker WA (1999) Part 1, section A(4). In Handbook of Mucosal Immunology, 2nd ed., pp. 41-48 [R Ogra and J Mestecky, editors]. San Diego: Academic Press.
3. Bevins CL, Martin-Porter E & Ganz T (1999) Defensins and innate host defence of the gastrointestinal tract. Gut 271, 14038-14045.
4. Wehkamp J, Schmid M & Stange EF (2007) Defensins and other antimicrobial peptides in inflammatory bowel disease. Curr Opin Gastroenterol 23, 370-378.
5. Sanderson IR & Walker WA (1993) Uptake and transport of macromolecules by the intestine: possible role in clinical disorders. Gastroenterology 104, 622-639.
6. Matthews DM (1975) Intestinal absorption of peptides. Physiol Rev 55, 537-608.
7. Cohnheim O (1901) Die Umwandlung des Eiweiss durch die Darmwand (The conversion of protein through the intestinal wall). Z Physiol Chem 33, 451-465.
8. Abderhalden E, Körösy KV & London ES (1907) Weitere Studien uber die normale Verdauung der Eiweißkörper im Magendarmkanal des Hundes (Further studies about the normal digestion of protein bodies in the gastrointestinal tract of the dog). Hoppe-Seylers Z Physiol Chem 53, 148-163.
9. Kutscher F & Seemann J (1901-1902) Zur Kenntniss der Verdauungsvorgange im Dunndarm. I (To the knowledge of the digestive system in the small intestine. I). Hoppe-Seylers Z Physiol Chem 34, 528-543.
10. Stevens BR (2010) Amino acid transport by epithelial membranes. In Epithelial Transport Physiology, pp. 353-378 [GA Gerencser, editor]. New York: Humana Press.
11. Newey H & Smyth DH (1959) The intestinal absorption of some dipeptides. J Physiol 145, 48-56.
12. Adibi SA (1971) Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption. J Clin Invest 50, 2266-2275.
13. Adibi SA, Morse EL, Masilamani SS, et al. (1975) Evidence for 2 different modes of tripeptide disappearance in human intestine-uptake by peptide carrier systems and hydrolysis by peptide hydrolases. J Clin Invest 56, 1355-1363.
14. Ganapathy V & Leibach FH (1983) Role of pH gradient and membrane potential in dipeptide transport in intestinal and renal brush-border membrane-vesicles from the rabbit-studies with l-carnosine and glycyl-L-proline. J Biol Chem 258, 4189-4192.
15. Fei YJ, Kanai Y, Nussberger S, et al. (1994) Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368, 563-566.
16. Brandsch M & Brandsch C (2003) Intestinal transport of amino acids, peptides and proteins. In Progress in Research on Energy and Protein Metabolism, pp. 667-680 [WB Souffrant and CC Metges, editors]. Wageningen: Wageningen Academic Publishers.
17. Matthews DM, Craft IL, Geddes DM, et al. (1968) Absorption of glycine and glycine peptides from the small intestine of the rat. Clin Sci 35, 415-424.
18. Matthews DM & Adibi SA (1976) Peptide absorption. Gastroenterology 71, 151-161.
19. Craft IL, Geddes D, Hyde CW, et al. (1968) Absorption and malabsorption of glycine and glycine peptides in man. Gut 9, 425-437.
20. Vermeirssen V, Van Camp J & Verstraete W (2004) Bio-availability of angiotensin I converting enzyme inhibitory peptides. Br J Nutr 92, 357-366.
21. Daniel H (2004) Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66, 361-384.
22. Yang CY, Dantzig AH & Pidgeon C (1999) Intestinal peptide transport systems and oral drug availability. Pharm Res 16, 1331-1343.
23. Adibi SA (2003) Regulation of expression of the intestinal oligopeptide transporter (Pept-1) in health and disease. Am J Physiol Gastrointest Liver Physiol 285, G779-G788.
24. Rubio-Aliaga I & Daniel H (2008) Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica 38, 1022-1042.
25. + symporter in the renal brush-border membrane. J Biol Chem 267, 9565-9573.
26. Adibi SA (1997) The oligopeptide transporter (Pept-1) in human intestine: biology and function. Gastroenterology 113, 332-340.
27. Terada T, Shimada Y, Pan XY, et al. (2005) Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract. Biochem Pharmacol 70, 1756-1763.
28. Hara H, Funabiki R, Iwata M, et al. (1984) Portal absorption of small peptides in rats under unrestrained conditions. J Nutr 114, 1122-1129.
29. +-coupled oligopeptide cotransporter PepT1. J Biol Chem 272, 7777-7785.
30. Foltz M, van der Pijl PC & Duchateau G (2010) Current in vitro testing of bioactive peptides is not valuable. J Nutr 140, 117-118.
31. Ganapathy V, Ganapathy ME & Leibach FH (2001) Intestinal transport of peptides and amino acids. In Gastrointestinal Transport: Molecular Physiology, Current Topics in Membranes, vol. 50, pp. 379-412 [KE Barrett and M Donowitz, editors]. San Diego: Academic Press.
32. Meredith D & Boyd CAR (2000) Structure and function of eukaryotic peptide transporters. Cell Mol Life Sci 57, 754-778.
33. Silva SV & Malcata FX (2005) Caseins as source of bioactive peptides. Int Dairy J 15, 1-15.
34. Meisel H (1997) Biochemical properties of bioactive pep-tides derived from milk proteins: potential nutraceuticals for food and pharmaceutical applications. Livest Prod Sci 50, 125-138.
35. Haque E, Chand R & Kapila S (2009) Biofunctional properties of bioactive peptides of milk origin. Food Rev Int 25, 28-43.
36. 2-terminus in type-II diabetic-patients and in healthy-subjects. Diabetes 44, 1126-1131.
37. Gardner MLG (1998) Transmucosal passage of intact peptides. In Peptides in Mammalian Protein Metabolism: Tissue Utilization and Clinical Targeting, vol. 11, pp. 11-29 [GK Grimble and FRC Backwell, editors]. London: Portland Press.
38. Weaver LT & Walker WA (1989) Uptake of macromolecules in the neonate. In Human Gastrointestinal Development, pp. 731-748 [E Lebenthal, editor]. New York: Raven Press.
39. Walker WA & Isselbacher KJ (1974) Uptake and transport of macromolecules by intestine-possible role in clinical disorders. Gastroenterology 67, 531-550.
40. Ménard S, Cerf-Bensussan N & Heyman M (2010) Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol 3, 247-259.
41. Izcue A, Coombes JL & Powrie F (2006) Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 212, 256-271.
42. Strobel S & Mowat AM (1998) Immune responses to dietary antigens: oral tolerance. Immunol Today 19, 173-181.
43. Travis S & Menzies I (1992) Intestinal permeability: functional assessment and significance. Clin Sci 82, 471-488.
44. Bjarnason I, Macpherson A & Hollander D (1995) Intestinal permeability: an overview. Gastroenterology 108, 1566-1581.
