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LACTOFERRIN Lactoferrin is secreted in milk, tears and bile. It is elevated by inflammation and some cancers. It has been suggested to have a number of functional properties including:
Review of Biological Properties through 1997 [See references for 1998-1999 and for 1999-2001 at the end of this section] Lactoferrin is an iron-binding protein found in milk and other secretory fluids of mammals, as well as in secondary gradual neutrophils. Interest in its biological function has grown in recent years. Med-Line cites over 1000 references in the past 6 years, with over 150 citations for 1996 alone. The structure and properties of lactoferrin have been reviewed (Kussendrager 1993; and Reiter 1985a). In human milk, lactoferrin is a major whey protein, with 6-8 g/l in colostrum and 2-4 g/l in the milk. Bovine colostrum and milk are much lower in lactoferrin content (~1 g/l and 0.2g/l for colostrum and milk respectively). The function lactoferrin has been associated with its iron binding capacity, as well as its glycation state. Lactoferrin consists of a single peptide chain, with a molecular weight of 77,000. Lactoferrin is folded into two globular units, each capable of binding up to 1.4 mg iron/g of protein. In its native state in milk, lactoferrin is only partially saturated (5-40%). Recombinant Lactoferrin and lactoferrin peptides Three patents have been assigned to the Baylor School of Medicine relating to the cloning of lactoferrin and lactoferrin peptides and the expression of recombinate lactoferrin by fungi and bacteria (Conneely et al. 1996a, 1996b, 1996c) They claim that the verified cDNA sequence for human, bovine and porcine lactoferrin protein have been used to prepare lactoferrin for therapeutic and nutritional applications. Regions of the cDNA, such as the Fe binding sites can be used to produce peptide products. The conversion of these concepts to commercial practice could be competitive with the current production of lactoferrin from whey. Biological Activity Until recently, the interest in lactoferrin has been primarily in regard to potential capability of acting in iron transport and as an antimicrobial agent related to its iron chelating ability – thus depriving microorganisms of a source of iron.. More recently it has been shown to have a number of other physiological and biological functions (Shinmoto et al. 1992; Brock 1995; Kussendrager 1993; Lonnerdal and Iyer 1995; Adamik and Wlaszczyk 1996; Shinoda et al. 1996). Although human and bovine lactoferrin differ, there is increasing evidence that both serve similar biological functions (Adamik and Wlaszczyk 1996; Shinoda et al. 1996; Miyauchi et al. 1997). The biological activities of lactoferrin include: -ion transport (Nagasako et al. 1993)-antimicrobial activity (Arnold
et. al. 1979; Ellison et al. 1991; Jones, et. al. 1994; Denisove et al 1996) Receptors for lactoferrin have been detected and isolated on activated T and B cells, monocytes, intestinal brush border cells, platelets and neoplastic cells (Adamik and Walszczyk 1996). Very low physiologic serum levels of lactoferrin increase upon infection and in some rheumatoid patients. Antimicrobial Activity: The antimicrobial activity of lactoferrin has been reviewed by Kussendrager (1993, 1995). Generally this activity has been attributed to iron binding by lactoferrin and a resulting iron depravation of the inhibited microorganisms (Reiter et al. 1985a, 1985b). More recently, there has been evidence of antimicrobial activity that is independent of iron. Feng et al. (1995) found that apolactoferrin had greater antimicrobial activity than lactoferrin isolated from milk. Yamauchi et al. (1993) reported that pepsin derived peptides had antimicrobial activity. Also, lactoferrin may act synergistically with other components, such as lysozyme (Suzuki et al.. (1989), immunoglobulins and lactoperoxidase. The in vitro antimicrobial activity of lactoferrin has been known for many years, but there is only limited information available on in vivo effects. Drescher et al. (1996) demonstrated a bacteriostatic effect for lactoferrin in the intestine of young (but not adult) pigs. Kakuka and Kurokua (1995) showed that lactoferrin had a protective effect against the infection of red sea bream by C. irritans. A synergistic effect of combining lactoferrin, lactoperoxidase and ß-lactoglobulin