|, GIG12, HEL110, HLF2, LF, lactotransferrin|
|View/Edit Human||View/Edit Mouse|
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMN and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum ("first milk") has the highest concentration, followed by human milk, then cow milk (150 mg/L).
Lactoferrin is one of the components of the immune system of the body; it has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses. In particular, lactoferrin provides antibacterial activity to human infants. Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.
- 1 History
- 2 Structure
- 3 Function
- 4 Clinical Significance
- 5 Nanotechnology
- 6 See also
- 7 References
- 8 External links
Occurrence of iron-containing red protein in bovine milk was reported as early as in 1939; however, the protein could not be properly characterized because it could not be extracted with sufficient purity. Its first detailed studies were reported around 1960. They documented the molecular weight, isoelectric point, optical absorption spectra and presence of two iron atoms per protein molecule. The protein was extracted from milk, contained iron and was structurally and chemically similar to serum transferrin. Therefore, it was named lactoferrin in 1961, though the name lactotransferrin was used in some earlier publications, and later studies demonstrated that the protein is not restricted to milk. The antibacterial action of lactoferrin was also documented in 1961, and was associated with its ability to bind iron.
Genes of lactoferrin
At least 60 gene sequences of lactoferrin have been characterized in 11 species of mammals. In most species, stop codon is TAA, and TGA in Mus musculus. Deletions, insertions and mutations of stop codons affect the coding part and its length varies between 2,055 and 2,190 nucleotide pairs. Gene polymorphism between species is much more diverse than the intraspecific polymorphism of lactoferrin. There are differences in amino acid sequences: 8 in Homo sapiens, 6 in Mus musculus, 6 in Capra hircus, 10 in Bos taurus and 20 in Sus scrofa. This variation may indicate functional differences between different types of lactoferrin.
In humans, lactoferrin gene LTF is located on the third chromosome in the locus 3q21-q23. In oxen, the coding sequence consists of 17 exons and has a length of about 34,500 nucleotide pairs. Exons of the lactoferrin gene in oxen have a similar size to the exons of other genes of the transferrin family, whereas the sizes of introns differ within the family. Similarity in the size of exons and their distribution in the domains of the protein molecule indicates that the evolutionary development of lactoferrin gene occurred by duplication. Study of polymorphism of genes that encode lactoferrin helps selecting livestock breeds that are resistant to mastitis.
Lactoferrin is one of the transferrin proteins that transfer iron to the cells and control the level of free iron in the blood and external secretions. It is present in the milk of humans and other mammals, in the blood plasma and neutrophils and is one of the major proteins of virtually all exocrine secretions of mammals, such as saliva, bile, tears and pancreas. Concentration of lactoferrin in the milk varies from 7 g/L in the colostrum to 1 g/L in mature milk.
X-ray diffraction reveals that lactoferrin is based on one polypeptide chain that contains about 700 amino acids and forms two homologous globular domains named N-and C-lobes. N-lobe corresponds to amino acid residues 1–333 and C-lobe to 345–692, and the ends of those domains are connected by a short α-helix. Each lobe consists of two subdomains, N1, N2 and C1, C2, and contains one iron binding site and one glycosylation site. The degree of glycosylation of the protein may be different and therefore the molecular weight of lactoferrin varies between 76 and 80 kDa. The stability of lactoferrin has been associated with the high glycosylation degree.
Lactoferrin belongs to the basic proteins, its isoelectric point is 8.7. It exists in two forms: iron-rich hololactoferrin and iron-free apolactoferrin. Their tertiary structures are different; apolactoferrin is characterized by "open" conformation of the N-lobe and the "closed" conformation of the C-lobe, and both lobes are closed in the hololactoferrin.
Each lactoferrin molecule can reversibly bind two ions of iron, zinc, copper or other metals. The binding sites are localized in each of the two protein globules. There, each ion is bonded with six ligands: four from the polypeptide chain (two tyrosine residues, one histidine residue and one aspartic acid residue) and two from carbonate or bicarbonate ions.