45. Gersemann M, Wehkamp J & Stange EF (2012) Innate immune dysfunction in inflammatory bowel disease. J Intern Med 271, 421-428.
46. Ingersoll SA, Ayyadurai S, Charania MA, et al. (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302, G484-G492.
47. Shan L, Molberg O, Parrot I, et al. (2002) Structural basis for gluten intolerance in celiac sprue. Science 297, 2275-2279.
48. Shan L, Qiao SW, Arentz-Hansen H, et al. (2005) Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue. J Proteome Res 4, 1732-1741.
49. Heyman M, Grasset E, Ducroc R, et al. (1988) Antigen absorption by the jejunal epithelium of children with cow's milk allergy. Pediatr Res 24, 197-202.
50. Kitts DD & Weiler K (2003) Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery. Curr Pharm Des 9, 1309-1323.
51. Moughan PJ, Fuller MF, Han KS, et al. (2007) Food-derived bioactive peptides influence gut function. Int J Sport Nutr Exerc Metab 17, S5-S22.
52. Meisel H (2004) Multifunctional peptides encrypted in milk proteins. Biofactors 21, 55-61.
53. Rowan AM, Haggarty NW & Ram S (2005) Milk biloactives: discovery and proof of concept. Aust J Dairy Technol 60, 114-120.
54. Wilkinson PC (1974) Surface and cell-membrane activities of leukocyte chemotactic factors. Nature 251, 58-60.
55. Miner-Williams W (2012) The protein composition of endogenous losses in the human gut. PhD thesis, Massey University, Palmerston North, New Zealand.
56. Rutherfurd-Markwick KJ & Moughan PJ (2005) Bioactive peptides derived from food. J AOAC Int 88, 955-966.
57. Korhonen H & Pihlanto A (2006) Bioactive peptides: production and functionality. Int Dairy J 16, 945-960.
58. Heyman M (2001) How dietary antigens access the mucosal immune system. Proc Nutr Soc 60, 419-426.
59. Mahe S, Messing B, Thuillier F, et al. (1991) Digestion of bovine-milk proteins in patients with a high jejunostomy. Am J Clin Nutr 54, 534-538.
60. Astwood JD, Leach JN & Fuchs RL (1996) Stability of food allergens to digestion in vitro. Nat Biotechnol 14, 1269-1273.
61. Furuse M, Fujita K, Hiiragi T, et al. (1998) Claudin-1 and-2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141, 1539-1550.
62. Furuse M, Hirase T, Itoh M, et al. (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123, 1777-1788.
63. Mandell KJ, McCall IC & Parkos CA (2004) Involvement of the junctional adhesion molecule-1 (JAM1) homodimer interface in regulation of epithelial barrier function. J Biol Chem 279, 16254-16262.
64. Ikenouchi J, Furuse M, Furuse K, et al. (2005) Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171, 939-945.
65. Gebbers JO & Laissue JA (1989) Immunologic structures and functions of the gut. Schweizer Archiv Fur Tierheilk-unde 131, 221-238.
66. Lennernäs H (2007) Intestinal permeability and its relevance for absorption and elimination. Xenobiotica 37, 1015-1051.
67. Madara JL (1990) Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J Membr Biol 116, 177-184.
68. Shimizu M, Tsunogai M & Arai S (1997) Transepithelial transport of oligopeptides in the human intestinal cell. Caco-2. Peptides 18, 681-687.
69. Shen WC, Wan JS & Ekrami H (1992) (3) Enhancement of polypeptide and protein-absorption by macromolecular carriers via endocytosis and transcytosis. Adv Drug Deliver Rev 8, 93-113.
70. Van Niel G, Mallegol J, Bevilacqua C, et al. (2003) Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice. Gut 52, 1690-1697.
71. Bockman DE & Winborn WB (1966) Light and electron microscopy of intestinal ferritin absorption. Observations in sensitized and nonsensitized hamsters (Mesocricetus auratus). Anat Rec 155, 603-621.
72. Volkheimer G (1964) Permeability of the intestinal mucous membrane to large corpuscular elements (Herbst effect). Z Gastroenterol 2, 57-67.
73. Weiner ML (1988) Intestinal transport of some macromol-ecules in food. Food Chem Toxicol 26, 867-880.
74. Agar WT, Hird FJR & Sidhu GS (1953) The active absorption of amino acids by the intestine. J Physiol 121, 255-263.
75. Wiggans DS & Johnston JM (1959) The absorption of peptides. Biochim Biophys Acta 32, 69-73.
76. Hueckel HJ & Rogers QR (1970) Urinary excretion of hydroxyproline-containing peptides in man, rat, hamster, dog and monkey after feeding gelatin. Comp Biochem Physiol 32, 7-16.
77. Hellier MD, Holdsworth CD, McColl I, et al. (1972) Dipeptide absorption in man. Gut 13, 965-969.
78. Boullin DJ, Crampton RF, Heading CE, et al. (1973) Intestinal absorption of dipeptides containing glycine, phenylalanine, proline, b-alanine or histidine in rat. Clin Sci Mol Med 45, 849-858.
79. Adibi SA (1976) Intestinal phase of protein assimilation in man. Am J Clin Nutr 29, 205-215.
80. Silk DBA, Perrett D, Webb JPW, et al. (1974) Absorption of 2 tripeptides by human small intestine: a study using a perfusion technique. Clin Sci Mol Med 46, 393-402.
81. Hellier MD, Holdsworth CD, Perrett D, et al. (1972) Intestinal dipeptide transport in normal and cystinuric subjects. Clin Sci 43, 659-668.
82. Silk DBA, Perrett D & Clark ML (1975) Jejunal and ileal absorption of dibasic amino acids and an arginine-containing dipeptide in cystinuria. Gastroenterology 68, 1426-1432.
83. Asatoor AM, Cheng B, Edwards KDG, et al. (1970) Intestinal absorption of two dipeptides in Hartnup disease. Gut 11, 380-387.
84. Tarlow MJ, Thomas AJ, Seakins JWT, et al. (1972) Absorption of amino acids and peptides in a child with a variant of Hartnup disease and coexistent celiac disease. Arch Dis Child 47, 798-803.
85. Adibi SA & Morse EL (1977) Number of glycine residues which limits intact absorption of glycine oligopeptides in human jejunum. J Clin Invest 60, 1008-1016.
86. Chung YC, Silk DBA & Kim YS (1979) Intestinal transport of a tetrapeptide, L-leucylglycylglycylglycine, in rat small intestine in vivo. Clin Sci 57, 1-11.
