Bioactive peptides: their absorption, utilization and functionality

doi:10.7506/spkx1002-6630-201309074

Abstract

Abstract:

Dietary proteins and their enzymolytic products exert a wide range of nutritional, functional and biological
activities for human health. A large number of data showed that protein hydrolytic products are absorbed and transited more
effectively than intact protein or free amino acids alone, supporting the notion that digestion is important for its uptake
and circulation even if the amino acid compositions are exactly balanced. Furthermore, when the protein was administered
orally as a hydrolysate instead of in an intact form or free amino acid, the healthy functions can be observed, suggesting
that bioactive peptides can be liberated by proteolytic enzymes. However, the body is a self-regulatory, self-renew, and selfstabilization
system, so the immune defense system never allows any dissident biomacromolecules, especially diet proteins
and peptides to be taken in, for that maybe some invaders. Even if a small amount of intact proteins are occasionally taken
up, which is due to the molecule structure recognition of substances around by sampling from intestinal tract. The major
functions are to establish as the adaptive immunity defense system for specific antigens. After absorbed, these peptides will
be rapidly hydrolyzed and processed by antigen presenting cells (APC) to present the antigenic determinants to Th cells.
The membranous microfold (M) cells can bring intact protein to B cells as antigen epitopes for antibody class switching and
secreting. Base on these investigations, diet proteins and corresponding enzymolytic peptides mainly offer their functions by
the interaction with gastrointestinal mucosal systems and intestinal microorganisms. On the other hand, the accumulated data
have demonstrated that transport of di- and tripeptides is a faster and effective route of uptake per unit of time than their free
AA or intact protein by intestinal peptide transporter, PepT1. Furthermore, the di- and tripeptides are more efficiently than
free AA or intact protein with the same respective AA compositions, and these peptides may be transported by circulation to
different tissues or organs and used for different purpose more efficiently. This review will also provide a theoretical basis
for the research and exploitation of bioactive peptides for special foods.

Key words: enzymolytic peptide, peptide absorption, peptide transporter (PepT1), bioactive peptides, functional food, special food

CLC Number:

R151.41

PANG Guang-chang，CHEN Qing-sen，HU Zhi-he，XIE Jun-bo. Bioactive peptides: their absorption, utilization and functionality[J]. FOOD SCIENCE, 2013, 34(9): 375-391.

References

[1] MICHAEL L. G. GARDNER, Amino acid and peptide absorption from partial digests of proteins in isolated rat small intestine[J]，J. Phyeiol. 1978, 284:83-104.

[2] E. R. GILBERT, E. A. WONG AND K. E. WEBB. JR., Peptide absorption and utilization: Implications for animal nutrition and health[J], J. Anim. Sci. 2008, 86:2135–2155.

[3] DANIEL, H., Molecular and integrative physiology of intestinal peptide transport[J]. Annu. Rev. Physiol. 2004, 66:361–384.

[4] MASAKI KAMAKURA, Royalactin induces queen differentiation in honeybees[J], Nature, 2011, 473(7348):478-83.

[5] 庞广昌王秋韫陈庆森，生物活性肽的研究进展理论基础与展望[J]，食品科学，2001, 22 (2):80-84.

[6] SHRIKANT SHARMA, RAGHVENDAR SINGH, SHASHANK RANA, Bioactive Peptides: A Review[J], INT. J. Bioautomation, 2011, 15(4):223-250.

[7] HANNU KORHONEN, ANNE PIHLANTO, Bioactive peptides: Production and functionality[J], International Dairy Journal, 2006, 16:945–960.

[8] CHIBUIKE C. UDENIGWE AND ROTIMI E. ALUKO, Food Protein-Derived Bioactive Peptides: Production, Processing, and Potential Health Benefits[J], Journal of Food Science, 2012, 71(1):R11-24.

[9] IBRAHIM MM., RAS inhibition in hypertension. J Hum Hypertens, 2006, 20:101–108.

[10] Segall L, Covic A, Goldsmith DJA. Direct renin inhibitors: the dawn of a new era, or just a variation on a theme? [J] Nephrol Dial Transplant 2007, 22:2435–2439.

[11] FERREIRA SH, BARTELT DC, GREENE LJ., Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom[J]. Biochemistry, 1970, 9:2583–2593.

[12] ALUKO RE. Technology for the production and utilization of food protein-derived antihypertensive peptides: a review[J]. Recent Pat Biotechnol, 2007, 1:260–267.

