Colostrum Research

Lactoferrin

 

Abe H, Saito H, Miyakawa H, Tamura Y, Shimamura S, Nagao E, Tomita M. Heat stability of bovine lactoferrin at acidic pH. Journal of Dairy Science. 74:65-71 (1991). Pasteurizing lactoferrin at pH 4.0 preserves its activity.


Andersen JH, Jenssen H, Gutteberg TJ.   Lactoferrin and lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit synergy when combined with acyclovir.  Antiviral Research 58(3):209-215 (2003).  When used against HSV-1 and -2, the combination of lactoferrin or its peptide lactoferricin with acyclovir demonstrated good synergy.  The effective dosage of both lactoferrin and acyclovir could be reduced 2-7 times.

PubMed Reference    PMID:12767468


Andersson Y, Lindquist S, Lagerqvist C, Hernell O.   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.

PubMed Reference    PMID:10996747


Appelmelk BJ, An YQ, Geerts M, Thijs BG, de Boer HA, MacLaren DM, de Graaff J, Nuijens JH. Lactoferrin is a lipid A-binding protein. Infection and Immunity. 62:2628-2632 (1994). Lactoferrin binds to lipopolysaccharides (LPS) secreted as endotoxin by pathogenic bacteria such as E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Neisseria meningitides,and Haemophilus influenzae, all dangerous pathogens. It also binds to lipid A, a component of LPS. This appears to be one of the ways in which lactoferrin expresses its antibacterial and anti-endotoxic effects.

PubMed Reference    PMID: 94245381


Arnold D, Di Biase AM, Marchetti M, Pietrantoni A, Valenti P, Seganti L, Superti F. Antiadenovirus activity of milk proteins: lactoferrin prevents viral infection.  Antiviral Research 53(2):153-158 (2002).  Lactoferrin prevented viral infection by adenovirus when added before or during the viral adsorption stage.

PubMed Reference    PMID:11750941


Artym J, Zimecki M.  [The role of lactoferrin in the proper development of newborns]  Postepy Higieny i Medycyny Doświadczalnej 59:421-432 (2005).  Lactoferrin has an immunotropic effect on the newborn, stimulating both local and systemic immune responses.  It also plays a role in the absorption of nutrients, particular metal ions such as iron, manganese and zinc.  It stimulates the proliferation of gut endothelial cells and gut-associated lymphatic follicles.  In addition, it controls the proper composition of gut flora, suppressing the growth of pathogenic bacteria while promoting the growth and colonization of beneficial bacteria.

PubMed Reference    PMID:16106243


Artym J.  [Antitumor and chemopreventive activity of lactoferrin]  Postepy Higieny i Medycyny Doświadczalnej 60:352-369 (2006).  Lactoferrin has direct anti-tumor activity, including lytic (causes tumor cells to burst), pro-apoptotic (causes programmed cell death of tumor cells), anti-proliferative, anti-angiogenic (prevents the growth of blood vessels into the tumor), anti-oxidant and chemopreventive properties.

PubMed Reference    PMID:16885906


Baker EN, Anderson BF, Baker HM, Day CL, Haridas M, Norris GE, Rumball SV, Smith CA, Thomas DH. Three-dimensional structure of lactoferrin in various functional states. Lactoferrin: Structure and Function. 1-12 (1994). The three dimensional structure of lactoferrin is important in its function.

PubMed Reference    PMID:7762421


Baveye S, Elass E, Mazurier J, Spik G, Legrand D. Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process.  Clinical Chemistry and Laboratory Medicine 37(3):281-286 (1999). Lactoferrin modulates the inflammatory process mainly by preventing the release of cytokines from monocytes and by regulating the proliferation and differentiation of immune cells.  It is also prophylactic against septicemia.  Lactoferrin is one of the key molecules which modulate the inflammatory response.

PubMed Reference    PMID:10353473


Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K, Tomita M. Identification of the bactericidal domain of lactoferrin. Biochemica et Biophysica Acta 1121(1-2):130-136 (1992). A domain near the N-terminus of lactoferrin appears to be responsible for the bactericidal activity of lactoferrin.

PubMed Reference    PMID:1599934


Beaumont SL, Maggs DJ, Clarke HE. Effects of bovine lactoferrin on in vitro replication of feline herpes virus.  Veterinary Ophthalmology 6(3):245-250 (2003).  Bovine lactoferrin has a notable inhibitory effect on the in vitro replication of feline herpes virus prior to and during viral adsorption, but not after.  It appears that the lactoferrin blocks adsorption to the cell surface and/or penetration of the virus into the cell.