from cow’s milk, as well as lactoferrin from human milk, has been shown in vivo for mice infected intr anasally with Shigella sonnei. None of the components alone were effective. The treatment eliminated the microorganisms and prevented death.Antiviral Activity Lactoferrin has been shown to be effective in protecting against a number of different viruses (Marchetti et al. 1996; Shimizu et al. 1996 ) Marchetti et al. (1996) reported that both human and bovine lactoferrin were effective against the herpes simplex virus type 1 (HSV-1) by inhibiting adsorption of the virus. This activity was independent of the iron with-holding, since both iron saturated and apolactoferrin were equally effective. Swart et al, (1998) found that lactoferrin from both human and bovine sources were able to completely block HCMV replications and to inhibit HIB-1 induced cytopathic effects. Anticancer Activity There is increasing evidence, based on animal studies, that lactoferrin may have therapeutic value in treatment of different types of cancer (Sekine et al 1997; Uchida et al. 1998; Ligo et al. 1999; Uchida et al. 1999). Iron Binding relationships Iron transport has been considered to be a significant function of lactoferrin ( Reiter 1985a, b; Lonnerdal and Iyer 1995; Adamik and Wlaszczyk 1996). Kawakami et al. (1993) found evidence that iron from iron saturated lactoferrin was absorbed across the intestinal mucosa by an alternative mechanism. Lactoferrin and lactoferrin digested with trypsin (forming lactoferricin) solubilized a greater than 70 fold molar equivalent of iron in the presence of bicarbonate or phosphate ions. This was higher than the iron binding capacity of lactoferrin. It was suggested that orally administered lactoferrin could solubilize inorganic iron in the intestine and could be useful in protection against iron-deficient anaemia. Nagasako, et al.. (1993) also showed iron could be bound by lactoferrin at sites other than its chelating binding sites. The ability of lactoferrin to bind large quantities of iron, needed for the growth of microorganisms and tumors, may provide protection against pathogens and their metabolites by enhancing phagocytosis, cell adherence and controlling release of pro-inflammatory cytokines (Adamik and Wlaszczyk 1996). The role of iron binding as the only mechanisms in the antibacterial action of lactoferrin has been brought into question by the work of Feng et al. (1995) who showed that apolactoferrin (iron free lactoferrin) has greater antimicrobial activity than lactoferrin. Miehkle et al. (1996) found the antibacterial effect of human lactoferrin against Heiliobacteria pylori isolates from patients with duodenal ulcers was independent of the iron concentration in the medium. The antibacterial effect was both time and concentration dependent. Eichenbaum et al. (1996) found the group A streptococci were unable to utilize the iron from iron saturated lactoferrin, but could use intracellular iron sources (ferritin, hemin, hemoglobin, myoglobin) to cause tissue destruction during infection. In contrast, Grey-Owen and Schryvers (1996) reported that pathogenic members of the Neisseriaceae and Pasteurellaceae express outer membrane receptors for transferrin and lactoferrin for the purpose of direct assimilation of iron from the host protein. Immuno-modulation Lactoferrin possesses immunotropic properties with regard to immature T and B cells, by promoting phenotypic and functional maturation of these cells. Lactoferrin also controls the effector phase of cellular immune response and inhibits manifestation of autoimmune response in mice. (Adamik and Wiszczyk 1996). Mattsby-Baltzer et al. (1996) showed that both human lactoferrin and lactoferricin suppressed the interleukin-6 response in a monocytic cell line that was stimulated by lipopolysaccharide. Nam et al. (1994) reported that bovine lactoferrin had a immunosuppresive action on interleukin-1-beta, which was not observed with human lactoferrin. The antiviral activity of lactoferrin, when fed to mice prior to infection with murine cytomegalovirus, was found to be through the augmentation of NK cell activity. (Shimizu et al. 1996).