87. Burston D, Taylor E & Matthews DM (1979) Intestinal handling of two tetrapeptides by rodent small intestine in vitro. Biochim Biophys Acta 353, 175-178.
88. Addison JM, Burston D, Payne JW, et al. (1975) Evidence for active transport of tripeptides by hamster jejunum in vitro. Clin Sci Mol Med 49, 305-312.
89. Kerchner GA & Geary LE (1983) Studies on the transport of enkephalin-like oligopeptides in rat intestinal mucosa. J Pharmacol Exp Ther 226, 33-38.
90. Matthews DM & Payne JW (1980) Current Topics in Membrane and Transport, vol. 14. New York: Academic Press.
91. Rogers CS, Heading CE & Wilkinson S (1980) Absorption of 2 tyrosine containing tetrapeptides from the ileum of the rat. IRCS Med Sci Biochem 8, 648-649.
92. Langguth P, Bohner V, Biber J, et al. (1994) Metabolism and transport of the pentapeptide metkephamid by brush-border membrane-vesicles of rat intestine. J Pharm Pharmacol 46, 34-40.
93. Fricker G, Bruns C, Munzer J, et al. (1991) Intestinal-absorption of the octapeptide SMS-201-995 visualized by fluorescence derivatization. Gastroenterology 100, 1544-1552.
94. Takaori K, Burton J & Donowitz M (1986) The transport of an intact oligopeptide across adult mammalian jejunum. Biochem Biophys Res Commun 137, 682-687.
95. Lundin S & Vilhardt H (1986) Absorption of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in rabbits. Acta Endocrinol 112, 457-460.
96. Amoss M, Rivier J & Guillemin R (1972) Release of gonadotropins by oral administration of synthetic LRF or a tripeptide fragment of LRF. J Clin Endocrinol Metab 35, 175-177.
97. Ptachcinski RJ, Burckart GJ & Venkataramanan R (1985) Cyclosporine. Drug Intell Clin Pharm 19, 90-100.
98. Drewe J, Meier R, Vonderscher J, et al. (1992) Enhancement of the oral absorption of cyclosporine in man. Br J Clin Pharmacol 34, 60-64.
99. Walker WA, Cornell R, Davenport LM, et al. (1972) Macromolecular absorption. Mechanism of horseradish peroxidase uptake and transport in adult and neonatal rat intestine. J Cell Biol 54, 195-205.
100. Heyman M, Ducroc R, Desjeux JF, et al. (1982) Horseradish peroxidase transport across adult rabbit jejunum in vitro. Am J Physiol 242, G558-G564.
101. Neutra MR, Phillips TL, Mayer EL, et al. (1987) Transport of membrane-bound macromolecules by M-cells in follicle-associated epithelium of rabbit Peyer patch. Cell Tissue Res 247, 537-546.
102. Weltzin R, Luciajandris P, Michetti P, et al. (1989) Binding and transepithelial transport of immunoglobulins by intestinal M-cells: demonstration using monoclonal IgA antibodies against enteric viral proteins. J Cell Biol 108, 1673-1685.
103. Keljo D & Hamilton JR (1983) Quantitative determination of macromolecular transport rate across intestinal Peyer's patches. Am J Physiol 244, G637-G644.
104. Hemmings C, Hemmings WA, Patey AL, et al. (1977) Inges-tion of dietary protein as large molecular mass degradation products in adult rats. Proc Royal Soc Lond B Biol Sci 198, 439-453.
105. Hemmings WA & Williams EW (1978) Transport of large breakdown products of dietary protein through the gut wall. Gut 19, 715-723.
106. Hemmings WA & Williams EW (1976) The use of direct deposition electron microscope autoradiography in studies of protein transport. J Microsc 106, 131-143.
107. Jones EA & Waldmann TA (1971) Mechanism of intestinal uptake and transcellular transport of IgG in neonatal rat. Gut 12, 855-856.
108. Mostov KE (1994) Transepithelial transport of immuno-globulins. Annu Rev Immunol 12, 63-84.
109. Bloch KJ, Wright JA, Bishara SM, et al. (1988) Uptake of polypeptide fragments of proteins by rat intestine in vitro and in vivo. Gastroenterology 95, 1272-1278.
110. Phelan M & Kerins D (2011) The potential role of milk-derived peptides in cardiovascular disease. Food Funct 2, 153-167.
111. Jahan-Mihan A, Luhovyy BL, El Khoury D, et al. (2011) Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract. Nutrients 3, 574-603.
112. Meisel H (2001) Bioactive peptides from milk proteins: a perspective for consumers and producers. Aust J Dairy Technol 56, 83-92.
113. Agyei D & Danquah MK (2012) Rethinking food-derived bioactive peptides for antimicrobial and immunomodula-tory activities. Trends Food Sci Technol 23, 62-69.
114. Agyei D & Danquah MK (2011) Industrial-scale manufacturing of pharmaceutical-grade bioactive peptides. Biotechnol Adv 29, 272-277.
115. Roberts PR, Burney JD, Black KW, et al. (1999) Effect of chain length on absorption of biologically active peptides from the gastrointestinal tract. Digestion 60, 332-337.
116. Erdmann K, Cheung BWY & Schroder H (2008) The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular disease. J Nutr Biochem 19, 643-654.
117. Foltz M, Cerstiaens A, van Meensel A, et al. (2008) The angiotensin converting enzyme inhibitory tripeptides Ile-Pro-Pro and Val-Pro-Pro show increasing permeabilities with increasing physiological relevance of absorption models. Peptides 29, 1312-1320.
118. Séverin S & Xia WS (2005) Milk biologically active components as nutraceuticals: review. Crit Rev Food Sci Nutr 45, 645-656.
119. Nakamura Y, Yamamoto N, Sakai K, et al. (1995) Anti-hypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme. J Dairy Sci 78, 1253-1257.
120. Robert MC, Razaname A, Mutter M, et al. (2004) Peptides derived from sodium caseinate hydrolysates produced by Lactobacillus helveticus NCC 2765. J Agric Food Chem 52, 6923-6931.
121. Zaloga GP & Siddiqui RA (2004) Biologically active dietary peptides. Mini Rev Med Chem 4, 815-821.
122. Miguel M, Muguerza B, Sanchez E, et al. (2005) Changes in arterial blood pressure in hypertensive rats caused by long-term intake of milk fermented by Enterococcus faecalis CECT 5728. Br J Nutr 94, 36-43.
123. Mizuno S, Matsuura K, Gotou T, et al. (2005) Antihyper-tensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild hypertension. Br J Nutr 94, 84-91.
124. Fitzgerald RJ & Murray BA (2006) Bioactive peptides and lactic fermentations. Int J Dairy Technol 59, 118-125.
125. Foltz M, Meynen EE, Bianco V, et al. (2007) Angiotensin converting enzyme inhibitory peptides from a lactotripep-tide-enriched milk beverage are absorbed intact into the circulation. J Nutr 137, 953-958.