[13] FITZGERALD RJ, MURRAY BA, WALSH DJ., Hypotensive peptides from milk proteins. J Nutr 2004, 134:980S–8S.

[14] UDENIGWE CC, LIN Y-S, HOU W-C, ALUKO RE. Kinetics of the inhibition of renin and angiotensin I-converting enzyme by flaxseed protein hydrolysate fractions[J]. J Funct Foods 2009, 1:199–207.

[15] GIRGIH AT, UDENIGWE CC, LI H, ADEBIYI AP, ALUKO RE. Kinetics of enzyme inhibition and antihypertensive effects of hemp seed (Cannabis sativa L.) protein hydrolysates[J]. J Am Oil Chem Assoc. 2011, 88(3):381-389.

[16] LI H, ALUKO RE., Identification and inhibitory properties of multifunctional peptides from pea protein hydrolysate[J]. J Agric Food Chem. 2010. 58:11471–11476.

[17] UDENIGWE CC, LI H, ALUKO RE., Quantitative structure-activity relationship modelling of renin-inhibiting dipeptides[J]. Amino Acids. 2012, 42(4):1379-1386.

[18] NAKAMURA Y, YAMAMOTO N, SAKAI K, et al. Purification and characterization of angiotensin I-converting enzyme inhibitors from a sour milk[J]. J Dairy Sci. 1995, 78:777–783.

[19] BOELSMA E, KLOEK J. IPP-rich milk protein hydrolysate lowers blood pressure in subjects with stage 1 hypertension, a randomized controlled trial[J]. Nutr J. 2010, 9:52-59. DOI: 10.1186/1475–2891-9–52.

[20] USINGER L, JENSEN LT, FLAMBARD B, et al. The antihypertensive effect of fermented milk in individuals with prehypertension or borderline hypertension[J]. J Hum Hypertens 2010, 24:678–683.

[21] HUANG D, OU B, PRIOR RL. The chemistry behind antioxidant capacity assays[J]. J Agric Food Chem. 2005, 53:1841–1856.

[22] CHEN HM, MURAMOTO K, YAMAUCHI F, et al. Antioxidant properties of histidine-containing peptides designed from peptide fragments found in the digests of a soybean protein[J]. J Agric Food Chem. 1998, 46:49–53.

[23] MEISEL H. Biochemical properties of peptides encrypted in bovine milk proteins. Curr Med Chem. 2005, 12:1905–1919.

[24] ERDMANN K, GROSSER N, SCHIPPOREIT K, SCHRODER H. The ACE inhibitory dipeptide Met-Tyr diminishes free radical formation in human endothelial cells via induction of heme oxygenase-1 and ferritin[J]. J Nutr. 2006, 136:2148–2152.

[25] LAHART N, O’CALLAGHAN Y, AHERNE SA, et al. Extent of hydrolysis effects on casein hydrolysate bioactivity: evaluation using the human Jurkat T cell line[J]. Int Dairy J. 2011, 21:777–782.

[26] DING J-F, LI Y-Y, XU J-J, et al. Study on effect of jellyfish collagen hydrolysate on anti-fatigue and anti-oxidation[J]. Food Hydrocoll. 2011, 25:1350–1353.

[27] HOOKS SS, MEANS AR. Ca2+/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol. 2001, 41:471–505.

[28] ITANO T, ITANO R, PENNISTON JT. Interactions of basic polypeptides and proteins with calmodulin[J]. Biochem J. 1980, 189:455–459.

[29] O’NEIL KT, DEGRADO WF. How calmodulin binds its targets: sequence independent recognition of amphiphilic α-helices[J]. Trends Biochem Sci. 1990, 15:59–64.

[30] BARNETT RD,WEISS B. Inhibition of calmodulin activity by insect venom peptides[J]. Biochem Pharmacol. 1983, 32:2929–2933.

[31] KIZAWA K. Calmodulin binding peptide comprising α-casein exorphin sequence[J]. J Agric Food Chem. 1997, 45:1579–1581.

[32] LI H, ALUKO RE. Kinetics of the inhibition of calcium/calmodulin-dependent protein kinase II by pea protein-derived peptides[J]. J Nutr Biochem. 2005, 16:656–662.

[33] OMONI AO, ALUKO RE. Effect of cationic flaxseed protein hydrolysate fractions on the in vitro structure and activity of calmodulin-dependent endothelial nitric oxide synthase[J]. Mol Nutr Food Res. 2006, 50:958–966.

