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Laktoferin

Abe H, Saito H, Miyakawa H, et al. (1991) Heat stability of bovine lactoferrin at acidic pH. Journal of Dairy Science. 74:65-71.

Andersson, Y, et al. Lactoferrin is responsible for the fungistatic effect of human milk. Early Human Development 59:95-105 (2000). Lactoferrin, through its iron-binding ability, is very effective against fungal infections with Candida and other fungi.

Applemelk BJ, An YQ, Geerts M, et al. (1994) Lactoferrin is a lipid A-binding protein. Infection and Immunity. 62:2628-2632.

Baker EN, Anderson BF, Baker HM, et al. (1994) Three-dimensional structure of lactoferrin in various functional states. Lactoferrin: Structure and Function. 1-12.

Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K, Tomita M. (1992) Identification of the bactericidal domain of lactoferrin. Biochemica Biophys Acta. 1121:130-136.

Bellamy, W., et al. Identification of the bactericidal domain of lactoferrin. Journal of Applied Bacteriology. 73:472-479, (1992).

Buchta R. (1991) Ovine lactoferrin: Isolation from colostrum and characterization. Journal of Dairy Research. 211-218.

Drobni, P, Naslund, J, Evander, M. (2004). Lactoferrin inhibits human papillomavirus binding and uptake in vitro. Antiviral Research 64(1):63-8. Human papillomavirus (HPV) causes genital warts and is a prerequisite for cervical cancer. Lactoferrin blocked entry of the virus into cells in vitro, most likely by competing for binding sites. Bovine lactoferrin was a more potent inhibitor of the virus than human lactoferrin.

Edde, L, et al. Lactoferrin protects neonatal rats from gut-related systemic infection. American Journal of Physiology: Gastrointestinal Liver Physiology 281:G1140-G1150 (2001). Lactoferrin protected neonatal rats from E. coli infection in the intestines. Lactoferrin plus lysozyme was bactericidal against the E. coli.

Fujita, K, et al. Down-regulation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in rats. Japanese Journal of Cancer Research 93(6):616-625 (2002). The mechanism of action of bovine lactoferrin on down regulating the expression of carcinogenic agents is explored.

Gahr, M, et al. Influence of lactoferrin on the function of human polymorphonuclear leukocytes and monocytes. Journal of Leukocyte Biology 49(5):427-433 (1991). White blood cells (polymorphonuclear leucocytes) exposed to lactoferrin from bovine colostrum exhibit increased motility and produce more superoxide (a powerful antioxidant).

Griffiths, CE, et al. Exogenous topical lactoferrin inhibits allergen-induced Langerhans cell migration and cutaneous inflammation in humans. British Journal of Dermatology 144(4):715-725 (2001). Lactoferrin influences inflammation inhibiting Langerhans cell migration, normally controlled by TNF-a and IL-1ß, which are inhibited by lactoferrin.

Gutteridge J, Paterson S, Segal A, Halliwell B. Inhibition of lipid peroxidation by the iron-binding protein lactoferrin. Biochem. Journal. 199:259-261.
Haridas M, Anderson BF, Baker HM, Norris GE, Baker EN. (1994) X-ray structure analysis of bovine lactoferrin at 2.5 Angstrom resolution. Lactoferrin: Structure and Function. pg235-238.

Harmsen MC, Swart PJ, de Bethune MP, et al. (1995) Antiviral effects of plasma and mild proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. Journal of Infectious Diseases. 172:380-388.

Hasegawa, K, et al. Inhibition with lactoferrin of in vitro infection with human herpes virus. Japanese Journal of Medical Science and Biology 47:73-85 (1994). Both human and bovine lactoferrin inhibit infection with human herpes simplex virus and human cytomegalovirus in cell cultures.

Hayashida, K, Takeuchi, T, Ozaki, T, Shimizu, H, Ando, K, Miyamoto, A, Harada, E. (2004). Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 286(2):R359-65. Bovine lactoferrin has a hypotensive effect via an endothelium- dependent vasodilation that is strongly mediated by NO production.

Iigo, M, et al. Inhibitory effects of bovine lactoferrin on colon carcinoma 26 lung metastasis in mice. Clinical and Experimental Metastasis 17(1):35-40 (1999). Lactoferrin increased levels of cytotoxic white blood cells and inhibited metastasis to the lung in experimentally induced colon cancer in mice.

Iigo, M, et al. Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: a possible explanation for inhibition of carcinogenesis and metastasis. Cytokine 25(1):36-44 (2004). Oral lactoferrin administration increased the production of IL-18 by intestinal epithelial cells followed by increases in caspase-1 and INF-g, which potentiate the activity of cytotoxic lymphocytes and natural killer cells in attacking cancer cells.