PubMed Reference    PMID:12950656


Britigan BE, Serody JS, Cohen MS.  The role of lactoferrin as an anti-inflammatory molecule.  Advances in Experimental Medicine and Biology 357:143-156 (1994).  The iron-lactoferrin complex can both promote and inhibit free radical production by neutrophils and monocytes.  Generally it plays an anti-inflammatory role in infections.

PubMed Reference    PMID:7762426


Britigan BE, Lewis TS, Waldschmidt M, McCormick ML, Krieg AM.   Lactoferrin binds CpG-containing oligonucleotides and inhibits their immunostimulatory effects on human B cells.  Journal of Immunology 167(5):2921-2928 (2001).  Unmethylated CpG dinucleotide motifs in bacterial DNA, as well as oligodeoxynucleotides (ODN) containing these motifs, are potent stimuli for many host immunological responses.  These CpG motifs may enhance host responses to bacterial infection and are being examined as immune activators for therapeutic applications in cancer, allergy/asthma, and infectious diseases.  Lactoferrin and lactoferricin B, but not transferrin, inhibited CpG ODN stimulation of CD86 expression in the human Ramos B cell line and decreased cellular uptake of ODN, a process required for CpG bioactivity.  Lactoferrin binding of CpG-containing ODN may serve to modulate and terminate host response to these potent immunostimulatory molecules at mucosal surfaces and sites of bacterial infection.

PubMed Reference    PMID:11509640


Buchta R. Ovine lactoferrin: Isolation from colostrum and characterization. Journal of Dairy Research 58(2):211-218 (1991). Lactoferrin was isolated from sheep colostrum and was found to have 80% homology with human lactoferrin.

PubMed Reference    PMID:1856354


Dial EJ, Hall LR, Serna H, Romero JJ, Fox JG, Lichtenberger LM.  Antibiotic properties of bovine lactoferrin on Helicobacter pylori.  Digestive Diseases and Sciences 43(12):2750-2756 (1998).  Lactoferrin was bacteriostatic against H. pylori when cultured at concentrations ≥0.5 mg/ml.  Neither lysozyme or lactoferricin B (a metabolite of lactoferrin) inhibited the growth of H. pylori, but the iron chelator deferoxamine mesylate also did.  The bacteriostatic action of lactoferrin could be reversed by adding excess iron to the medium, indicating lactoferrin inhibited growth by competing for free iron, necessary for the growth of many bacteria.

PubMed Reference    PMID:9881510


Drobni P, Naslund J, Evander M. (2004)  Lactoferrin inhibits human papilloma virus binding and uptake in vitro.  Antiviral Research 64(1):63-68.  Lactoferrin, particularly bovine lactoferrin, blocks entry of human papilloma virus (HPV) into target cells in vitro.  HPV has been implicated in the development of cervical and other cancers.

PubMed Reference    PMID:15451180


Ellison RT III, Giehl TJ.  Killing of gram-negative bacteria by lactoferrin and lysozyme.  Journal of Clinical Investigation 88(4):1080-1091 (1991).  Lactoferrin alters the outer membrane of Gram-negative bacteria, allowing lysozyme to enter the cells and cause lysis, which kills the bacteria.  Both lactoferrin and lysozyme are found in high concentrations in mucosal secretions and neutrophil granules, suggesting they are integral to host defense.

PubMed Reference    PMID:1918365


Elrod, KC, Moore WR, Abraham WM, Tanaka RD. Lactoferrin, a potent tryptase inhibitor, abolishes late-phase airway responses in allergic sheep.  American Journal of Respiratory Critical Care Medicine 156(2 Pt 1):375-381 (1997).  Lactoferrin released from neutrophil granules inhibits tryptase, which is involved in late-phase bronchoconstriction and airway hyperactivity in asthma.

PubMed Reference    PMID:9279212


Erhardt G, Meyer F, Senft B.  Growth inhibition of Staphylococcus aureus after experimental infection of the udder by high and low concentration of lactoferrin and lysozyme in milk.  Acta Microbiologica Polonica 30(3):239-246 (1981).  The ability of cows to defend against Staphylococcus aureus infection was found to directly correlated to the lysozyme concentration in their udders.