[34] YOU SJ, UDENIGWE CC, ALUKO RE, WU J. Multifunctional peptides from egg white lysozyme[J]. Food Res Int. 2010, 43:848–855.

[35] CHO, SJ, JUILLERAT MA, LEE CH. Identification of LDL-receptor transcription stimulating peptides from soybean hydrolysate in human hepatocytes[J]. J Agric Food Chem. 2008, 56:4372–4376.

[36] KIRANA C, ROGERS PF, BENNETT LE, et al. Naturally derived micelles for rapid in vitro screening of potential cholesterol-lowering bioactives[J]. J Agric Food Chem. 2005, 53:4623–4627.

[37] KAYASHITA J, SHIMAOKA I, NAKAJOH M,ET al. Consumption of buckwheat protein lowers plasma cholesterol and raises fecal neutral sterols in cholesterol-fed rats because of its low digestibility[J]. J Nutr. 1997, 127:1395–1400.

[38] MANSO MA, MIGUEL M, EVEN J, et al. Effects of the long-term intake of an egg white hydrolysate on the oxidative status and blood lipid profile of spontaneously hypertensive rats. Food Chem. 2008, 109:361–367.

[39] WERGEDAHL H, LIASET B, GUDBRANDSEN OA, et al. Fish protein hydrolysate reduces plasma total cholesterol, increases the proportion of HDL cholesterol, and lowers acyl-CoA: cholesterol acyltransferase activity in liver of Zucker rats[J]. J Nutr. 2004, 134:1320–1327.

[40] KAYASHITA J, SHIMAOKA I, NAKAJOH M, et al. Consumption of buckwheat protein lowers plasma cholesterol and raises fecal neutral sterols in cholesterol-fed rats because of its low digestibility[J]. J Nutr. 1997, 127:1395–1400.

[41] AOYAMA T, FUKUI K, TAKAMATSU K, et al. Soy protein isolate and its hydrolysate reduce body fat of dietary obese rats and genetically obese mice (yellow KK) [J]. Nutrition, 2000, 16:349–354.

[42] HORI G, WANG M-F, CHAN Y-C,et al. Soy protein hydrolyzate with bound phospholipids reduces serum cholesterol levels in hypercholesterolemic adult male volunteers[J]. Biosci Biotechnol Biochem. 2001, 65:72–78.

[43] LOVATI MR, MANZONI C, GIANAZZA E, SIRTORI CR. Soybean protein products as regulators of liver low-density lipoprotein receptors[J]. I. Identification of active β-conglycinin subunits. J Agric Food Chem. 1998, 46:2474–2480.

[44] LOVATI MR, MANZONI C, GIANAZZA E, et al. Soy protein peptides regulate cholesterol homeostasis in Hep G2 cells[J]. J Nutr. 2000, 130:2543–2549.

[45] KOHNO M, HIROTSUKA M, KITO M, MATSUZAWA Y. Decreases in serum triacylglycerol and visceral fat mediated by dietary soybean beta-conglycinin[J]. J Atheroscler Thromb. 2006, 13: 247–255.

[46] CHO S, JUILLERAT MA, LEE C. Cholesterol lowering mechanism of soybean protein hydrolysate[J]. J Agric Food Chem. 2007, 55:10599–10604.

[47] HIGAKI N, SATO K, SUDA H, et al. Evidence for the existence of a soybean resistant protein that captures bile acid and stimulates its fecal excretion. Biosci Biotechnol Biochem[J]. 2006, 70:2844–2852.

[48] KAYASHITA J, SHIMAOKA I, NAKAJOH M, et al. Consumption of buckwheat protein lowers plasma cholesterol and raises fecal neutral sterols in cholesterol-fed rats because of its low digestibility[J]. J Nutr. 1997, 127:1395–1400.

[49] HERNANDEZ-LEDESMA B, HSIEH C-C, de Lumen BO. Lunasin, a novel seed peptide for cancer prevention[J]. Peptides, 2009, 30:426–430.

[50] DIA VP, TORRES S, DE LUMEN BO, et al. Presence of lunasin in plasma of men after soy protein consumption[J]. J Agric Food Chem. 2009, 57:1260–1266.

[51] JEONG HJ, LEE JR, JEONG JB, et al. The cancer preventive seed peptide lunasin from rye is bioavailable and bioactive. Nutr Cancer. 2009, 61:680–686.

[52] WANG W, BRINGE NA, BERHOW MA, GONZALEZ DE MEJIA E. β-Conglycinins among sources of bioactives in hydrolysates of different soybean varieties that inhibit leukemia cells in vitro[J]. J Agric Food Chem. 2008, 56:4012–4020.