Ikeda M, Sugiyama K, Tanaka T, et al. (1998) Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes. Biochemical and biophysical research communications 245:549-553.

Jenssen, H, Andersen, JH, Uhlin-Hansen, L, Gutteberg, TJ, Rekdal, O. (2004). Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate. Antiviral Research 61(2):101-109. It has been shown that bovine lactoferricin (a biologically active peptide derived from lactoferrin) blocks herpes simplex virus (HSV) binding by competing for receptor (heparin sulfate) sites on target cells. However, this is apparently not the only mechanism that accounts for the anti-HSV activity of lactoferricin. Hydrophobicity, molecular size, spatial distribution of charged and lipophilic amino acids, and the ring structure of lactoferricin also seem to be important factors.

Kawakami H. (1988) Effects of iron-saturated Lactoferrin on iron absorption. Agric. Biol. Chem. 52:903-908.

Kuhara, T, et al. Orally administered lactoferrin exerts an antimetastatic effect and enhances production of IL-18 in the intestinal epithelium. Nutrition and Cancer 38(2):192-199 (2000). A similar study on the protective effects of lactoferrin supplementation on protecting from lung metastasis in experimentally induced colon cancer. In addition to the increase in cytotoxic cells seen in other studies, there was also an increase in IL-18 production in the intestinal epithelium, suggesting it plays a role in mediating the inhibition of the cancers.

Kimber, I, et al. Lactoferrin: influences on Langerhans cells, epidermal cytokines, and cutaneous inflammation. Biochemistry and Cell Biology 80(1):103-107 (2002). Apart from its modulation anti-inflammatory cytokines, lactoferrin also expresses an anti-inflammatory effect through controlling the migration of epidermal Langerhans cells. Lactoferrin inhibited the migration of these cells when the skin was exposed to an irritant, thus decreasing the inflammatory response.

Kussendrager KD. Effects of heat treatment on structure and iron-binding capacity of bovine lactoferrin. Indigenous Antimicrobial Agents of Milk - Recent Developments 133-146.

Kwiat G. (1998) Lactoferrin. NutriCology in Focus.

Levay PF, Viljoen M. (1980) Lactoferrin: A general review. Haematologica. 3:252-267.

Li Y, Tan A, Vlassara T, Vlassara H. (1995) Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif. Nature Medicine. 1(10):1057-61.

Lonnerdal B, Lyer S. (1995) Lactoferrin: molecular structure and biological function. Annual Review of Nutrition. 15:93-110.

Masuda, C, et al. Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis. Japanese Journal of Cancer Research 91:582-588 (2000). Bovine lactoferrin also prevented the development of bladder cancer in another experimental animal system.

Masaaki I, and et al. (1999) Inhibitory effects of bovine lactoferrin on colon carcinoma 26 lung metastasis in mice. Clinical and Experimental Metastasis. 17:35-40.

Mikogami T. (1995) Effect of intracellular iron depletion by picolinic acid on expression of the lactoferrin receptor in the human colon carcinoma cell sub-clone HT29-18-C1. Biochemistry Journal. 308:391-397.

Petschow B, Talbott R, Batema R. (1999) Ability of lactoferrin to promote the growth of Bifidobacterium spp. in vitro is independent of receptor binding capacity and iron saturation level. Journal of Microbiology. 48:541-549.
Polla B. (1999) Therapy by taking away: The case of iron. Biochemical Pharmacology. 57:1345-1349.

Qiu, J, et al. Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae. Proceedings of the National Academy of Sciences USA 95:12641-12646 (1998). Lactoferrin prevents colonization of Haemophilus influenzae, the primary cause of otitis media and other respiratory infections in children, by inactivating two colonization factors expressed by the bacteria.

Saito H, Miyakawa H, Tamura Y, Shimamura S, Tomita M. (1991) Potent bactericidal activity of bovine lactoferrin hydrolysate produced by heat treatment at acidic pH. Journal of Dairy Science. 74:3724-3730.

Samaranayake, YH, et al. Antifungal effects of lysozyme and lactoferrin against genetically similar, sequential Candida albicans isolates from a human immunodeficiency virus-infected Southern Chinese cohort. Journal of Clinical Microbiology 39(9):3296-3302 (2001). Lactoferrin plus lysozyme is very effective in killing nearly all oral strains of Candida, which is of particular importance to AIDS sufferers who are often unable to fight off Candida overgrowths, such as thrush.

Shin K, Yamauchi K, Teraguchi S, et al. (1998) Antibacterial activity of bovine lactoferrin and its peptides against enterohaemorrhagic E. coli O157:H7. Letters in Applied Microbiology. 26:407-411.