PubMed Reference    PMID:6174025


Florisa R, Recio I, Berkhout B, Visser S. Antibacterial and antiviral effects of milk proteins and derivatives thereof. Current Pharmaceutical Design 9(16):1257-1275 (2003). The action of digestive enzymes on milk and colostrum activates antibacterial and antiviral activities of a number of proteins in milk and colostrum, including lactoferrin, lactoperoxidase, and lysozyme.  Of these, only lactoferrin has antiviral activity against HIV and HCMV.

PubMed Reference    PMID:12769735


Gahr M, Speer CP, Damerau B, Sawatzki G. 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).

PubMed Reference    PMID:1849951


Gutteridge J, Paterson S, Segal A, Halliwell B. Inhibition of lipid peroxidation by the iron-binding protein lactoferrin. Biochem. Journal 199(1):259-261 (1981). Lactoferrin is an inhibitor of lipid peroxidation induced by iron and ascorbic acid. Therefore lactoferrin as an antioxidant may help to protect neutrophils, inflammatory foci and secretions from metal-ion-dependent oxidative damage.

PubMed Reference    PMID:7337708


Hara K, Ikeda M, Saito S, Matsumoto S, Numata K, Kato N, Tanaka K, Sekihara H. Lactoferrin inhibits hepatitis B virus infection in cultured human hepatocytes.  Hepatology Research 24(3):228 (2002).  Bovine lactoferrin prevents infection of cultured human liver cells with hepatitis B virus, while transferrin, casein and lactalbumin had no effect.

PubMed Reference    PMID:12393024


Haridas M, Anderson BF, Baker HM, Norris GE, Baker EN. X-ray structure analysis of bovine lactoferrin at 2.5 Ångstrom resolution. Lactoferrin: Structure and Function pp 235-238 (1994). High resolution X-ray crystallography revealed the two dimensional structure of lactoferrin.

PubMed Reference    PMID:7762437


Harmsen MC, Swart PJ, de Bethune MP, Pauwels R, De Clercq E, The TH, Meijer DK. Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. Journal of Infectious Diseases. 172(2):380-388 (1995). Lactoferrin from bovine or human milk and colostrum completely blocks Human Cytomegalus Virus (CMV) infection and inhibited HIV-1-induced cytopathic effect. It appears to exert its effect at the level of virus adsorption and penetration (or both).

PubMed Reference    PMID:7622881


Hasegawa K, Motsuchi W, Tanaka S, Dosako S. Inhibition with lactoferrin of in vitro infection with human herpes virus. Japanese Journal of Medical Science and Biology 47(2):73-85 (1994). Both human and bovine lactoferrin inhibited human herpes simplex virus-1 in vitro.

PubMed Reference    PMID:7853749


Hashizume S, Kuroda K, Murakami H. Identification of lactoferrin as an essential growth factor for human lymphocytic cell lines in serum-free medium.  Biochimica et Biophysica Acta 763(4):377-382 (1983).  Lactoferrin is an essential growth factor for lymphocytes.  It has higher growth stimulatory activity than transferrin.  Bovine lactoferrin was found to be as effective as human.

PubMed Reference    PMID:6652116


Hayashida K, Takeuchi T, Ozaki T, Shimizu H, Ando K, Miyamoto A, Harada E.   Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats.  American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 286(2):R359-R365 (2004).  Bovine lactoferrin has a hypotensive effect via an endothelium- dependent vasodilation that is strongly mediated by NO production.

PubMed Reference    PMID:14563657


Hayashida K, Kaneko T, Takeuchi T, Shimizu H, Ando K, Harada E.   Oral administration of lactoferrin inhibits inflammation and nociception in rat adjuvant-induced arthritis.  Journal of Veterinary Medical Science 66(2):149-154 (2004).  Lactoferrin is an immunomodulator and has also been found to produce micro-opioid receptor-mediated analgesia.  In an rat experimental arthritis model, bovine lactoferrin suppressed the development of the arthritis and lessened the pain (as determined by hyperalgesia of the infected paw).  Lactoferrin also suppressed TNF-alpha (pro-inflammatory) production and increased IL-10 (anti-inflammatory) production.  Thus lactoferrin has both preventive and therapeutic effects on both the inflammation and pain associated with arthritis.

PubMed Reference    PMID:15031542


Iigo M, Kuhara T, Ushida Y, Sekine K, Moore MA, Tsuda H. Inhibitory effects of bovine lactoferrin on colon carcinoma 26 lung metastasis in mice. Clinical and Experimental Metastasis. 17(1):35-40 (1999).  Bovine lactoferrin exhibited significant inhibition of lung metastatic colony formation from implanted tumors in mice. AsialoGM+1 and CD8+ cell levels increased after treatment with the lactoferrin, suggesting they play a role in tumor inhibition.