[53] SILVA-SANCHEZ C, BARBA DE LA ROSA AP, LEON-GALVAN MF, et al. Bioactive peptides in amaranth (Amarathus hypochondriacus) seed[J]. J Agric Food Chem. 2008, 56:1233–1240.

[54] KIM SE, KIM HH, KIM JY, et al. Anticancer activity of hydrophobic peptides from soy proteins[J]. BioFactors. 2000, 12:151–155.

[55] HSU K, LI-CHAN ECY, JAO C. Antiproliferative activity of peptides prepared from enzymatic hydrolysates of tuna dark muscle on human breast cancer cell line MCF-7[J]. Food Chem. 2011, 126:617–622.

[56] BARRIO DA, ANON MC. Potential antitumor properties of a protein isolate obtained from the seeds of Amaranthus mantegazzianus[J]. Eur J Nutr. 2010, 49:73–82.

[57] HARTMANN R, MEISEL H. Food-derived peptides with biological activity: from research to food applications[J]. Curr Opin Biotechnol. 2007, 18:163–169.

[58] TAKAHASHI M, MORIGUCHI S, YOSHIKAWA M, SASAKI R. Isolation and characterization of oryzatensin: a novel bioactive peptide with ileum-contracting and immunomodulating activities derived from rice albumin[J]. Biochem Mol Biol Int. 1994, 33:1151–1158.

[59] MINE Y, KOVACS-NOLAN J. New insights in biologically active proteins and peptides derived from hen’s egg[J]. Worlds Poult Sci J. 2006, 62:87–95.

[60] NDIAYE F, VUONG T, et al. Antioxidant, anti-inflammatory and immunomodulatory properties of an enzymatic protein hydrolysate from yellow field pea seeds[J]. Eur J Nutr. 2012, 51(1):29-37.

[61] HORIGUCHI N, HORIGUCHI H, SUZUKI Y. Effect of wheat gluten hydrolysate on the immune system in healthy human subjects[J]. Biosci Biotechnol Biochem. 2005, 69:2445–2449.

[62] GAUTHIER S, POULIOT Y, SAINT-SAUVEUR D. Immunomodulatory peptides obtained by the enzymatic hydrolysis of whey proteins[J]. Int Dairy J. 2006, 16:1315–1323.

[63] DIA VP, TORRES S, DE LUMEN BO, et al. Presence of lunasin in plasma of men after soy protein consumption[J]. J Agric Food Chem. 2009, 57:1260–1266.

[64] GONZALEZ DE MEJIA E, DIA VP. Lunasin and lunasin-like peptides inhibit inflammation through suppression of NF-κB pathway in the macrophage[J]. Peptides, 2009, 30:2388–2398.

[65] PHELAN M, AHERNE-BRUCE SA, O’SULLIVAN D, et al. Potential bioactive effects of casein hydrolysates on human cultured cells[J]. Int Dairy J. 2009, 19:279–285.

[66] YANG R, PEI X, WANG J, et al. Protective effect of a marine oligopeptide preparation from chum salmon (Oncorhynchus keta) on radiation-induced immune suppression in mice[J]. J Sci Food Agric. 2010, 90:2241–2248.

[67] 庞广昌，陈庆森，胡志和，谢军波，食品与机体中的移动通讯网络[J], 食品科学, 2010, 31(21):1-9.

[68] E. R. GILBERT, E. A. WONG, AND K. E. WEBB JR., Peptide absorption and utilization: Implications for animal nutrition and health[J]. J. Anim. Sci. 2008, 86:2135–2155.

[69] FEI, Y. J., Y. KANAI, S. NUSSBERGER, et al. Expression cloning of a mammalian proton-coupled oligopeptide transporter[J]. Nature, 1994, 368:563–566.

[70] NEWEY, H., AND D. H. SMYTH., The intestinal absorption of some dipeptides[J]. J. Physiol. 1959, 145:48–56.

[71] REEDS, P. J., D. G. BURRIN, B. STOLL, AND J. B. VAN GOUDOEVER. Role of the gut in the amino-acid economy of the host. In Peptides and Amino Acids in Enteral Nutrition[J]. Nestle Nutr Workshop Ser Clin Perform Programme. 2000, 3:25-40.

[72] LEVENSON, S. M., H. ROSEN, H. L. UPJOHN, AND R. W. CLARKE. Nature and appearance of protein digestion products in upper mesenteric blood[J]. Proc. Soc. Exp. Biol. Med. 1959, 101:178–180.