Peptide derivatives of Lactoferrin The action of pepsin on lactoferrin produces peptides that have enhanced antimicrobial action as compared to lactoferrin (Jones et al. 1994; Wakabayshi et al. 1994; Facon, 1996; Facon and Skura, 1996; Dionysius and Milne, 1997; Richter (1997) Tomita, et al, 1998; ). A peptide with 28 residues from the N-terminal of lactoferrin has been names lactoferricin B and has much stronger antibiotic activity than lactoferrin (Jones, et al. , 1994). Multiple peptides have been isolated from pepsin hydrolysates of lactoferrin, with varying microbial activities (Dionysius and Milne 1997; Richter, 1997). Dionysius and Milne (1997) isolated 3 peptides with different structures and activities. Peptide I had essentially the same structure as lactoferricin B. The three peptides displayed varying antibacterial activity against a number of different spoilage and pathogenic organisms. Peptide I was most effective against Listeria monocytongenes. Antimicrobial activity shown in media is lost in food products and inhibited by 5 mM calcium and bile salts (Facon, 1996; Falcon and Skura, 1996). Lactoferricin B has been shown also to be effective at concentrations as low as 3 ug/l against a number of different strains of yeasts and filamentous fungi (Bellamy et al. 1994) Konig et al. (1995) claimed an immuno-stimulating peptide derived from lactoferrin having the ability to modulate the release of inflammatory mediators from the cells of the immune system. References:Adamik, B and Walszczyk, A. (1996): [Lactoferrin: its role in defence against infection and immunotropic properties.] Postepy Higieny Medycyny Doswiadczalnej 50:33-41. Arnold, R.R., Cole, M. F. and McGhee, J. R. (1979) A bacteriocidal role for human lactoferrin. Sci. 197:784-787. Bayeye, S., Elass, E., Nazuruier, J., Spik, G. and Legrqnd, D. (1999) Lactoferrin, a multifuctional glycoprotein involved in the modulation of the inflammatory process. Clinical Chem and Lab. Med. 37:281-286. Bellamy, W., Yamauchi, K., Wakabayashi, H., Takakura, N., Shimamura, S. and Tomita, M (1994) Antifungal properties of lactoferricin B, a peptide derived from the N-terminal region of lactoferrin. Letters Appl. Microbiol. 18:230-233. Bockman, R. and Guidon, P. (1996) Methods of enhancing wound healing and tissue repair. U. S. Patent 5 556 645. Brock, J. (1995) Lactoferrin: a multifunctional immunoregulatory protein Immunol. Today. 16 (9): 417-419. Burrin, D.G., Wang, H., Heath, J., Dudley, M.A. (1996). Orally administered lactoferrin increases hepatic protein synthesis in formula for new-born pigs. Paediatric Res. 40(1):72-76. Burling, H. (1989) Process for extracting pure fractions of lactoperoxidase and lactoferrin from milk serum. International-Patent-Application WO 89/04608 A1. Conneely, O. M., Heason, D.R,. and O’Malley, B.W. (1996a) Production of recombinant lactoferrin and lactoferrin polypeptides using CDNA sequences in various organisms. U.S. Patent 5 571 691. Conneely, O. M., Heason, D.R., and O’Malley, B.W. (1996b) Expression of processed recombinant and lactoferrin polypeptide fragments from a fusion product in Aspergillus. U.S. Patent 5 571 697. Conneely, O. M., Heason, D.R., and O’Malley, B.W. (1996c) Production of recombinant human lactoferrin. U.S. Patent 5 571 896. Dionysius, D.A. and Milne, J.M. (1997) Actibacterial peptides of bovine lactoferrin: purification and characterization. J. Dairy Sci. 80:667-674. Drescher, K., Roos, N. and Hagemeister, H. (1996) [Biological activity and digestibility of lactoferrin.] Deutsche Milchwirschaft 47(7): 326-327. Ekstrand, B. (1994) Lactoperoxidase and lactoferrin. In: Natural AntimicrobialSystems and Food Preservation. (Dillon, V. D. and Board, R. G. eds) pp 15-63. CAB Intentional p 15 Ellison, R.T. and Giehl, T. G. (1991) Killing of Gram negative bacteria by lactoferrin and lysozyme.. J. Clin. Invest. 83:1980-1091. Ellison, R.T., La Rorce, F. M., Giehl, T.G., Boose, D.S. and Dunn, B.E. (1990) Lactoferrin and transferrin damage of Gram-negative outer membrane is modulated by calcium and magnesium ions. J.Gen. Microbiol. 106: 1437-1446. Facon, M.J. (1996) Antibacterial factors of cow’s milk and colostrom: immunoglobulin and lactoferrin. Dissert. Abs. B 56:4077. Facon, M. J. and Skura, B. J. (1996) Antibacterial activity of lactoferricin, lysozyme and EDTA against Salmonella enteritidis Int. Dairy J. 6:303-313 Feng, M., Van der Does, L. and Bantjes, A. (1995) Preparation of apolactoferrin with a very low iron saturation. J. Dairy Sci. 78(11):2352-2357. Giugliano, L.G., Ribeiro, S.T., Vainstein, M.H. and Ulhoa, C. J. (1995) Free secretory component and lactoferrin of human milk inhibit the adhesion of enterotoxigenic Eschericia coli. J. Med. Microbiol. 