PubMed Reference    PMID:10390145


Ikeda M, Sugiyama K, Tanaka T, Tanaka K, Sekihara H, Shimotohno K, Kato N.  Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes. Biochemical and biophysical research communications 245(2):549-553 (1998). Bovine lactoferrin effectively prevented infection with Hepatitis C virus in cultured human hepatocytes (liver cells), which are very susceptible to infection with the virus. Lactoferrin may prove to be very effective in the treatment of patients with chronic hepatitis, and it is very well tolerated.

PubMed Reference    PMID:9571193


Jenssen H, Andersen JH, Uhlin-Hansen L, Gutteberg TJ, Rekdal O.   Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate.  Antiviral Research 61(2):101-109 (2004).  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.

PubMed Reference    PMID:14670583


Jenssen H. Anti-herpes simplex virus activity of lactoferrin/lactoferricin – an example of antiviral activity of antimicrobial protein/peptide.  Cellular and Molecular Life Sciences 62(24):3002-3013 (2005).  Lactoferrin and a peptide derived from lactoferrin, lactoferricin, block entry of HSV into cells.

PubMed Reference    PMID:16261265


Kawakami H. Effects of iron-saturated Lactoferrin on iron absorption. Agricultural and Biological Chemistry 52(4):903-908 (1988). Iron absorption was studied in iron-deficient anemic rats. Rats fed iron-saturated lactoferrin showed statistically significant increases in red blood cell density, hematocrit and hemoglobin values compared to rats receiving ferrous sulfate. This suggests that iron from iron-saturated lactoferrin is absorbed across the intestinal mucosa by a mechanism other than that used by soluble ferrous sulfate.


Kawasaki Y, Isoda H, Shinmoto H, Tanimoto M, Dosako S, Idota T, Nakajima I.   Inhibition by kappa-casein glycomacropeptide and lactoferrin of influenza virus hemagglutination.  Bioscience, Biotechnology, and Biochemistry 57(7):1214-1215 (1993).  Lactoferrin inhibits the hemagglutination (clumping of blood cells) of the influenza virus.  Hemagglutination inhibition is one of the tests which show the effectiveness of influenza vaccines.

PubMed Reference    PMID:7763995


Kruzel M, Bacsi A, Choudhury B, Sur S, Boldogh I. Lactoferrin decreases pollen antigen-induced allergic airway inflammation in a murine model of asthma.  Immunology 119(2):159-166 (2006).  Pollen grains contain reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and in contact with mucosal surfaces generate superoxide anion (O2*-). In the presence of iron, O2*- may be converted to more reactive oxygen radicals, such as to H2O2 and/or *OH, which may augment antigen-induced airway inflammation. LF lowered the increase in cellular reactive oxygen species (ROS) levels in bronchial epithelial cells. The results suggest the utility of LF in human allergic inflammatory disorders.

PubMed Reference    PMID:16800860


Kuhara T, Yamauchi K, Tamura Y, Okamura H. Oral administration of lactoferrin increases NK cell activity in mice via increased production of IL-18 and type I IFN in the small intestine.  Journal of Interferon and Cytokine Research 26(7):489-499 (2006).  Orally administered bovine lactoferrin increases NK cell populations in blood and spleen and enhances interferon-gamma production.  It also increases the production of IL-18 and increases the production of interferon-alpha and interferon-beta in the Peyer's Patches in the intestines and mesenteric lymph nodes.

PubMed Reference    PMID:16800788


Kussendrager KD. Effects of heat treatment on structure and iron-binding capacity of bovine lactoferrin. Indigenous Antimicrobial Agents of Milk - Recent Developments, International Dairy Foundation pp 133-146, 2003. As heat treatment of lactoferrin derived from milk and colostrum may impair its bioactive state and functionality, it is necessary to determine the optimum conditions of pH, salts and whey protein to achieve optimal conditions for pasteurization.


Kwiat G. Lactoferrin. NutriCology in Focus pp 1-13 (1998). Lactoferrin influences many disease processes from cancer to immune deficiency in addition to its normal bodily functions such as the transport of iron.

Levay PF, Viljoen M. Lactoferrin: A general review. Haematologica 3:252-267 (1980). Receptors for lactoferrin can be found on intestinal tissue, monocytes and macrophages, neutrophils, lymphocytes, platelets, and on certain bacteria.