[73] WIGGANS, D. S., AND J. M. JOHNSTON. The absorption of peptides[J]. Biochim. Biophys. Acta. 1959, 32:69–73.

[74] GARDNER, M. L. G. Absorption of amino acids and peptides from a complex mixture in the isolated small intestine of the rat[J]. J. Physiol. 1975, 253:233–256.

[75] TAGARI, H., K. E. WEBB JR., B. THEURER, et al. Mammary uptake, portal-drained visceral flux, and hepatic metabolism of free and peptide-bound amino acids in cows fed steam-flaked or dry-rolled sorghum grain diets[J]. J. Dairy Sci. 2008, 91:679–697.

[76] LOCHS, H., E. L. MORSE, AND S. A. ADIBI. Uptake and metabolism of dipeptides by human red blood cells. Biochem. J. 1990, 271:133–137.

[77] KRZYSIK, B. A., AND S. A. ADIBI. Comparison of metabolism of glycine injected intravenously in free and dipeptide forms[J]. Metabolism. 1979, 28:1211–1217.

[78] WEBB, K. E. JR., D. B. DIRIENZO, AND J. C. MATTHEWS. Recent developments in gastrointestinal absorption and tissue utilization of peptides: A review[J]. J. Dairy Sci. 1993, 76:351–361.

[79] PAN, Y.-L., P. K. BENDER, R. M. AKERS, AND K. E. WEBB JR. Methionine-containing peptides can be used as methionine sources for protein accretion in cultured C2C12 and MAC-T cells[J]. J. Nutr. 1996, 126:232–241.

[80] MABJEESH, S. J., M. COHEN, O. GAL-GARBER, A. SHAMAY, AND Z. UNI. Aminopeptidase N gene expression and abundance in caprine mammary gland is influenced by circulating plasma peptide. J. Dairy Sci. 2005, 88:2055–2064.

[81] TAGARI, H., K. E. WEBB JR., B. THEURER, T. HUBER, et al. Portal drained visceral flux, hepatic metabolism, and mammary uptake of free and peptide-bound amino acids and milk amino acid output in dairy cows fed diets containing corn grain steam flaked at 360 or steam rolled at 490 g/L[J]. J. Dairy Sci. 2004, 87:413–430.

[82] KIM, Y. S., W. BIRTWHISTLE, AND Y. W. KIM. Peptide hydrolases in the brush border and soluble fractions of small intestinal mucosa of rat and man[J]. J. Clin. Invest. 1972, 51:1419–1430.

[83] TERADA, T., K. SAWADA, H. SAITO, et al. Functional characteristics of basolateral peptide transporter in the human intestinal cell line Caco-2[J]. Am. J. Physiol. Gastrointest. Liver Physiol. 1999, 276:1435–1441.

[84] DANIEL, H., AND G. KOTTRA. The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology[J]. Pflugers Arch. 2004, 447:610–618.

[85] WEITZ, D., D. HARDER, F. CASAGRANDE, et al. Functional and structural characterization of a prokaryotic peptide transporter with features similar to mammalian PEPT1[J]. J. Biol. Chem. 2007, 282:2832–2839.

[86] LEIBACH, F. H., AND V. GANAPATHY. Peptide transporters in the intestine and kidney. Annu[J]. Rev. Nutr. 1996, 16:99–119.

[87] BRANDSCH, M., I. KNUTTER, AND F. LEIBACH. The intestinal H+/ peptide symporter pepT1: Structure-affinity relationships[J]. Eur. J. Pharm. Sci. 2004, 21:53–60.

[88] STEFFANSEN, B., C. NIELSEN, B. BRODIN, et al. Intestinal solute carriers: An overview of trends and strategies for improving oral drug absorption[J]. Eur. J. Pharm. Sci. 2004, 21:3–16.

[89] STEEL, A., S. NUSSBERGER, M. ROMERO, et al. Stoichiometry and pH dependence of the rabbit proton-dependent oligopeptide transporter PepT1[J]. J. Physiol. 1997, 498:563–569.

[90] SHIMAKURA, J., T. TERADA, Y. SHIMADA, et al. The transcription factor Cdx2 regulates the intestinespecific expression of human peptide transporter 1 through functional interaction with Sp1[J]. Biochem. Pharmacol. 2006, 71:1581–1588.