42:3-9. Grey-Owen, S.D. and Schryvers, A. B., (1996) Bacterial transferrin and lactoferrin receptors. Trends Microbiol 4:185-191. Jones. E.M., Smart, A., Bloomberg, G., Burgess, I., and Miller, M.R. (1994) Lactoferricin, a new antrimicrobial peptide. J. Appl. Microbiol 77:208-214. Kakuka, I. and Kurokura, H. (1995) Defensive effect of orally administered bovine lactoferrin agains Cryptocaryon irritans infection of red sea bream. Fish Pathology 30:289-290. Kawakami, H., Dosako, S. and Nakajima, I. (1993) Effect of lactoferrin on iron solubility under neutral conditions. Biosci.. Biotechnol. Biochem. 57:1376-1377. Kawasaki, Y., Isoda, H., Tanimoto, M., Dosako, S., Idota, T. and Ahiko, K. (1992) Inhibition by lactoferrin and kappa-casein glycomacropeptide of binding of Cholera toxin to its receptor. Bosci. Biotehnol. Biochem. 56:195-198. Kawasaki, Y., Isoda, H., Shinomoto, H., Tanimoto, M., Dosako, S., Idota, T. and Nakajima, I. (1993) Inhibition by ?-casein gl ycopetide and lactoferrin of influenza virus haemaggllutination. Biosci. Biotech. Biochem. 57:1214-1215.Kawasaki, Y., Isoda, H., Tanimoto, M., Dosako, S. and Ahiko, K. (1982) Inhibition by lactoferrin and ?-casein glycopetide of binding of cholera toxin to its receptor. Biosci. Biotech. Biochem. 56:195-198.Kussendrager, K. (1993) Lactoferrin and lactoperoxydase. Int. Food Ingred. 6:17-21. Kussendrager, K. (1995) Lactoferrin and lactoperoxydase bio-active milk proteins. Food-Tech-Europe; 2:39-43. Kusendrager, K.D., Kivits, M.G.C. and Verveer, A.B. (1997) Process for isolateing lactoferrin and lactoperoxidase from milk and milk products, and products obtained by such process. U. S. Patent 5 596 082. Ligo, M., Kuhara, T., Ushida, Y., Sekine, K., Moore M.A. and Tsuda, H. (1999) Inhibitory effect of bovine lactoferrin on colon carcinoma 26 lung metastasis in mice. Clinical and Exp. Metastasis 17:35-40. Lonnerdal, B. and Iyer, S. (1995) Lactoferrin: Molecular structure and biological function. Annual Rev. Nutr. 15:93-110. Marchetti, M., Longhim, C., Conte, M. P., Pisanti, S., Valenti, P. and Seganti, L. (1996) Lactoferrin inhibits herpes simplex virus type 1 adsorption to Vero cells. Antviral Res. 29:221-231. Mattsby-Baltzer, I.., Roseanu, A., Motas, C., Elveerfors, J., Engberg, I. and Hanson, L. A. (1996) Lactoferrin or a fragment thereof inhibits the endotoxin induced interleukin-6 response in human monocytic cells. Ped. Res. 40: 257-262 Miehlke, S., Reddy, R., Osato, M.S., Ward, P.P., Connellely, O.M. and Graham, D.Y. (1996) Direct activity of recombined human lactoferrin against Iheliobacteria pylori. J. Clin. Microbiol. 34:2593-2594. Miyauchi, H.],. Kaino, A., Shinoda, I., Fukuwatari, Y. and Hayasawa H. (1997) Immunomodulatory effect of bovine lactoferrin pepsin hydrolysate on murine splenocytes and Peyer's Patch cells. J. Dairy Sci. 80: 2330-2339. Nagasako, Y., Saito, H., Tamura, Y., Shimamura, S. and Tomita, M. (1993) Iron binding properties of bovine lactoferrin in iron rich solution. J. Dairy Sci. 76:1876-1881. Nam, M. S., Choe, I.S. and Lee, S.W. (1994) Studies on the physiological properties of lactoferrin III. Effect of the inhibition activity for interleuking-1 beta of lactoferrin. Korean J. Dairy Sci. 16:193-201. Nichols, B.L. and McKee, K.S. (1988) Lactoferrin as a dietary ingredient promoting the growth of the gastrointestinal tract. Eur. Pat. Appl 0 295 009 A2. Nichols, B.L. and McKee, K.S. (1990) Lactoferrin as a dietary ingredient promoting growth of the intestinal tract. U.S. Pat. 4 977 137 Quian, S.Y., Jolles, P., Migliore-Samour, D. and Fiat, A. M. (1995) Isolation and characterization of sheep lactoferrin, in inhibitor of platelet aggregation and comparison with human lactoferrin. Biochim. Biophys. Acta. 1243:25-32. Shimizu, K., Matsuzawa, H., Okada, K., Tazume, S., Dosako, S., Kawasaki, Y., Hashimoto, K. and Koga, Y. (1996) Lactoferrin-mediated protection of the host from murine cytomegalovirus infection by a T-cell dependent augmentation of natural killer cell activity. Archiv. Virol. 141: 1875-1889. Shinmoto, H., Dosako, S. and Nakajima, I (1992) Anti-oxidant activity of bovine lactoferrin on iron/ascorbate induce lipid peroxidation. Biosci. Biotechnol. Biochem. 