Tinari, A, Pietrantoni, A, Ammendolia, MG, Valenti, P, Superti, F. (2005). Inhibitory activity of bovine lactoferrin against echovirus induced programmed cell death in vitro. International Journal of Antimicrobial Agents 25(5):433-8. Cells infected with echovirus 6 die as a result of apoptosis (programmed cell death). Lactoferrin inhibits this effect.

Thaler C, Labarrer C, Hunt J, McIntyre J, Faulk P. (1999) Unique epitopes of lactoferrin expressed in human cytotrophoblasts involved in immunologic reactions. Am J Obstet Gynecol. 181(2):460-7.

Viani RM, Gutteberg TJ, Lathey JL, Spector SA. (1999) Lactoferrin inhibits HIV-1 replication in vitro and exhibits synergy when combined with zidovudine. AIDS. 13:1273-4.

Tsuda, H, et al. Prevention of colon carcinogenesis and carcinoma metastasis by orally administered bovine lactoferrin in animals. BioFactors 12:83-88 (2000). In an experimental animal study, supplementation with bovine lactoferrin showed significant protection from development of cancerous tumors in the colon as well as protection against lung metastasis. Administration of the lactoferrin was accompanied by marked increases in cytotoxic white blood cells in the blood.

Tanaka, T, et al. Chemopreventive effect of bovine lactoferrin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Japanese Journal of Cancer Research 91(1):25-33 (2000). The same effect of lactoferrin was found in an experimental tongue cancer system.

Ushida, Y, et al. Possible chemopreventive effects of bovine lactoferrin on esophagus and lung carcinogenesis in the rat. Japanese Journal of Cancer Research 90:262-267 (1999). Lactoferrin was also found to protect the esophagus and the lung from experimental cancer induction.

Tsuda, H, et al. Milk and dairy products in cancer prevention: focus on bovine lactoferrin. Mutation Research 462(2-3):227-233 (2000). In addition to the protection provided by lactoferrin against the development of cancers, conjugated linoleic acid (CLA) also plays an inhibitory role on cancer development.

Tsuda, H, et al. Cancer prevention by bovine lactoferrin and underlying mechanisms-a review of experimental and clinical studies. Biochemistry and Cell Biology 80(1):131-136 (2002). Lactoferrin supplementation in experimental animal models of colon cancer show that it also suppresses phase I enzymes, such as cytochrome P450 1A2, by cancer cells, while enhancing the activity of phase II enzymes, such as glutathione S-transferase, both of which act to inhibit the development of these cancers. Lactoferrin also boosts local and systemic immunity, particularly the activity of cytotoxic lymphocytes and natural killer cells in the intestinal mucosa and peripheral blood, which in turn stimulates the production of IL-18 and caspase-1 in intestinal epithelial cells and possibly the appearance of interferon-gamma (INF-g) positive cells. Bovine lactoferrin was also found to have anti-hepatitis C activity. Chronic hepatitis due to infection with hepatitis C virus is a major causative factor in the development of hepatocellular carcinoma.

Vorland L, Ulvatne H, Andersen J, et al. (1999) Antibacterial effects of lactoferricin B. Scandinavian Journal of Infected Disease. 31:179-184.
Yamauchi K, Tomita M, Giehl TJ, Ellison RT. Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infection and Immunity. 61:719-728, (1993).

van der Strate, BW, et al. Antiviral activities of lactoferrin. Antiviral Research 52(3):225-239 (2001). Lactoferrin is effective against both DNA and RNA viruses, including rotavirus, respiratory syncytial virus, herpes virus and HIV, both by blocking cellular receptors and by directly binding to the viruses.

Ward, PP, et al. Lactoferrin and host defense. Biochemistry and Cell Biology 80(1):95-102 (2002). Lactoferrin is a prominent component of the first line of defense against infection and inflammation. It accomplishes its activity through a variety of methods, most notably iron sequestration and its effect on down-regulating TNF-a, which controls the inflammatory cascade.

Zagulski T, Jarzabek Z, Zagulska A, Zimecki M. (1998) The main systemic, highly effective mechanisms generated by lactoferrin in mammals in vitro. Advances in Lactoferrin Research. 443:247-50.

Zimecki, M, Spiegel, K, Wlaszczyk, A, Kubler, A, Kruzel, ML. (1999). Lactoferrin increases the output of neutrophil precursors and attenuates the spontaneous production of TNF-alpha and IL-6 by peripheral blood cells. Archivum Immunologiae et Therapie Experimentalis 47(2):113-118. Lactoferrin supplementation profoundly decreased the product of TNF-alpha and IL-6 (pro-inflammatory cytokines) in blood cultures while causing a transient increase of immature neutrophils in the blood.

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