PubMed Reference    PMID:7672721


Li YM, Tan A, Vlassara T, Vlassara H. Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif. Nature Medicine. 1(10):1057-1061 (1995). Diabetes is associated with abnormally high sensitivity to infection. Lysozyme and lactoferrin, two major antibacterial antibodies found in colostrum and milk, specifically bind glucose-modified proteins with advanced glycation end-products (AGE). AGE is elevated in tissues and serum of diabetic patients which may inhibit antibacterial proteins by binding to them, thus increasing susceptibility to infection.

PubMed Reference    PMID:7489363


Lonnerdal B, Iyer S. Lactoferrin: molecular structure and biological function. Annual Review of Nutrition 15:93-110 (1995). Lactoferrin functions are tied to both its iron-binding capability as well as other functions, such as a growth factor and bactericidal agent.

PubMed Reference    PMID:8527233


Lonnerdal B.  Nutritional and physiologic significance of human milk proteins.  American Journal of Clinical Nutrition 77(6):1537S-1543S (2003).  Lactoferrin is a milk protein with immunomodulatory effects.

PubMed Reference    PMID:12812151


Marchetti M, Pisani S, Antonini G, Valenti P, Seganti L, Orsi N. Metal complexes of bovine lactoferrin inhibit in vitro replication of herpes simplex virus type 1 and 2.  Biometals 11(2):89-94 (1998).  Bovine lactoferrin saturated with iron, manganese or zinc proved strongly inhibitory to viral replication of herpes simplex virus types 1 and 2 in cell cultures (Vero).

PubMed Reference    PMID:9542061


Marchetti M, Superti F, Ammendolia MG, Rossi P, Valenti P, Seganti L. Inhibition of poliovirus type 1 infection by iron-, manganese- and zinc-saturated lactoferrin.  Medical Microbiology and Immunology 187(4):199-204 (1999). The actions of human and bovine lactoferrin on the infection of Vero cell cultures by poliovirus type 1 were compared to other milk proteins, including mucin, alpha-lactalbumin and beta-lactoglobulin.  Only the lactoferrins were able to inhibit infection by blocking attachment to the cells.  Only lactoferrin combined with zinc was able to inhibit infection after the stage of attachment.

PubMed Reference    PMID:10363676


McCann KB, Lee A, Wan J, Roginski H, Coventry MJ.   The effect of bovine lactoferrin and lactoferricin B on the ability of feline calicivirus (a norovirus surrogate) and poliovirus to infect cell cultures.  Journal of Applied Microbiology 95(5):1026-1033 (2003).  Lactoferrin interfered with the infection of cells by both feline calicivirus and poliovirus.

PubMed Reference    PMID:14633031


Mikogami T, Marianne T, Spik G. Effect of intracellular iron depletion by picolinic acid on expression of the lactoferrin receptor in the human colon carcinoma cell subclone HT29-18-C1. Biochemistry Journal. 308:391-397 (1995). Picolinic acid, an iron chelator, was used to deplete intracellular iron in a cell culture. This was followed by an increase in the synthesis of lactoferrin receptors in the cells, resulting in a 30% increase in iron uptake by the cells.

PubMed Reference    PMID:7772018


Murphy ME, Kariwa H, Mizutani T, Tanabe H, Yoshimatsu K, Arikawa J, Takashima I.   Characterization of in vitro and in vivo antiviral activity of lactoferrin and ribavirin upon hanta virus.  Journal of Veterinary Medicine and Science 63(6):637-645 (2001).  Lactoferrin alone or ribavirin alone significantly inhibited hantavirus focus formation in vitro.  When combined, the two completely inhibited focus formation.  Lactoferrin inhibits adsorption of the virus to cells, and ribavirin inhibits viral protein synthesis.

PubMed Reference    PMID:11459009


Ng TB, Lam TL, Au TK, Ye XY, Wan CC. Inhibition of human immunodeficiency virus type 1 reverse transcriptase, protease and integrase by bovine milk proteins.  Life Science 69(19):2217-2223 (2001).  Lactoferrin strongly inhibits HIV-1 reverse transcriptase and slightly inhibited HIV-1 protease and integrase, enzymes which are crucial to the HIV-1 life cycle.