126. Escudero E, Sentandreu MA, Arihara K, et al. (2010) Angio-tensin I-converting enzyme inhibitory peptides generated from in vitro gastrointestinal digestion of pork meat. J Agric Food Chem 58, 2895-2901.
127. Muguerza B, Ramos M, Sanchez E, et al. (2006) Antihyper-tensive activity of milk fermented by Enterococcus faecalis strains isolated from raw milk. Int Dairy J 16, 61-69.
128. Nakamura T, Mizutani J, Sasaki K, et al. (2009) Beneficial potential of casein hydrolysate containing Val-Pro-Pro and Ile-Pro-Pro on central blood pressure and hemodynamic index: a preliminary study. J Med Food 12, 1221-1226.
129. Hata Y, Yamamoto M, Ohni M, et al. (1996) Placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr 64, 767-771.
130. Sano J, Ohki K, Higuchi T, et al. (2005) Effect of casein hydro-lysate, prepared with protease derived from Aspergillus oryzae, on subjects with high-normal blood pressure or mild hypertension. J Med Food 8, 423-430.
131. Seppo L, Jauhiainen T, Poussa T, et al. (2003) A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr 77, 326-330.
132. Jauhiainen T, Vapaatalo H, Poussa T, et al. (2005) Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement. Am J Hypertens 18, 1600-1605.
133. Xu J-Y, Qin L-Q, Wang P-Y, et al. (2008) Effect of milk tri-peptides on blood pressure: a meta-analysis of randomized controlled trials. Nutrition 24, 933-940.
134. Boelsma E & Kloek J (2009) Lactotripeptides and antihyper-tensive effects: a critical review. Br J Nutr 101, 776-786.
135. Masuda O, Nakamura Y & Takano T (1996) Antihyperten-sive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. J Nutr 126, 3063-3068.
136. Nilsson D, Fagerholm U & Lennernas H (1994) The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum. Pharm Res 11, 1540-1544.
137. Lennernäs H, Ahrenstedt O & Ungell AL (1994) Intestinal drug absorption during induced net water absorption in man: a mechanistic study using antipyrine, atenolol and enalaprilat. Br J Clin Pharmacol 37, 589-596.
138. Fagerholm U, Nilsson D, Knutson L, et al. (1999) Jejunal permeability in humans in vivo and rats insitu: investigation of molecular size selectivity and solvent drag. Acta Physiol Scand 165, 315-324.
139. Satake M, Enjoh M, Nakamura Y, et al. (2002) Transepithe-lial transport of the bioactive tripeptide, Val-Pro-Pro, in human intestinal Caco-2 cell monolayers. Biosci Biotechnol Biochem 66, 378-384.
140. Camenisch G, Alsenz J, van de Waterbeemd H, et al. (1998) Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight. Eur J Pharm Sci 6, 317-324.
141. Daniel H & Herget M (1997) Cellular and molecular mechanisms of renal peptide transport. Am J Physiol 273, F1-F8.
142. Brandsch M, Knutter I & Bosse-Doenecke E (2008) Pharmaceutical and pharmacological importance of peptide transporters. J Pharm Pharmacol 60, 543-585.
143. Picariello G, Ferranti P, Fierro O, et al. (2010) Peptides surviving the simulated gastrointestinal digestion of milk proteins: biological and toxicological implications. J Chromatogr B Analyt Technol Biomed Life Sci 878, 295-308.
144. van der Pijl PC, Kies AK, Ten Have GAM, et al. (2008) Pharmacokinetics of proline-rich tripeptides in the pig. Peptides 29, 2196-2202.
145. van Platerink CJ, Janssen HGM & Haverkamp J (2007) Development of an at-line method for the identification of angiotensin-I inhibiting peptides in protein hydrolysates. J Chromatogr B Analyt Technol Biomed Life Sci 846, 147-154.
146. Korhonen H (2009) Milk-derived bioactive peptides: from science to applications. J Funct Food 1, 177-187.
147. Ricci I, Artacho R & Olalla M (2010) Milk protein peptides with angiotensin I-converting enzyme inhibitory (ACEI) activity. Crit Rev Food Sci Nutr 50, 390-402.
148. Fitzgerald RJ, Murray BA & Walsh DJ (2004) Hypotensive peptides from milk proteins. J Nutr 134, 980S-988S.
149. Matsufuji H, Matsui T, Seki E, et al. (1994) Angiotensin I-converting enzyme-inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle. Biosci Biotechnol Biochem 58, 2244-2245.
150. Yamamoto N, Ejiri M & Mizuno S (2003) Biogenic peptides and their potential use. Curr Pharm Des 9, 1345-1355.
151. Li GH, Le GW, Shi YH, et al. (2004) Angiotensin I-convert-ing enzyme inhibitory peptides derived from food proteins and their physiological and pharmacological effects. Nutr Res 24, 469-486.
152. Gobbetti M, Minervini F & Rizzello CG (2004) Angiotensin I-converting-enzyme-inhibitory and antimicrobial bioactive peptides. Int J Dairy Technol 57, 173-188.
153. Matsui T, Tamaya K, Seki E, et al. (2002) Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system. Clin Exp Pharmacol Physiol 29, 204-208.
154. Clare DA & Swaisgood HE (2000) Bioactive milk peptides: a prospectus. J Dairy Sci 83, 1187-1195.
155. Shah NP (2000) Effects of milk-derived bioactives: an overview. Br J Nutr 84, S3-S10.
156. Lonnerdal B (2003) Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 77, 1537S-1543S.
157. Meisel H (2005) Biochemical properties of peptides encrypted in bovine milk proteins. Curr Med Chem 12, 1905-1919.
158. Martinez-Maqueda D, Miralles B, Recio I, et al. (2012) Anti-hypertensive peptides from food proteins: a review. Food Funct 3, 350-361.
159. Fitzgerald RJ & Meisel H (2000) Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme. Br J Nutr 84, S33-S37.
160. van Platerink CJ, Janssen HGM, Horsten R, et al. (2006) Quantification of ACE inhibiting peptides in human plasma using high performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 830, 151-157.
161. Klee WA, Zioudrou C & Streaty RA (1978) Endorphins in Mental Health Research. New York: Macmillan.
162. Fukudome S & Yoshikawa M (1992) Opioid peptides derived from wheat gluten: their isolation and characterization. FEBS Lett 296, 107-111.
163. Fanciulli G, Dettori A, Demontis MP, et al. (2005) Gluten exorphin B5 stimulates prolactin secretion through opioid receptors located outside the blood-brain barrier. Life Sci 76, 1713-1719.