[91] SHIMAKURA, J., T. TERADA, T. KATSURA, AND K.-I. INUI. Characterization of the human peptide transporter PEPT1 promoter: Sp1 functions as a basal transcriptional regulator of human PEPT1[J]. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289:G471–G477.

[92] SHIRAGA, T., K. MIYAMOTO, H. TANAKA, et al. Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/peptide transporter PepT1[J]. Gastroenterology, 1999, 116:354–362.

[93] IHARA, T., T. TSUJIKAWA, Y. FUJIYAMA, AND T. BAMBA. Regulation of PepT1 peptide transporter expression in the rat small intestine under malnourished conditions[J]. Digestion. 2000, 61:59–67.

[94] PAN, X., T. TERADA, M. OKUDA, AND K.-I. INUI. The diurnal rhythm of the intestinal transporters SGLT1 and PEPT1 is regulated by the feeding conditions in the rat[J]. J. Nutr. 2004, 134:2211–2215.

[95] SHIMAKURA, J., T. TERADA, H. SAITO, et al. Induction of intestinal peptide transporter 1 expression during fasting is mediated via peroxisome proliferator-activated receptor α. Am. J. Physiol[J]. Gastrointest. Liver Physiol. 2006, 291:G851–G856.

[96] THAMOTHARAN, M., S. BAWANI, X. ZHOU, AND S. ADIBI. Hormonal regulation of oligopeptide transporter Pept-1 in a human intestinal cell line[J]. Am. J. Physiol. Cell Physiol. 1999, 276:C821–C826.

[97] BUYSE, M., F. BERLIOZ, S. GUILMEAU, et al. PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine[J]. J. Clin. Invest. 2001, 108:1483–1494.

[98] NIELSEN, C., J. AMSTRUP, R. NIELSEN, et al. Epidermal growth factor and insulin short-term increase hPepT1-mediated glycylsarcosine uptake in Caco-2 cells[J]. Acta. Physiol. Scan. 2003, 178:139–148.

[99] ASHIDA, K., T. KATSURA, H. MOTOHASHI, et al. Thyroid hormone regulates the activity and expression of the peptide transporter PepT1 in Caco-2 cells[J]. Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 282:G617–G623.

[100] ADIBI, S. A. Regulation of expression of the intestinal oligopeptide transporter (PepT-1) in health and disease[J]. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 285:G779–G788.

[101] FORD, D., A. HOWARD, AND B. HIRST. Expression of the peptide transporter hPepT1 in human colon: A potential route for colonic protein nitrogen and drug absorption. Histochem. Cell Biol. 2003, 119:37–43.

[102] ZIEGLER, T., C. FERNANDEZ, L. GU, et al. Distribution of the H+/peptide transporter PepT1 in human intestine: Up-regulated expression in the colonic mucosa of patients with short-bowel syndrome[J]. Am. J. Clin. Nutr. 2002, 75:922–930.

[103] SEKIKAWA, S., Y. KAWAI, A. FUJIWARA, et al. Alterations in hexose, AA and peptide transporter expression in intestinal epithelial cells during Nippostrongylus brasiliensis infection in the rat[J]. Int. J. Parasitol. 2003, 33:1419–1426.

[104] PALM, C., M. JAYAMANNE, M. KJELLANDER, AND M. HALLBRINK. Peptide degradation is a critical determinant for cell-penetrating peptide uptake[J]. Biochim. Biophys. Acta. 2007, 1768:1769–1776.

[105] MORRIS, M. C., P. VIDAL, L. CHALOIN, et al. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells[J]. Nucleic Acids Res. 1997, 25:2730–2736.

[106] Eriksson, M., P. E. Nielson, and L. Good. Cell permeabilization and uptake of antisense peptide-peptide nucleic acid (PNA) into Escherichia coli. J. Biol. Chem. 2002, 277:7144–7147.

[107] SAALIK, P., A. ELMQUIST, M. HANSEN, et al. Protein cargo delivery properties of cell-penetrating peptides. A comparative study[J]. Bioconjug. Chem. 2004, 15:1246–1253.

[108] ZAMBONINO INFANTE, J. L., C. L. CAHU, AND A. PERES. Partial substitution of di- and tripeptides for native proteins in sea bass diet improves Dicentrarchus labrax larval development[J]. J. Nutr. 1997, 127:608–614.

[109] RONNESTAD, I., P. J. GAVAIA, C. S. VIEGAS, et al. Oligopeptide transporter PepT1 in Atlantic cod (Gadus morhua L.): Cloning, tissue expression and comparative aspects[J]. J. Exp. Biol. 2007, 210:3883–3896.