56(12):2079-2080. Shinoda, I., Takase, M., Fukuwateri, Y., Shimamura, S., Koller, M. and Konig, W. (1996) Effect of lactoferrin and lactoferricin on the release of interleukcin 8 from human polymorphonuclear leukocytes. Biotechnol. Bioche, 60:521-523. Superti, F, Ammendolia, M.G., Valente, P and Seganti, L. (1997). Antiviral activity of milk proteins: lactoferrin prevents rotovirus infection in the enterocyte-like cell line HT-29. Med. Microbiol. Immunol. 186:83-91. Suzuki, T., Yaumauchi, K., Tomita, M., Kiosawa, I. and Okonogi, S. (1989) Collaborative bacteriostatic activity of bovine lactoferrin with lysozyme against E. coli 0111. Agr. Biol. Chem. 53:1705-1706. Swart, P.J., Kuipers., M.E., Smit, C., Van der Strate, B.W., Harmsen, M.C. and Meijer, D.K. (1998) Lactoferrin: Antiviral activity of lactoferrin. Adv. Exp. Med. Biol. 443:205-13. Tomita, S., Shirasaki, N., Hayashizaki, H., Matsuyama, J., Benno, Y. and Kiyosawa, I (1998) Binding characteristics of bovine lactoferrin to the cell surface of Cl.ostridia species and identification of the lactoferrin-binding siste. Biosci. Biotechnol. Biochem 62:1476-1482. Uchida, Y., Sekine, K, Kuhara, T., Takasuka, N., Ligo, M. and Tsuda, H. (1998) Inhibitory effects of bovine lactoferrin on intestianl polyposi in the Apc(min) mouse. Cancer Letters 134:141-145. Uchida, Y., Sekine, K., Kuhara, T., Takasuka, N., Ligo, M., Maeda, M. and Tsuda, H. (1999) Possible chemopreventative effects of bovine lactoferrin on esophagus and lung carcinogensis in the rat. Jap. J. Cancer Res. 90:262-267. Wakabayshi, H., Bellamy, W., Takase, M. and Tomito, M. (1994) Inactivation of Listeria monocytogenes by lactoferricin: a potent antimicrobial peptide dervided from cow’s milk. J. Food Protect. 55: 238-240. 1998-1999 References related to biological activities of lactoferrin Yamauchi-K; Teraguchi-S; Hayasawa-H 1999 Potential for usefulness of bovine lactoferrin in human beings Milk-Science; 48 (3) 227 Wakabayashi-H; Matsumoto-H; Hashimoto-K; Teraguchi-S; Takase-M; Hayasawa-H 1999 Inhibition of iron/ascorbate-induced lipid peroxidation by an N-terminal peptide of bovine lactoferrin and its acylated derivatives. Bioscience,-Biotechnology,-and-Biochemistry; 63 (5) 955-957 Huffman-LM; Harper-WJ 1999 Maximizing the value of milk through separation technologies Journal-of-Dairy-Science; 82 (10) 2238- Wakabayashi-H; Uchida-K; Yamaguchi-H 1999 In vitro and in vivo activities of lactoferrin against dermatophytes, with special respect to the effect of orally administered lactoferrin in the guinea pig model of dermatophytosis. Milk-Science; 48 (1) 45-49 Sanchez-MS; Watts-JL 1999 Enhancement of the activity of novobiocin against Escherichia coli by lactoferrin. Journal-of-Dairy-Science; 82 (3) 494-499 Murakami-A; Ohigashi-H; Koshimizu-K 1999 Chemoprevention: insights into biological mechanisms and promising food factors. Food-Reviews-International; 15 (3) 335-395 Venkitanarayanan-KS; Tong-Zhao; Doyle-MP 1999 Antibacterial effect of lactoferricin B on Escherichia coli O157:H7 in ground beef.Journal-of-Food-Protection; 62 (7) 747-750 McIntosh-GH; Royle-PJ; Leu-RKle; Regester-GO; Johnson-MA; Grinsted-RL; Kenward-RS; Smithers-GW 1998 Whey proteins as functional food ingredients? International-Dairy-Journal; 8 (5/6) 425-434. Tome-D; Debabbi-H 1998 Physiological effects of milk protein components. International-Dairy-Journal; 8 (5/6) 383-392 Bihel-S; Birlouez-Aragon-I 1998 Inhibition of tryptophan oxidation in the presence of iron-vitamin C by bovine lactoferrin. International-Dairy-Journal; 8 (7) 637-641 Potjewijd-R 1999 Lactoferrin, those extra benefits. World-of-Ingredients; Mar./April, 58 Nam-MS 1999 Biochemical properties of Korean native goat lactoferrin. Korean-Journal-of-Dairy-Science; 21 (1) 67-72, Shu-Wen-Huang; Satue-Gracia-MT; Frankel-EN; German-JB 1999 Effect of lactoferrin on oxidative stability of corn oil emulsions and liposomes. Journal-of-Agricultural-and-Food-Chemistry; 47 (4) 1356-1361, 44 ref. Chabance-B; Marteau-P; Rambaud-JC; Migliore-Samour-D; Boynard-M; Perrotin-P; Guillet-R; Jolles-P; Fiat-AM 1998 Casein peptide release and passage to the blood in humans during digestion of milk or yogurt. Biochimie-; 80 (2) 155-165 Ajello-M; Greco-R; Donnarumma-G; Palomba-M; Polidoro-M; Valenti-P 1998 The effect of bovine lactoferrin on the invasiveness of Listeria monocytogenes in cultured cells. Igiene-Moderna; 110 (6) 671-682 Nam-MS; Yu-DY; Shimazaki-K 1998 Comparison of antibacterial activities on Korean native goat, bovine, goat, sheep and horse lactoferrin. Korean-Journal-of-Dairy-Science; 20 (3) 223-228 Sujata-Sharma; Singh-TP; Bhatia-KL 1999 Preparation and characterization of the N and C monoferric lobes of buffalo lactoferrin produced by proteolysis using proteinase K. Journal-of-Dairy-Research; 66 (1) 81-90 Tomita-S; Shirasaki-N; Hayashizaki-H; Matsuyama-J; Benno-Y; Kiyosawa-I 1998 Binding characteristics of bovine lactoferrin to the cell surface of Clostridium species and identification of the lactoferrin-binding protein. Bioscience,-Biotechnology,-and-Biochemistry; 62 (8) 1476-1482