164. Ivanov VT, Karelin AA, Philippova MM, et al. (1997) Hemoglobin as a source of endogenous bioactive peptides: the concept of tissue-specific peptide pool. Biopolymers 43, 171-188.
165. Zhao Q, Garreau I, Sannier F, et al. (1997) Opioid peptides derived from hemoglobin: hemorphins. Biopolymers 43, 75-98.
166. Brantl V, Teschemacher H, Henschen A, et al. (1979) Novel opioid peptides derived from casein (b-casomorphins). 1. Isolation from bovine casein peptone. Hoppe Seylers Z Physiol Chem 360, 1211-1216.
167. Zioudrou C, Streaty RA & Klee WA (1979) Opioid peptides derived from food proteins-exorphins. J Biol Chem 254, 2446-2449.
168. Teschemacher H (2003) Opioid receptor ligands derived from food proteins. Curr Pharm Des 9, 1331-1344.
169. Teschemacher H, Koch G & Brantl V (1997) Milk protein-derived opioid receptor ligands. Biopolymers 43, 99-117.
170. Meisel H & Fitzgerald RJ (2000) Opioid peptides encrypted in intact milk protein sequences. Br J Nutr 84, S27-S31.
171. 3H]etorphine to rat-brain homogenate. Proc Natl Acad Sci USA 70, 1947-1949.
172. Pert CB & Snyder SH (1973) Opiate receptor: demonstration in nervous tissue. Science 179, 1011-1014.
173. Terenius L (1973) Characteristics of the receptor for narcotic analgesics in synaptic plasma membrane fraction from rat brain. Acta Pharmacol Toxicol 33, 377-384.
174. Mansour A & Watson SJ (1993) Handbook of Experimental Pharmacology, vol. 104/I. Berlin: Springer.
175. Satoh M & Minami M (1995) Molecular pharmacology of the opioid receptors. Pharmacol Ther 68, 343-364.
176. Nishimura E, Buchan AMJ & McIntosh CHS (1986) Auto-radiographic localization of m-and d-type opioid receptors in the gastrointestinal tract of the rat and guinea-pig. Gastroenterology 91, 1084-1094.
177. Karras PJ & North RA (1981) Acute and chronic effects of opiates on single neurons of the myenteric-plexus. J Pharmacol Exp Ther 217, 70-80.
178. Teschemacher H, Koch G & Brantl V (1994) Milk protein derived atypical peptides and related compounds with opioid antagonist activity (review). In b-Casomorphins and Related Peptides: Recent Developments, pp. 3-17 [V Brantl and H Teschemacher, editors]. Weinheim: VCH.
179. Höllt V (1986) Opioid peptide processing and receptor selectivity. Annu Rev Pharmacol Toxicol 26, 59-77.
180. Paterson SJ, Robson LE & Kosterlitz HW (1983) Classification of opioid receptors. Br Med Bull 39, 31-36.
181. Chang KJ, Killian A, Hazum E, et al. (1981) Morphiceptin (NH4-Tyr-Pro-Phe-Pro-ConH2): a potent and specific agonist for morphine (Mu) receptors. Science 212, 75-77.
182. Mierke DF, Nossner G, Schiller PW, et al. (1990) Morphiceptin analogs containing 2-aminocyclopentane carboxylic-acid as a peptidomimetic for proline. Int J Pept Protein Res 35, 35-45.
183. Schulte-Frohlinde E, Schimd R, Brantl V, et al (1994) Effect of bovine b-casomorphins-4-amide on gastrointestinal transit and pancreatic endocrine function in man. In b-Casomorphins and Related Peptides: Recent Developments, pp. 155-160 [V Brantl and H Teschemacher, editors]. Weinheim: VCH.
184. Froetschel MA (1996) Bioactive peptides in digesta that regulate gastrointestinal function and intake. J Anim Sci 74, 2500-2508.
185. Allescher HD, Storr M, Brechmann C, et al. (2000) Modula-tory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum. Neuropeptides 34, 62-68.
186. Brandsch M, Brust P, Neubert K, et al (1994) Evidence for a functional significance of natural b-casomorphins. b-Casomorphins: chemical signals of intestinal transport systems. In b-Casomorphins and Related Peptides: Recent Developments, pp. 207-219 [V Brantl and H Teschemacher, editors]. Weinheim: VCH.
187. Daniel H, Vohwinkel M & Rehner G (1990) Effect of casein and b-casomorphins on gastrointestinal motility in rats. J Nutr 120, 252-257.
188. Matthies H, Stark H, Hartrodt B, et al. (1984) Derivatives of b-casomorphins with high analgesic potency. Peptides 5, 463-470.
189. Taira T, Hilakivi LA, Aalto J, et al. (1990) Effect of b-casomorphin on neonatal sleep in rats. Peptides 11, 1-4.
190. Yamada Y, Matoba N, Usui H, et al. (2002) Design of a highly potent anti-hypertensive peptide based on ovokinin(2-7). Biosci Biotechnol Biochem 66, 1213-1217.
191. Jiang Z, Tian B, Brodkorb A, et al. (2010) Production, analysis and in vivo evaluation of novel angiotensin-I-converting enzyme inhibitory peptides from bovine casein. Food Chem 123, 779-786.
192. s1-casein. In b-Casomorphins and Related Peptides: Recent Developments, pp. 43-48 [V Brantl and H Teschemacher, editors]. Weinheim: VCH.
193. Hernández-Ledesma B, del Mar Contreras M & Recio I (2011) Antihypertensive peptides: production, bioavailability and incorporation into foods. Adv Colloid Interface Sci 165, 23-35.
194. Nurminen ML, Sipola M, Kaarto H, et al. (2000) a-Lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats. Life Sci 66, 1535-1543.
195. Sipola M, Finckenberg P, Vapaatalo H, et al. (2002) a-Lactorphin and b-lactorphin improve arterial function in spontaneously hypertensive rats. Life Sci 71, 1245-1253.
196. Miguel M, Gómez-Ruiz JÁ, Recio I, et al. (2010) Changes in arterial blood pressure after single oral administration of milk-casein-derived peptides in spontaneously hypertensive rats. Mol Nutr Food Res 54, 1422-1427.
197. Miguel M, Manso MA, López-Fandino R, et al. (2007) Vascular effects and antihypertensive properties of k-casein macropeptide. Int Dairy J 17, 1473-1477.
198. Miguel M, Manso M, Aleixandre A, et al. (2007) Vascular effects, angiotensin I-converting enzyme (ACE)-inhibitory activity, and anti hypertensive properties of peptides derived from egg white. J Agric Food Chem 55, 10615-10621.
199. Miguel M, Alvarez Y, López-Fandino R, et al. (2007) Vasodilator effects of peptides derived from egg white proteins. Regul Pept 140, 131-135.