[110] KOTZAMANIS, Y. P., E. GISBERT, F. J. GATESOUPE, et al. Effects of different dietary levels of fish protein hydrolysates on growth, digestive enzymes, gut microbiota and resistance to Vibrio anguillarum in European sea bass (Dicentrarchus labrax) larvae[J]. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 2007, 147:205–214.

[111] VERMEIRSSEN V, VAN CAMP J, VERSTRAETE W. Bioavailability of angiotensin I converting enzyme inhibitory peptides[J]. Brit J Nutr. 2004, 92:357–366.

[112] DAREWICZ M, DZIUBA B, MINKIEWICZ P, DZIUBA J. The preventive potential of milk and colostrum proteins and protein fragments[J]. Food Rev Int. 2011, 27:357–388.

[113] MARTIN FOLTZ, EVELYNE E. MEYNEN, VERONIQUE BIANCO, et al. Angiotensin Converting Enzyme Inhibitory Peptides from a Lactotripeptide-Enriched Milk Beverage Are Absorbed Intact into the Circulation[J]. J. Nutr. 2007, 137: 953–958.

[114] WANG W, GONZALEZ DE MEJIA E. A new frontier in soy bioactive peptides that may prevent age-related chronic diseases[J]. Compr Rev Food Sci Food Safety. 2005, 4: 63–78.

[115] 庞广昌，陈庆森，胡志和，解军波，五味调与营养平衡及其信号传导, 食品科学, 2012, 33(13):1-20.

[116] GEIBEL, J.P., AND HEBERT, S.C. The functions and roles of the extracellular Ca2+-sensing receptor along the gastrointestinal tract[J]. Annu. Rev. Physiol. 2009, 71:205–217.

[117] CHOI, S., LEE, M., SHIU, A.L., et al. GPR93 activation by protein hydrolysate induces CCK transcription and secretion in STC-1 cells[J]. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 292:G1366–G1375.

[118] BISSETTE, G., NEMEROFF, C. B., LOOSEN, P. T., PRANGE, A. J. JR & LIPTON, M. A. Hypothermia and intolerance to cold induced by intracisternal administration of the hypothalamic peptide neurotensin[J]. Nature, 1976, 262:607–609

[119] JIM F. WHITE, NICHOLAS NOINAJ, YOKO SHIBATA, et al. Structure of the agonist-bound neurotensin receptor[J]. Nature, 2012, 490: 508-513.

[120] MARTAFILIZOLA & LAKSHMIA, DEVI, How opioid drugs bind to receptors[J]. Nature, 2012, 485: 314-317.

[121] AARON A. THOMPSON, WEI LIU, EUGENE CHUN, et al. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic, nature, 2012, 485:395-399.

[122] KIM J, GUAN KL. Amino acid signaling in TOR activation[J]. Annu Rev Biochem. 2011, 80:1001–1032.

[123] TOLHURST G, REIMANN F, GRIBBLE FM. Nutritional regulation of glucagon-like peptide-1 secretion[J]. J Physiol. 2009, 587:27–32.

[124] DAVID A. RELMAN, Undernutrition-Looking Within for Answers[J]. Science, 2013, 339:530-532.

[125] 庞广昌，陈庆森，胡志和，食品是如何通过细胞因子网络控制人类健康的（I）[J]，食品科学 2006 Vol.27 No.05: 258-264.

[126] 庞广昌，陈庆森，胡志和，食品是如何通过细胞因子网络控制人类健康的（II）[J]，食品科学 2006 Vol.27 No.06：260-270.

[127] 黄栩林，庞广昌，杨静静，Trpi免疫调节功能的研究[J]，食品科学，2008，Vol.29, No.4,381-385.

[128] 李扬，庞广昌等，牛初乳中的IgG对肠粘膜免疫系统调节的初步研究[J]，食品科学 2009，Vol.30, No.17, 297-301.

[129] 滑艳君，庞广昌，郭丽, 口服酪蛋白复合肽对细胞通讯网络的作用[J]，食品科学，2010,310(17):310-317.

[130] 庞广昌，于立芹，马田野，食品- 家兔体温- 免疫调节的因果关系研究[J]，2008, 29(10):568-574.

[131] S. SALMINEN', C. BOULEY2, M.-C. BOUTRON-RUAULT, et al. Functional food science and gastrointestinal physiology and function[J], British Journal of Nutrition. 1998, 80(I): S147-Sl71.