Lactoferrin forms reddish complex with iron; its affinity for iron is 300 times higher than that of transferrin. The affinity increases in weakly acidic medium. This facilitates the transfer of iron from transferrin to lactoferrin during inflammations, when the pH of tissues decreases due to accumulation of lactic and other acids. The saturated iron concentration in lactoferrin in human milk is estimated as 10 to 30% (100% corresponds to all lactoferrin molecules containing 2 iron atoms). It is demonstrated that lactoferrin is involved not only in the transport of iron, zinc and copper, but also in the regulation of their intake. Presence of loose ions of zinc and copper does not affect the iron binding ability of lactoferrin, and might even increase it.
Both in blood plasma and in secretory fluids lactoferrin can exist in different polymeric forms ranging from monomers to tetramers. Lactoferrin tends to polymerize both in vitro and in vivo, especially at high concentrations. Several authors found that the dominant form of lactoferrin in physiological conditions is a tetramer, with the monomer:tetramer ratio of 1:4 at the protein concentrations of 10−5 M.
It is suggested that the oligomer state of lactoferrin is determined by its concentration and that polymerization of lactoferrin is strongly affected by the presence of Ca2+ ions. In particular, monomers were dominant at concentrations below 10−10−10−11 M in the presence of Ca2+, but they converted into tetramers at lactoferrin concentrations above 10−9−10−10 M. Titer of lactoferrin in the blood corresponds to this particular "transition concentration" and thus lactoferrin in the blood should be presented both as a monomer and tetramer. Many functional properties of lactoferrin depend on its oligomeric state. In particular, monomeric, but not tetrameric lactoferrin can strongly bind to DNA.
Lactoferrin belongs to the innate immune system. Apart from its main biological function, namely binding and transport of iron ions, lactoferrin also has antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, and anti-allergic functions and properties.
Enzymatic activity of lactoferrin
Lactoferrin hydrolyzes RNA and exhibits the properties of pyrimidine-specific secretory ribonucleases. In particular, by destroying the RNA genome, milk RNase inhibits reverse transcription of retroviruses that cause breast cancer in mice. Parsi women in West India have the milk RNase level markedly lower than in other groups, and their breast cancer rate is three times higher than average. Thus, ribonucleases of milk, and lactoferrin in particular, might play an important role in pathogenesis of diseases caused by various retroviruses.
The lactoferrin receptor plays an important role in the internalization of lactoferrin; it also facilitates absorption of iron ions by lactoferrin. It was shown that gene expression increases with age in the duodenum and decreases in the jejunum. The moonlighting glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been demonstrated to function as a receptor for lactoferrin.
Ribonuclease-enriched lactoferrin has been used to examine how lactoferrin affects bone. Lactoferrin has shown to have positive effects on bone turnover. It has aided in decreasing bone resorption and increasing bone formation. This was indicated by a decrease in the levels of two bone resorption markers (deoxypyridinoline and N-telopeptide) and an increase in the levels two bone formation markers (osteocalcin and alkaline phosphatase). It has reduced osteoclast formation, which signifies a decrease in pro-inflammatory responses and an increase in anti-inflammatory responses  which indicates a reduction in bone resorption as well.
Interaction with nucleic acids
One of the important properties of lactoferrin is its ability to bind with nucleic acids. The fraction of protein extracted from milk, contains 3.3% RNA, besides, the protein preferably binds to the double-stranded than to the single-stranded DNA. The ability of lactoferrin to bind DNA is used for the isolation and purification of lactoferrin using affinity chromatography with columns containing immobilized DNA-containing sorbents, such as agarose with the immobilized single-stranded DNA.
Lactoferrin's primary role is to sequester free iron, and in doing so remove essential substrate required for bacterial growth. Antibacterial action of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to lipopolysaccharide of bacterial walls, and the oxidized iron part of the lactoferrin oxidizes bacteria via formation of peroxides. This affects the membrane permeability and results in the cell breakdown (lysis).
Although lactoferrin also has other antibacterial mechanisms not related to iron, such as stimulation of phagocytosis, the interaction with the outer bacterial membrane described above is the most dominant and most studied. Lactoferrin not only disrupts the membrane, but even penetrates into the cell. Its binding to the bacteria wall is associated with the specific peptide lactoferricin, which is located at the N-lobe of lactoferrin and is produced by in vitro cleavage of lactoferrin with another protein, trypsin. A mechanism of the antimicrobial action of lactoferrin has been reported as lactoferrin targets H+-ATPase and interferes with proton translocation in the cell membrane, resulting in a lethal effect in vitro.