Tomita-S; Hagiwara-K; Matsuyama-J; Kiyosawa-I 1998Binding of lactoferrin to bacterial cells of the Clostridium species and their agglutination. Bioscience,-Biotechnology,-and-Biochemistry; 62 (8) 1471-1475 Tome-D; Ledoux-N 1998 Nutritional and physiological role of milk protein components. Bulletin-of-the-International-Dairy-Federation; No. 336, Dairy foods in health., 11-16 Qiu-J; Hendrixson-DR; Baker-EN; Murphy-TF; StGeme-JW III; Plaut-AG 1998 Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae. Proceedings-of-the-National-Academy-of-Sciences-of-the-United-States-of-America; 95 (21) 12641-12646 Nordmark-B 1998 Dairy foods in health. Food-Technology-in-New-Zealand; 33 (4) 11 Boehles-H; Gebhardt-B; Beeg-T 1998 Reflections about possible nutritional supplements in infant milk formula. Zeitschrift-fuer-Ernaehrungswissenschaft; 37 (2) 132-146 Kim-JW; Lee-JY; Keum-JS; Yu-DY 1997 A study on changes in antibacterial activity of bovine apo-lactoferrin at various method for pasteurizations and pH values. Korean-Journal-of-Dairy-Science; 19 (3) 201-212 Debbabi-H; Dubarry-M; Rautureau-M; Tome-D 1998 Bovine lactoferrin induces both mucosal and systemic immune response in mice. Journal-of-Dairy-Research; 65 (2) 283-293 Klont-R; Mannion-P 1998 Nutritionals. The final frontier. World-of-Ingredients; March/April, 39-40, 42, 44 1999-2001 LACTOFERRIN Lactoferrin
continues to be the protein in whey that receives the most attention as a
bioactive component with multiple functions.
Shimazaki (2000) has provided an up-to-date review of the role of
lactoferrin in respect to its multiple suggested health benefits, including:
iron transport, antimicrobial activity, antimicrobial peptide derived from
lactoferrin, antiviral activity, bioactive peptides derived from lactoferrin,
anti-inflammatory, immunomodulatory properties, anti-cancer activities,
antioxidant activity, cell growth-promoting activity and regulation of myelopoiesis.
Recent references relating to the bioactive properties of lactoferrin
include: General Mannie E (2000) Deconstructing milk.
Prepared Foods 169(6):NS6, NS8. Murakami A, Ohigashi H & Koshimizu K (1999) Chemo prevention: insights into biological
mechanisms and promising food factors. Food Reviews International 15(3):335-395. Potjewijd R (1999) Lactoferrin, those extra benefits. World of Ingredients Mar./April,
58. Ohr LM (2000) A fresh look at food safety. Prepared Foods 169(5):51-52, 54, 58, 60. Shimazaki K (2000) Lactoferrin: a marvelous protein in milk? Animal Science Journal 71(4):329-347. Shimazaki
K, Tazume
T, Uji
K, Tanaka
M, Kumura
H, Mikawa
K & Shimo-Oka
T(1998) Properties of a heparin-binding peptide derived from bovine
lactoferrin.
Journal-of-Dairy-Science;
81 (11) 2841-2849. Spik
G, Legrand D, Mazuier J, Pierce A & Perrauden JP (editors) (1998) Advances
in lactoferrin research. In Advances in Experimental Medicine and Biology
Volume 443. Plenum Press, New York. Steijns JM & Hooijdonk ACM van (2000) Occurence,
structure, biochemical properties and technological characteristics of
lactoferrin. British Journal of Nutrition 84
(Supplement 1): 11-17 Yamauchi K, Teraguchi S & Hayasawa H (1999) : Potential for usefulness of bovine lactoferrin in human
beings. Milk Science 48(3):227-232. Yamauchi K, Toida T, Nishimura S, Nagano E, Kusuoka O, Teraguchi S, Hayasawa H, Shimamura S & Tomita M (2000) 13-week oral repeated administration toxicity
study of bovine lactoferrin in rats. Food and Chemical Toxicology
38(6):503-512. Anticancer Iigo
M, Kuhara T, Ushida Y, Sekine K, Moore MA & Tsuda H (1999) Inhibitory effect
of bovine lactoferrin on colon carcinoma: 26 lung metastasis in mice. Clinical
and Experimental Metastasis 17(1):43-49. Norrby
K, Mattsby-Baltzer I, Innocenti M & Tuneberg S (2001) Orally administered
bovine lactoferrin inhibits VEGF165mediate angigensis in the rat.