[132] B.P. WILLING, A.G. VAN KESSEL, Host pathways for recognition: Establishing gastrointestinal microbiota as relevant in animal health and nutrition[J]. Livestock Science, 2010, 133:82–91.

[133] LEBLANC, J.G., MATAR, C., VALDEZ, J.C., LEBLANC, J., PERDIGON, G., Immunomodulating effects of peptidic fractions issued from milk fermented with lactobacillus helveticus[J]. J. Dair. Sci. 2002, 85, 2733–2742.

[134] TROMPETTE, A., CLAUSTRE, J., CAILLON, F., JOURDAN, G., CHAYVIALLE, J.A., PLAISANCIE, P., 2003. Milk bioactive peptides and beta-casomorphins induce mucus release in rat jejunum[J]. J. Nutr. 133, 3499–3503.

[135] ZOGHBI, S., TROMPETTE, A., CLAUSTRE, J., et al. Beta-casomorphin-7 regulates the secretion and expression of gastrointestinal mucins through a mu-opioid pathway. Am. J. Physiol.-Gastroint[J]. Liver. Physiol. 2006, 290:G1105–G1113.

[136] THOREUX, K., BALAS, D., BOULEY, C., SENEGAS-BALAS, F., Diet supplemented with yoghurt or milk fermented by lactobacillus casei dn-114 001 stimulates growth and brush-border enzyme activities in mouse small intestine[J]. Digest. 1998, 59:349–359.

[137] FIANDER, A., BRADLEY, S., JOHNSON-GREEN, P.C., GREEN-JOHNSON, J.M., Effects of lactic acid bacteria and fermented milks on eicosanoid production by intestinal epithelial cells[J]. J. Food Sci. 2005, 70:M81–M86.

[138] TANIDA, M., YAMANO, T., MAEDA, K., et al. Effects of intraduodenal injection of Lactobacillus johnsonii la1 on renal sympathetic nerve activity and blood pressure in urethaneanesthetized rats[J]. Neurosci. Lett. 2005, 389:109–114.

[139] DUARTE, J., VINDEROLA, G., RITZ, B., et al. Immunomodulating capacity of commercial fish protein hydrolysate for diet supplementation[J]. Immunobiol. 2006, 211:341–350.

[140] PERDIGON, G., VINTINI, E., ALVAREZ, S., et al. Study of the possible mechanisms involved in the mucosal immune system activation by lactic acid bacteria[J]. J. Dair. Sci. 1999, 82:1108–1114.

[141] PANG GUANG-CHANG, XIE JUN-BO, CHEN QING-SEN, HU ZHI-HE, How functional foods play critical roles in human health, Food Science and Human Wellness[J], 2012, 1:26–60.

[142] Kristen Mueller, Caroline Ash, Elizabeth Pennisi and Orla Smith，introduction The Gut Microbiota[J], Science, 2012, 336:1245.

[143] JEREMY K. NICHOLSON, ELAINE HOLMES, JAMES KINROSS, Host-Gut Microbiota Metabolic Interactions[J], Science, 2012, 336:1262-1267.

[144] TSUTOMU MATSUBARA, FEI LI AND FRANK J. GONZALEZ, FXR signaling in the enterohepatic system, Matsubara, T., et al. FXR signaling in the enterohepatic system[J]. Molecular and Cellular Endocrinology, 2012, http:// dx.doi.org/10.1016/j.mce.2012.05.004

[145] AMIR H. SAM, RACHEL C. TROKE, TRICIA M. TAN AND GAVIN A. Bewick, The role of the gut/brain axis in modulating food intake[J], Neuropharmacology, 2012, 63:46-56.

[146] NINA L. CLUNY, RAYLENE A. REIMER, KEITH A. SHARKEY, Cannabinoid signalling regulates inflammation and energy balance: The importance of the brain–gut axis[J], Brain, Behavior, and Immunity, 2012, 26:691–698.

[147] YOSHIE, O., IMAI, T., NOMIYAMA, H., Chemokines in immunity[J]. Adv Immunol. 2001, 78:57-110.

[148] MICHELE WEBER ROBERT HAUSCHILD JAN SCHWARZ et al. Interstitial Dendritic Cell Guidance by Haptotactic Chemokine Gradients[J], Science, 2013, 339:328-332.

[149] TERESA LORENZI, ROSARIA MELI, DANIELA MARZIONI, et al. Ghrelin: a metabolic signal affecting the reproductive system[J]. Cytokine & Growth Factor Reviews, 2009, 20:137–152.