PubMed Reference    PMID:11669464


Nozaki A, Ikeda M, Naganuma A, Nakamura T, Inudoh M, Tanaka K, Kato N. Identification of a lactoferrin-derived peptide possessing binding activity to hepatitis C virus E2 envelope protein.  Journal of Biological Chemistry 278(12):10162-73 (2003).  Both human and bovine lactoferrin prevent hepatitis C infection in vitro.  A peptide in the lactoferrin molecule has been shown to a viral envelope protein, by which it apparently blocks the viral particles from binding to target cells.

PubMed Reference    PMID:12522210


Ohashi A, Murata E, Yamamoto K, Majima E, Sano E, Le QT, Katunuma N. New functions of lactoferrin and beta-casein in mammalian milk as cysteine protease inhibitors.  Biochemistry and Biophysics Research Communications 306(1):98-103 (2003).  Lactoferrin inhibits cathepsin L (a cysteine protease inhibitor), an activity which is dependent on the tertiary structure of lactoferrin.  A peptide of lactoferrin shows 90% homology with the sequences of a common active site of cystatins.

PubMed Reference    PMID:12788072


Petschow B, Talbott R, Batema R. 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 (1999). Lactoferrin promotes the growth of beneficial bacteria, such as bifidobacteria, while inhibiting the growth of pathogenic bacteria. This study showed that the promotion of growth of bifidobacteria by lactoferrin is not correlated to the iron saturation level of the lactoferrin, and binding of lactoferrin to bifidobacteria, while it may occur, is not sufficient for stimulation of bifidobacterial growth.

PubMed Reference    PMID:10359303


Pietrantoni A, Di Biase AM, Tinari A, Marchetti M, Valenti P, Seganti L, Superti F. Bovine lactoferrin inhibits adenovirus infection by interacting with viral structural polypeptides. Antimicrobial Agents and Chemotherapy 47(8):2688-2691 (2003) .  In addition to competeing for common receptors on target cells, lactoferrin also neutralizes infection by adenovirus by binding to adenovirus particles, specifically viral III and IIIa polypeptides.

PubMed Reference    PMID:12878543


Pietrantoni A, Ammendolia MG, Tinari A, Siciliano R, Valenti P, Superti F.  Bovine lactoferrin peptidic fragments involved in inhibition of Echovirus 6 in vitro infection.  Antiviral Research 69(2):98-106 (2006).  Lactoferrin inhibits Echovirus 6 infection by blocking viral attachment to cell receptors, possibly due to the cluster of positive charges at its N-terminus.

PubMed Reference    PMID:16386316


Polla B. Therapy by taking away: The case of iron. Biochemical Pharmacology. 57:1345-1349 (1999). Iron deprivation has been shown to have a beneficial effect on muscle necrosis in an animal model of genetic myopathy. It is proposed that taking away of iron, such as with lactoferrin, may also have a beneficial effect on other diseases with a free radical component, and may also have an antioxidant effect that could be important in anti-aging.

PubMed Reference    PMID:10353254


Qiu J, Hendrixson DR, Baker EN, Murphy TF, St Geme JW III, Plaut AG. 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.

PubMed Reference    PMID:9770539


Saito H, Miyakawa H, Tamura Y, Shimamura S, Tomita M. Potent bactericidal activity of bovine lactoferrin hydrolysate produced by heat treatment at acidic pH. Journal of Dairy Science 74(11):3724-3730 (1991). Heat treatment at acidic pH produces a fragment of lactoferrin with antibacterial properties at only 10µg/ml. This indicates that antibacterial domains of lactoferrin have no relation to iron saturation.

PubMed Reference    PMID:1757616


Seganti L, Di Biase AM, Marchetti M, Pietrantoni A, Tinari A, Superti F.   Antiviral activity of lactoferrin towards naked viruses.  Biometals 17(3):295-299 (2004).  Lactoferrin is a well-known potent inhibitor of naked viruses, including rotavirus, enterovirus, and adenovirus.  Lactoferrin is especially potent against viruses which replicate in the gastrointestinal system as it is resistant to tryptic digestion.  Against rotavirus, it prevents viral attachment to the gastrointestinal wall by binding to viral particles, and it inhibits a post adsorption step.  Lactoferrin interferes with an early infection step of the polio virus, and iron-saturated lactoferrin inhibits viral replication after the adsorption phase.

PubMed Reference    PMID:15222481


Shau H, Kim A, Golub SH. Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin.  Journal of Leukocyte Biology 51(4):343-349 (1992).  Lactoferrin strongly augments the cytotoxic functions of natural killer (NK) cells and lymphokine-activated killer (LK) cells.  Newborn infants have low NK and LK activity so lactoferrin may ‘turn on’ these cells in the infant.