200. Dávalos A, Miguel M, Bartolome B, et al. (2004) Antioxidant activity of peptides derived from egg white proteins by enzymatic hydrolysis. J Food Prot 67, 1939-1944.
201. del Mar Contreras M, Carron R, Jose Montero M, et al. (2009) Novel casein-derived peptides with antihypertensive activity. Int Dairy J 19, 566-573.
202. Hirota T, Ohki K, Kawagishi R, et al. (2007) 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-convert-ing enzyme. Hypertens Res 30, 489-496.
203. Wong TP, Debnam ES & Leung PS (2007) Involvement of an enterocyte renin-angiotensin system in the local control of SGLT1-dependent glucose uptake across the rat small intestinal brush border membrane. J Physiol 584, 613-623.
204. Leung PS (2010) Local RAS. In Renin-Angiotensin System: Current Research Progress in the Pancreas: The RAS in the Pancreas, vol. 690, pp. 69-87 [PS Leung, editor]. Dordrecht: Springer.
205. Stevens BR, Fernandez A, Kneer C, et al. (1988) Human intestinal brush-border angiotensin-converting enzyme-activity and its inhibition by antihypertensive Ramipril. Gastroenterology 94, 942-947.
206. Bruneval P, Hinglais N, Alhenc-Gelas F, et al. (1986) Angiotensin I converting enzyme in human intestine and kidney. Ultrastructural immunohistochemical localization. Histochemistry 85, 73-80.
207. Cox HM, Munday KA & Poat JA (1986) Identification of selective, high-affinity I-125 angiotensin and I-125 brady-kinin binding-sites in rat intestinal epithelia. Br J Pharmacol 87, 201-209.
208. Jin XH, Wang ZQ, Siragy HM, et al. (1998) Regulation of jejunal sodium and water absorption by angiotensin subtype receptors. Am J Physiol 275, R515-R523.
209. Yoshioka M, Erickson RH, Woodley JF, et al. (1987) Role of rat intestinal brush-border membrane angiotensin-converting enzyme in dietary-protein digestion. Am J Physiol 253, G781-G786.
210. Dorey PG, King J, Munday KA, et al. (1983) Intestinal fluid absorption in spontaneously hypertensive rats. J Physiol 344, 1-9.
211. Catalanotto F, Schechter PJ & Henkin RI (1972) Preference for NaCl in spontaneously hypertensive rat. Life Sci 1 11, 557-564.
212. Dahl LK (1961) Possible role of chronic excess salt consumption in pathogenesis of essential hypertension. Am J Cardiol 8, 571-575.
213. Ehlers MRW & Riordan JF (1989) Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry 28, 5311-5318.
214. Amidon GL & Sadée WE (1999) Membrane Transporters as Drug Targets. Pharmaceutical Biotechnology, vol. 12. New York: Kluwer Academic/Plenum Publishers.
215. Bai JPF & Amidon GL (1992) Structural specificity of mucosal-cell transport and metabolism of peptide drugs-implication for oral peptide drug delivery. Pharm Res 9, 969-978.
216. Chabance B, Marteau P, Rambaud JC, et al. (1998) Casein peptide release and passage to the blood in humans during digestion of milk or yogurt. Biochimie 80, 155-165.
217. Meisel H & Schlimme E (1990) Milk proteins: precursors of bioactive peptides. Trends Food Sci Technol 1, 41-43.
218. Meisel H (1997) Biochemical properties of regulatory pep-tides derived from milk proteins. Biopolymers 43, 119-128.
219. Clare DA, Catignani GL & Swaisgood HE (2003) Biodefense properties of milk-the role of antimicrobial proteins and peptides. Curr Pharm Des 9, 1239-1255.
220. Korhonen H & Pihlanto A (2003) Food-derived bioactive peptides-opportunities for designing future foods. Curr Pharm Des 9, 1297-1308.
221. Petrilli P, Picone D, Caporale C, et al. (1984) Does casomor-phin have a functional role? FEBS Lett 169, 53-56.
222. Kreil G, Umbach M, Brantl V, et al. (1983) Studies on the enzymatic degradation of b-casomorphins. Life Sci 33, 137-140.
223. Daniel H & Hahn A (1990) b-Casomorphins opioid-peptides derived from milk proteins. Ernährungs-Umschau 37, 95-101.
224. Schmelzer CEH, Schöps R, Reynell L, et al. (2007) Peptic digestion of b-casein. Time course and fate of possible bioactive peptides. J Chromatogr A 1166, 108-115.
225. Tome D & Debabbi H (1998) Physiological effects of milk protein components. Int Dairy J 8, 383-392.
226. Pihlanto-Leppala A (2000) Bioactive peptides derived from bovine whey proteins: opioid and ACE-inhibitory peptides. Trends Food Sci Technol 11, 347-356.
227. Gardner MLG (1988) Gastrointestinal absorption of intact proteins. Annu Rev Nutr 8, 329-350.
228. Paganelli R & Levinsky RJ (1980) Solid-phase radioimmuno-assay for detection of circulating food protein antigens in human serum. J Immunol Methods 37, 333-341.
229. Kenrick KG (1970) Immunoglobulins and dietary protein antibodies in childhood coeliac disease. Gut 11, 635-640.
230. Roberton DM, Paganelli R, Dinwiddie R, et al. (1982) Milk antigen absorption in the preterm and term neonate. Arch Dis Child 57, 369-372.
231. Bazin H, Andre C & Heremans JF (1973) Immunological responses to orally ingested antigens. Ann D Immunol C124, 253-272.
232. Cunningham-Rundles C (1987) Failure of antigen exclusion. In Food Allergy and Intolerance, pp. 223-236 [J Brostoff and CJ Challocombe, editors]. London: Bailliere Tindall.
233. Husby S, Foged N, Høst A, et al. (1987) Passage of dietary antigens into the blood of children with celiac disease. Quantification and size distribution of absorbed antigens. Gut 28, 1062-1072.
234. Jakobsson I, Lindberg T, Lothe L, et al. (1986) Human alpha-lactalbumin as a marker of macromolecular absorption. Gut 27, 1029-1034.
235. McLean E & Ash R (1987) The time-course of appearance and net accumulation of horseradish peroxidase (HRP) presented orally to rainbow trout Salmo gairdneri (Richardson). Comp Biochem Physiol A Comp Physiol 88, 507-510.
236. McLean E & Ash R (1986) The time-course of appearance and net accumulation of horseradish peroxidase (HRP) presented orally to juvenile carp Cyprinus carpio (L.). Comp Biochem Physiol A Comp Physiol 84, 687-690.
237. Walker WA, Abel SN, Wu M, et al. (1976) Intestinal uptake of macromolecules 5. Comparison of in vitro uptake by rat small intestine of antigen-antibody complexes prepared in antibody or antigen excess. J Immunol 117, 1028-1032.