International Journal of Cancer 91(1):236-240. Tsuda
H, Sekine K, Ushida Y, Kuhara T, Takasuka N and Iigo M (2000) Milk and dairy
products in cancer prevention: focus on bovine lactoferrin. Research/Reviews in
Mutation Research 462(2):227-233. Ushida,
Y, Sekine K, Kahara T, Takasuka N & Iigo M & Tsuda H (1998) Inhibitory
effects of bovine lactoferrin on intestinal polyposis in the Apcmin
mouse. Cancer Letters 134:141-145. Ushida,
Y, Sekine K, Kahara T, Takasuka N & Iigo M & Tsuda H (1999) Possible
chemo preventative effects of bovine lactoferrin on esophagus and lung
carcinogensis by bovine lactoferrin administration in F344 rats. Japanese
Journal of Cancer Research 88:523-526. Antimicrobial Ajello
M, Greco
R, Donnarumma
G, Palomba
M Polidoro
M & Valenti
P (1998) The effect of bovine lactoferrin on the invasiveness of
Listeria monocytogenes in cultured cells. Igiene
Moderna 110(6):671-682. Chantaysakorn P & Richter RL (2000) Antimicrobial properties of pepsin-digested
lactoferrin added to carrot juice and filtrates of carrot juice. Journal of Food Protection 63(3):376-380. Groenink J, Walgreen-Weterings E, Hof W van 't, Veerman ECI & Nieuw-Amerongen AV (1999) Cationic amphipathic peptides,
derived from bovine and human lactoferrins, with antimicrobial activity against
oral pathogens. FEMS Microbiology Letters 179(2):217-222, 20. Kawasaki Y, Tazume S, Shimizu K, Matsuzawa H, Dosako S, Isoda H, Tsukiji M, Fujimura R , Muranaka Y & Isihida H (2000) Inhibitory effects of bovine lactoferrin on
the adherence of enterotoxigenic Escherichia coli to host cells. Bioscience, Biotechnology and Biochemistry
64(2):348-354. Marinez-Gomez J, Ferandez-Solanas A, Vinas M & Gonzales P
(1999) Effects of topical application of free and liposome-encapsulated
lactoferrin and lactoperoxidasse on oral microbiota and dental carries in rats.
Archives of Oral Biology 44(11):901-906. Recio, I & Visser S (2000) Antibacterial and binding
characteristics of bovine and caprine lactoferrin: a comparative study.
International Dairy Journal 10(9):597-605. Rekdal O, Anderson J, Vorland LH & Svendsen JS (1999)
Construction and synthesis of lactoferrin derivative with enhanced antimicrobial
activity. Journal of Peptide Science 5(1):32-45. Sanchez MS & Watts JL (1999) Enhancement of the activity of novobiocin
against Escherichia coli by lactoferrin. Journal of Dairy Science 82(3):494-499. Tomito S (1998a) Binding of lactoferrin to bacterial cells of
the Clostridium species and their agglutination. Bioscience, Biotechnology and Biochemistry 62:1471-1475. Tomito S (1998b) Binding characteristics of bovine lactoferrin
to the cell surface of Clostridium species and identification of the
lactoferrin-binding protein. Bioscience, Biotechnology and
Biochemistry 62:1176-1492. Tomita
S, Shirasaki
N, Hayashizaki
H, Matsuyama
J, Benno
Y & Kiyosawa
I (1998) Binding characteristics of bovine lactoferrin to the cell
surface of Clostridium species and identification of the lactoferrin-binding
protein.
Bioscience, Biotechnology and Biochemistry 62(8):1476-1482. Valenti P, Greco R, Pitari G, Rossi P, Ajello M & Milna G
(1999) Apitosis of Caco-2 intestinal cells invaded by Listeria monocytogenes:
Protective effect of lactoferrin. Experimental Cell Research 250 (1) 197-202. Venkitanarayanan KS, Tong Zhao & Doyle MP (1999) Antibacterial effect of lactoferricin B on
Escherichia coli O157:H7 in ground beef. Journal of Food Protection 62(7):747-750. Antiviral Hanson LA, Lonnroth I, Lange S, Bjersing J & Dahlgren-UI (2000) Nutrition resistance to viral propagation. Nutrition Reviews 58(2,
Part 2): S31-S37. Ikeda M, Nozaki A, Sgiyama K, Tanaka T, Naganuma A &
Katsaki K (2000) Characterization of antiviral activity of lactoferrin against
hepatitis C virus infection in human cultured cells. Virus Research 66(1):
51-53. Ikeda
M, Sugiyama K, Tanaka T, Tanaka K, Sekihara H,Shimotohno K,and Kato N. (1998)
Lactoferrin markedly inhibits
hepatitis C virus infection in cultured human hepatocytes.