PubMed Reference    PMID:1564398


Shimizu K, Matsuzawa H, Okada K, Tazume S, Dosako S, Kawasaki Y, Hashimoto K, Koga Y. Lactoferrin-mediated protection of the host from murine cytomegalovirus infection by a T-cell-dependent augmentation of natural killer cell activity.  Archives of Virology 141(10):1875-1889 (1996).  Lactoferrin protected mice from cytomegalovirus infection.  The mechanism of action was apparently through the stimulation of NK cell activity, as athymic nude mice showed no increase in NK cell activity and no protection against cytomegalovirus infection.

PubMed Reference    PMID:8920822


Shin K, Yamauchi K, Teraguchi S, Hayasawa H, Tomita M, Otsuka Y, Yamazaki S. Antibacterial activity of bovine lactoferrin and its peptides against enterohaemorrhagic E. coli O157:H7. Letters in Applied Microbiology. 26(6):407-411 (1998). E. coli O157:H7, a form of E. coli that causes gastrointestinal bleeding, is susceptible to the antibacterial effects of lactoferrin and its peptides.

PubMed Reference    PMID:98383038


Shin K, Wakabayashi H, Yamauchi K, Teraguchi S, Tamura Y, Kurokawa M, Shiraki K. Effects of orally administered bovine lactoferrin and lactoperoxidase on influenza virus infection in mice.  Journal of Medical Microbiology 54(Pt8):717-723 (2005).  Mice infected with influenza virus were given either lactoferrin (LF) or lactoperoxidase (LPO) by mouth.  While neither eliminated the virus, both caused a significantly lower lung consolidation score on day 6 (compared to control), significantly lower numbers of infiltrated leukocytes from bronchoalveolar lavage, and significantly lower levels of IL-6, a pro-inflammatory cytokine, indicating that both LF and LPO were effective in treating the pneumonia associated with the influenza.

PubMed Reference    PMID:16014423


Superti F, Ammendolia MG, Valenti P, Seganti L. Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29.  Medical Microbiology and Immunology (Berlin) 186(2-3):83-91 (1997).  Beta-lactoglobulin, apo- and iron-saturated lactoferrin inhibit rotaviral infection in a dose-dependent manner.  Apo-lactoferrin prevents both rotavirus hemagglutination and viral binding to susceptible cells.  It also markedly inhibits rotavirus antigen synthesis when added during the virus adsorption step.

PubMed Reference    PMID:9403835


Swart PJ, Kuipers EM, Smit C, Pauwels R, de Bethune MP, De Clercq E, Meijer DK, Huisman JG. Antiviral effects of milk proteins: acylation results in polyanionic compounds with potent activity against human immunodeficiency virus types 1 and 2 in vitro. AIDS Research and Human Retroviruses 12(9):769-775 (1996). Lactoferrin and negatively charged peptides derived from lactoferrin all showed strong antiviral activity against HIV-1 and HIV-2.

PubMed Reference    PMID:8738428


Swart PJ, Kuipers EM, Smit C, van der Strate BW, Harmsen MC, Meijer DK. Lactoferrin. Antiviral activity of lactoferrin. Advances in Experimental and Medical Biology 443:205-413 (1998). Lactoferrin has antiviral activity against Human Immunodeficiency Virus (HIV) and Human Cytomegalovirus (HCMV).

PubMed Reference    PMID:9781360


Swart PJ, Harmsen MC, Kuipers EM, Van Dijk AA, van der Strate BW, Van Berkel PH, Nuijens JH, Smit C, Witvrouw M, De Clercq E, de Bethune MP, Pauwels R, Meijer DK. Charge modification of plasma and milk proteins results in antiviral active compounds. Journal of Peptide Science 5(12):563-576 (1999). Lactoferrin has known antiviral activity against HIV and HCMV.  Increasing the negative charge of lactoferrin through amylation or amination increases its antiviral activity.

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Tanaka T, Nakatani S, Xuan X, Kumura H, Igarashi I, Shimazaki K.   Antiviral activity of lactoferrin against canine herpes virus.  Antiviral Research 60(3):193-199 (2003).  Bovine lactoferrin inhibits both the infection and replication of canine herpes virus in vitro.

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Thaler C, Labarrere C, Hunt J, Mcintyre J, Faulk P. Unique epitopes of lactoferrin expressed in human cytotrophoblasts involved in immunologic reactions. American Journal of Obstetrics and Gynecology 181(2):460-467 (1999). Cytotrophoblasts of the placenta expressed a unique form of lactoferrin in the presence of activated macrophages. This may be a response to inflammation and maternal allogenic recognition.