238. Walker WA, Wu M, Isselbacher KJ, et al. (1975) Intestinal uptake of macromolecules 4. Effect of pancreatic duct ligation on breakdown of antigen and antigen-antibody complexes on intestinal surface. Gastroenterology 69, 1223-1229.
239. Fiat AM, Miglioresamour D, Jolles P, et al. (1993) Biologically-active peptides from milk proteins with emphasis on 2 examples concerning antithrombotic and immunomodula-ting activities. J Dairy Sci 76, 301-310.
240. Wolf JL, Rubin DH, Finberg R, et al. (1981) Intestinal M-cells: a pathway for entry of reovirus into the host. Science 212, 471-472.
241. Gardner MLG (1984) Intestinal assimilation of intact pep-tides and proteins from the diet-a neglected field. Biol Rev Camb Philos Soc 59, 289-331.
242. Teschemacher H, Umbach M, Hamel U, et al. (1986) No evidence for the presence of b-casomorphins in human-plasma after ingestion of cows milk or milk products. J Dairy Res 53, 135-138.
243. Mahe S, Tome D, Dumontier AM, et al. (1989) Absorption of intact morphiceptin by diisopropylfluorophosphate-treated rabbit ileum. Peptides 10, 45-52.
244. Read LC, Lord APD, Brantl V, et al. (1990) Absorption of b-casomorphins from autoperfused lamb and piglet small intestine. Am J Physiol 259, G443-G452.
245. Tiruppathi C, Miyamoto Y, Ganapathy V, et al. (1993) Genetic evidence for role of DPP-IV in intestinal hydrolysis and assimilation of prolyl peptides. Am J Physiol 265, G81-G89.
246. Gill HS, Doull F, Rutherfurd KJ, et al. (2000) Immunoregu-latory peptides in bovine milk. Br J Nutr 84, S111-S117.
247. Bray GA (2000) Afferent signals regulating food intake. Proc Nutr Soc 59, 373-384.
248. Bakalkin GY, Demuth HU & Nyberg F (1992) Relationship between primary structure and activity in exorphins and endogenous opioid peptides. FEBS Lett 310, 13-16.
249. Nyberg F, Sanderson K & Glamsta EL (1997) The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers 43, 147-156.
250. Yoshikawa M, Tani F, Ashikaga T, et al. (1986) Purification and characterization of an opioid antagonist from a peptic digest of bovine k-casein. Agric Biol Chem 50, 2951-2954.
251. Lin L, Umahara M, York DA, et al. (1998) b-Casomorphins stimulate and enterostatin inhibits the intake of dietary fat in rats. Peptides 19, 325-331.
252. Hedner J & Hedner T (1987) b-Casomorphins induce apnea and irregular breathing in adult rats and newborn rabbits. Life Sci 41, 2303-2312.
253. Cheng FY, Liu YT, Wan TC, et al. (2008) The development of angiotensin I-converting enzyme inhibitor derived from chicken bone protein. Anim Sci J 79, 122-128.
254. Medhus AW, Sandstad O, Bredesen J, et al. (1999) Delay of gastric emptying by duodenal intubation: sensitive measurement of gastric emptying by the paracetamol absorption test. Aliment Pharmacol Ther 13, 609-620.
255. Fone DR, Horowitz M, Heddle R, et al. (1991) Comparative effects of duodenal and ileal intubation on gastric emptying and postprandial antral, pyloric, and duodenal motility. Scand J Gastroenterol 26, 16-22.
256. Read NW, Aljanabi MN, Bates TE, et al. (1983) Effect of gastrointestinal intubation on the passage of a solid meal through the stomach and small intestine in humans. Gastroenterology 84, 1568-1572.
257. Hendrix TR & Bayless TM (1970) Digestion: intestinal secretion. Annu Rev Physiol 32, 139-164.
258. Rao RK, Koldovsky O & Davis TP (1990) Inhibition of intestinal degradation of somatostatin by rat milk. Am J Physiol 258, G426-G431.
259. Sarfati P & Morisset J (1988) Inhibition of pancreatic exocrine secretion of intraintestinal somatostatin possible mechanism of action involving the proximal duodenum. Pancreas 3, 616.
260. Konturek SJ, Tasler J, Cieszkowski M, et al. (1981) Studies on the inhibition of pancreatic secretion by luminal somato-statin. Am J Physiol 241, G109-G115.
261. Konturek SJ, Bilski J, Jaworek J, et al. (1988) Comparison of somatostatin and its highly potent hexapeptide and octapeptide analogs on exocrine and endocrine pancreatic secretion. Proc Soc Exp Biol Med 187, 241-249.
262. Jones RE (1977) De-iodination of labeled protein during intestinal transmission in suckling rat. Proc R Soc Lond B Biol Sci 199, 279-290.
263. Moriya H, Moriwaki C, Akimoto S, et al. (1967) Studies on passage of a-chymotrypsin across intestine. Chem Pharm Bull (Tokyo) 15, 1662-1668.
264. Miller JM, Williard RF & Polachek AA (1960) An investigation of trypsin I-131 in patients. Exp Med Surg 18, 352-370.
265. Kabacoff BL, Avakian S, Wohlman A, et al. (1963) Absorption of chymotrypsin from intestinal tract. Nature 199, 815.
266. Ambrus JL, Lassman HB & Demarchi JJ (1967) Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharm Ther 8, 362-368.
267. Avakian S (1964) Further studies on absorption of chymo-trypsin. Clin Pharm Ther 5, 712-715.
268. Goldberg DM, Campbell R & Roy AD (1968) Binding of trypsin and chymotrypsin by human intestinal mucosa. Biochim Biophys Acta 167, 613-615.
269. Katayama K & Fujita T (1972) Studies on biotransfor-mation of elastase 2. Intestinal-absorption of I-131-labeled elastase in-vivo. Biochim Biophys Acta 288, 181-189.
270. Megel H, Beiler M, Ho R, et al. (1964) Detection of trypsin-like activity in plasma of rats after oral administration of trypsin. Arch Biochem Biophys 108, 193-199.
271. Urban E, Zingery AA, Bundrant T, et al. (1982) Permeability of adolescent rat intestine to pancreatic ribonuclease. J Pediatr Gastroenterol Nutr 1, 267-272.
272. Walker WA, Isselbacher KJ & Bloch KJ (1972) Intestinal uptake of macromolecules: effect of oral immunization. Science 177, 608-610.
273. Warshaw AL, Walker WA & Isselbacher KJ (1974) Protein uptake by intestine: evidence for absorption of intact macromolecules. Gastroenterology 66, 987-992.