Biochem.Biophys.Res.Com. 245:549-553. Ikeda M, Sugiyama K, Tanaka T, Nozaki A, Naganuma A, Tanaka K, Sekihara H, Shimotohno K, Saito M and Kato N (2000) : Antiviral activity of lactoferrin against HIV infection in human cultured cells : Lactoferrin, Structure, Function and Application. Shimazaki S, eds. Elsevier Science pp225-232. Marchetti M, Superti F, Amenedolia MG, Rossi P & Valenti P
(1999) Inhibition of poliovirus type I by iron, magnesium and zinc saturated
lactoferrin. Medical Microbiology
and Immunology 187(4):199-204. Murphy ME, Kariwa H, Mizutani T, Yoshimatsu K, Arikawa J &
Takashima I (2000) In vitro antiviral activity of lactoferrin and ribavirin upon
hantavirus. Archives of Virology 145 (8):1571-1582. Puddau P, Borghi P, Gessani S, Valenti P, Belardelli F &
Seganti L (1998) Antiviral effect of bovine lactoferrin saturated with metal
ions on early steps of human immunodeficiency virus type I infection. The
International Journal of Biochemistry and Cell Biology 30(9):1055-1063 Tanaka
K, Ikeda M, Nozaki A, Kato N, Tsuda H, Saito S and Sekihara H. (1999)
Lactoferrin inhibits hepatitis C virus viremia in patients with chronic
hepatitis C - A pilot studyJapanese Journal of Virus Research 90:367-371. Antioxidative
effects Satue-Gracia MT, Frankel EN, Nagendra Rangavajhyala & German JB (2000) Lactoferrin in infant formulas: effect on
oxidation. Journal of Agricultural and Food Chemistry 48(10):4984-4990. Shuen Huang, Satue-Gracia MT, Frankel EN & German JB (1999) Effect of lactoferrin on oxidative stability
of corn oil emulsions and liposomes. Journal of Agricultural and Food Chemistry 48(10):1356-1361. Wakabayashi H, Matsumoto H, Hashimoto K, Teraguchi S, Takase M & Hayasawa H (1999) Inhibition of iron/ascorbate-induced lipid
peroxidation by an N-terminal peptide of bovine lactoferrin and its acylated
derivatives. Bioscience, Biotechnology and-Biochemistry
63(5):955-957. Immunomodulation Debbabi
H, Dubarry
M, Rautureau
M & Tome
D (1998) Bovine lactoferrin induces both mucosal and systemic immune
response in mice. Journal
of Dairy Research 65(2):283-293. Lygren B, Sveir H, Hjeltes B & Waagbe R (1999) Examination
of the immunomodulatory properties and the effect on disease resistance of
dietary bovine lactoferrin and vitamin C fed to Atlantic salmon (Salmo salar)
for a short-term period. Fish and Shellfish Immunology 9(2):95-107. Miyauchi
H, Hashimoto S, Nakajima M, Shinoda I & Yasuo Y (1998) Bovine lactoferrin
stimulates the phagocytic activity of human neutrophils: Identification of its
active domain. Cellular Immunology
187(1):34-37. Miyauchi
H, Kaino
A, Shinoda
I, Fukuwatari
Y & Hayasawa
H (1997) Immunomodulatory effect of bovine lactoferrin pepsin
hydrolysate on murine splenocytes and Peyer's Patch cells. Journal
of Dairy Science 80(10):2330-2339. Insulin-like growth factor Baumrucker CR & Erondu NE (2000) Insulin-like growth
factor (IGF) in the bovine mammary gland and milk. Journal of Mammary gland
Biology and Neoplasia 5(1):53-64. Iron transport Jiang DM, Li YH & Zhao ZM (1999) The research on effects of iron-saturated lactoferrin on iron absorption. China Dairy Industry 27(1):22-25, 43. Links to Lactoferrin products and further information: http://www.iherb.com/lactoferrin.html http://www.askpeak.com/colpluslacch.html http://www.myvitanet.com/altmedcollac.html http://search.msn.com/results.asp?RS=CHECKED&FORM=MSNH&v=1&TK=2&q=lactoferrin http://www.colostrumdirect.com/ http://store.yahoo.com/iherb/lactoferrin1.html
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