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Tinari A, Pietrantoni A, Ammendolia MG, Valenti P, Superti F.   Inhibitory activity of bovine lactoferrin against echovirus induced programmed cell death in vitro.  International Journal of Antimicrobial Agents 25(5):433-438 (2005).  Cells infected with echovirus 6 die as a result of apoptosis (programmed cell death).  Lactoferrin inhibits this effect.

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Valenti P, Marchetti M, Superti F, Amendolia MG, Puddu P, Gessani S, Borghi P, Belardelli F, Antonini G, Seganti L. Antiviral activity of lactoferrin.  Advances in Experimental and Medical Biology 443:199-203 (1998).

PubMed Reference    PMID:9781359


van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK.   Antiviral activities of lactoferrin.  Antiviral Research 52(3):225-239 (2001).  Lactoferrin has antiviral activity against both DNA and RNA viruses, including respiratory syncytial virus, herpes virus, rotavirus and HIV.  Its mechanism of action is mainly to block entry of the virus into target cells, either by blocking receptors on target cells or directly binding to virus particles.

PubMed Reference    PMID:11675140


van der Strate BW, De Boer FM, Bakker HI, Meijer DK, Molema G, Harmsen MC. Synergy of bovine lactoferrin with the anti-cytomegalovirus drug cidofovir in vitro.  Antiviral Research 58(2):159-165 (2003).  Combining lactoferrin with acyclovir or foscarnet resulted in antagonism, lactoferrin and ganciclovir showed neither antagonism or synergy, but lactoferrin with cidofovir showed marked synergy against cytomegalovirus.

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Viani RM, Gutteberg TJ, Lathey JL, Spector SA. Lactoferrin inhibits HIV-1 replication in vitro and exhibits synergy when combined with zidovudine.  AIDS 13(10):1273-1274 (1999).  Lactoferrin in combination with zidovudine is more effective than either alone in inhibiting HIV-1 replication.

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Vorland L, Ulvatne H, Andersen J, Haukland HH, Rekdal O, Svendsen JS, Gutteberg TJ. Antibacterial effects of lactoferricin B. Scandinavian Journal of Infected Disease 31:179-184 (1999). Lactoferricin is produced by cleaving the lactoferrin protein. Lactoferricin was found to maximum effect against bacteria when it did not have to act through a cell wall.

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Waarts BL, Aneke OJ, Smit JM, Kimata K, Bittman R, Meijer DK, Wilschut J.  Antiviral activity of human lactoferrin: inhibition of alpha virus interaction with heparan sulfate.  Virology 333(2):284-292 (2005).  Lactoferrin inhibits viral infection by alphaviruses (Sindbis and Semliki Forest) by interfering with virus-receptor interaction.

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Ward PP, Uribe-Luna S, Conneely OM.  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-α, which controls the inflammatory cascade.

PubMed Reference    PMID:11908649


Weinberg ED.  Human lactoferrin: a novel therapeutic with broad spectrum potential.  Journal of Pharmacy and Pharmacology 53(10):1303-1310 (2001).  Lactoferrin is a broad spectrum antimicrobial with antibacterial, antimycotic, antiviral, antineoplastic and anti-inflammatory activity.

PubMed Reference    PMID:11697537


Weng TY, Chen LC, Shyu HW, Chen SH, Wang JR, Yu CK, Lei HY, Yeh TM.  Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells.  Antiviral Research 67(1):31-37 (2005).  Lactoferrin binds to host cells, preventing enterovirus 71 from attaching to them.  It also interferes with the virus by binding to its VP1 protein.

PubMed Reference    PMID:15916817


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). Lactoferrin and lactoferricin damage the outer membranes of gram-negative bacteria. Lactoferricin also has direct bactericidal activity by the formation of "membrane blisters" on the bacteria.

PubMed Reference    PMID:8423097


Zagulski T, Jarzabek Z, Zagulska A, Zimecki M. The main systemic, highly effective, and quickly acting antimicrobial mechanisms generated by lactoferrin in mammals in vivo. Activity in health and disease. Advances in Lactoferrin Research. 443:247-250 (1998).  Review of the principal ways lactoferrin defends against pathogens.

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Zimecki M, Spiegel K, Wlaszczyk A, Kubler A, Kruzel ML. 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 (1999).  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.

PubMed Reference    PMID:10202564

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