274. Rothman S, Liebow C & Isenman L (2002) Conservation of digestive enzymes. Physiol Rev 82, 1-18.
275. Goetze H & Rothman SS (1978) Amylase transport across ileal epithelium in-vitro. Biochim Biophys Acta 512, 214-220.
276. Liebow C & Rothman SS (1974) Enteropancreatic circulation of an intact digestive enzyme. Fed Proc 33, 409.
277. Levitt MD, Ellis CJ, Murphy SM, et al. (1981) Study of the possible enteropancreatic circulation of pancreatic amylase in the dog. Am J Physiol 241, G54-G58.
278. Rosenblum JL, Raab BK & Alpers DH (1982) Hepatobiliary and pancreatic clearance of circulating pancreatic amylase. Am J Physiol 243, G21-G27.
279. Levitt MD (1983) Is there an enteropancreatic circulation of digestive enzyme? Am J Physiol 244, G103-G104.
280. Rohr G, Kern H & Scheele G (1981) Enteropancreatic circulation of digestive enzymes does not exist in the rat. Nature 292, 470-472.
281. Rothman SS & Grendell JH (1983) Is there an entero-pancreatic circulation of digestive enzyme? Am J Physiol 244, G101-G102.
282. Rohr G, Kern H & Scheele G (1983) Is there an entero-pancreatic circulation of digestive enzyme? Am J Physiol 244, G104-G106.
283. Rosenblum JL, Raab BK & Alpers DH (1983) Is there an enteropancreatic circulation of digestive enzyme?-reply. Am J Physiol 244, G103.
284. Joo K & Kato Y (2006) Assessment of allergenic activity of a heat-coagulated ovalbumin after in vivo digestion. Biosci Biotechnol Biochem 70, 591-597.
285. Matsubara T, Aoki N, Honjoh T, et al. (2008) Absorption, migration and kinetics in peripheral blood of orally administered ovalbumin in a mouse model. Biosci Biotechnol Biochem 72, 2555-2565.
286. Furrie E, Turner MW & Strobel S (1995) Partial characterization of a circulating tolerogenic moiety which, after a feed of ovalbumin, suppresses delayed-type hypersensitivity in recipient mice. Immunology 86, 480-486.
287. Tsume Y, Taki Y, Sakane T, et al. (1996) Quantitative evaluation of the gastrointestinal absorption of protein into the blood and lymph circulation. Biol Pharm Bull 19, 1332-1337.
288. Moreno FJ (2007) Gastrointestinal digestion of food allergens: effect on their allergenicity. Biomed Pharmacother 61, 50-60.
289. Wharton CW (1974) Structure and mechanism of stem bromelain. Evaluation of homogeneity of purified stem bromelain, determination of molecular-weight and kinetic analysis of bromelain-catalyzed hydrolysis of N-benzyloxy-carbonyl-L-phenylalanyl-L-serine methyl-ester. Biochem J 143, 575-586.
290. Soderholm JD, Peterson KH, Olaison G, et al. (1999) Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease? Gastroenterology 117, 65-72.
291. Chehade M & Mayer L (2005) Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol 115, 3-12.
292. Frossard CP, Hauser C & Eigenmann PA (2004) Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy. J Allergy Clin Immunol 114, 377-382.
293. Dannaeus A, Inganas M, Johansson SGO, et al. (1979) Intestinal uptake of ovalbumin in malabsorption and food allergy in relation to serum IgG antibody and orally-administered sodium cromoglycate. Clin Allergy 9, 263-270.
294. Diesner SC, Knittelfelder R, Krishnamurthy D, et al. (2008) Dose-dependent food allergy induction against ovalbumin under acid suppression: a murine food allergy model. Immunol Lett 121, 45-51.
295. James JM (2004) Food allergy: opportunities and challenges in the clinical practice of allergy and immunology. Clin Rev Allergy Immunol 27, 105-114.
296. Castell JV, Friedrich G, Kuhn CS, et al. (1997) Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol Gastrointest Liver Physiol 273, G139-G146.
297. Walker WA (1987) Pathophysiology of intestinal uptake and absorption of antigens in food allergy. Ann Allergy 59, 7-16.
298. Heyman M (2005) Gut barrier dysfunction in food allergy. Eur J Gastroenterol Hepatol 17, 1279-1285.
299. Gupta S, Jain A, Chakraborty M, et al. (2013) Oral delivery of therapeutic proteins and peptides: a review on recent developments. Drug Deliv 20, 237-246.
300. Rabanel JM, Aoun V, Elkin I, et al. (2012) Drug-loaded nanocarriers: passive targeting and crossing of biological barriers. Curr Med Chem 19, 3070-3102.
301. Kamei N, Nielsen EJB, Khafagy el-S, et al. (2013) Noninva-sive insulin delivery: the great potential of cell-penetrating peptides. Ther Del 4, 315-326.
302. Renukuntla J, Vadlapudi AD, Patel A, et al. (2013) Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 447, 75-93.
303. Swaminathan J & Ehrhardt C (2012) Liposomal delivery of proteins and peptides. Expert Opin Drug Deliv 9, 1489-1503.
304. Zhang YL, Wei W, Lv PP, et al. (2011) Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin. Eur J Pharm Biopharm 77, 11-19.
305. Mukhopadhyay P, Mishra R, Rana D, et al. (2012) Strategies for effective oral insulin delivery with modified chitosan nanoparticles: a review. Prog Polymer Sci 37, 1457-1475.
306. Olaison G, Sjodahl R & Tagesson C (1990) Abnormal intestinal permeability in Crohn's-disease-a possible pathogenic factor. Scand J Gastroenterol 25, 321-328.
307. Hollander D (1992) The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn's disease. Scand J Gastroenterol 27, 721-726.
308. Charrier L & Merlin D (2006) The oligopeptide transporter hPepT1: gateway to the innate immune response. Lab Invest 86, 538-546.
309. Dalmasso G, Nguyen HTT, Charrier-Hisamuddin L, et al. (2010) PepT1 mediates transport of the proinflammatory bacterial tripeptide L-Ala-g-D-Glu-meso-DAP in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 299, G687-G696.
310. Terada T, Sawada K, Saito H, et al. (1999) Functional characteristics of basolateral peptide transporter in the human intestinal cell line Caco-2. Am J Physiol 276, G1435-G1441.
311. +/peptide cotransporter 2 causes a complete loss of transport function. Biochem Biophys Res Commun 316, 416-420.
312. Shepherd EJ, Lister N, Affleck JA, et al. (2002) Identification of a candidate membrane protein for the basolateral pep-tide transporter of rat small intestine. Biochem Biophys Res Commun 296, 918-922.
313. Irie M, Terada T, Okuda M, et al. (2004) Efflux properties of basolateral peptide transporter in human intestinal cell line Caco-2. Pflugers Arch 449, 186-194.