Lactoferrin prevents the attachment of H. pylori in the stomach, which in turn, aids in reducing digestive system disorders. Bovine lactoferrin has more activity against H. pylori than human lactoferrin.
Lactoferrin acts, mostly in vitro, on a wide range of human and animal viruses based on DNA and RNA genomes, including the herpes simplex virus 1 and 2, cytomegalovirus, HIV, hepatitis C virus, hantaviruses, rotaviruses, poliovirus type 1, human respiratory syncytial virus and murine leukemia viruses.
The most studied mechanism of antiviral activity of lactoferrin is its diversion of virus particles from the target cells. Many viruses tend to bind to the lipoproteins of the cell membranes and then penetrate into the cell. Lactoferrin binds to the same lipoproteins thereby repelling the virus particles. Iron-free apolactoferrin is more efficient in this function than hololactoferrin; and lactoferricin, which is responsible for antimicrobial properties of lactoferrin, shows almost no antiviral activity.
Beside interacting with the cell membrane, lactoferrin also directly binds to viral particles, such as the hepatitis viruses. This mechanism is also confirmed by the antiviral activity of lactoferrin against rotaviruses, which act on different cell types.
Lactoferrin also suppresses virus replication after the virus penetrated into the cell. Such an indirect antiviral effect is achieved by affecting natural killer cells, granulocytes and macrophages – cells, which play a crucial role in the early stages of viral infections, such as severe acute respiratory syndrome (SARS).
Lactoferrin and lactoferricin inhibit in vitro growth of Trichophyton mentagrophytes, which are responsible for several skin diseases such as ringworm. Lactoferrin also acts against the Candida albicans – a diploid fungus (a form of yeast) that causes opportunistic oral and genital infections in humans. Fluconazole has long been used against Candida albicans, which resulted in emergence of strains resistant to this drug. However, a combination of lactoferrin with fluconazole can act against fluconazole-resistant strains of Candida albicans as well as other types of Candida: C. glabrata, C. krusei, C. parapsilosis and C. tropicalis. Antifungal activity is observed for sequential incubation of Candida with lactoferrin and then with fluconazole, but not vice versa. The antifungal activity of lactoferricin exceeds that of lactoferrin. In particular, synthetic peptide 1–11 lactoferricin shows much greater activity against Candida albicans than native lactoferricin.
Administration of lactoferrin through drinking water to mice with weakened immune systems and symptoms of aphthous ulcer reduced the number of Candida albicans strains in the mouth and the size of the damaged areas in the tongue. Oral administration of lactoferrin to animals also reduced the number of pathogenic organisms in the tissues close to the gastrointestinal tract. Candida albicans could also be completely eradicated with a mixture containing lactoferrin, lysozyme and itraconazole in HIV-positive patients who were resistant to other antifungal drugs. Such antifungal action when other drugs deem inefficient is characteristic of lactoferrin and is especially valuable for HIV-infected patients. Contrary to the antiviral and antibacterial actions of lactoferrin, very little is known about the mechanism of its antifungal action. Lactoferrin seems to bind the plasma membrane of C. albicans inducing an apoptotic-like process.
The anticancer activity of bovine lactoferrin (bLF) has been demonstrated in experimental lung, bladder, tongue, colon, and liver carcinogeneses on rats, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2). Also, in another experiment done on hamsters, bovine lactoferrin decreased the incidence of oral cancer by 50%. Because bLF by far did not show any toxicity and because it's readily available in milk, bLF offers promise as a potential chemopreventive agent for oral cancer. Currently, bLF is used as an ingredient in yogurt, chewing gums, infant formulas, and cosmetics.
The human lung and saliva contain a wide range of antimicrobial compound including lactoperoxidase system, producing hypothiocyanite and lactoferrin, with hypothiocyanite missing in cystic fibrosis patients. Lactoferrin, a component of innate immunity, prevents bacterial biofilm development. The loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity is observed in patients with cystic fibrosis. In cystic fibrosis, antibiotic susceptibility may be modified by lactoferrin These findings demonstrate the important role of lactoferrin in human host defense and especially in lung. Lactoferrin with hypothiocyanite has been granted orphan drug status by the EMEA and the FDA.
Lactoferrin levels in tear fluid have been shown to decrease in dry eye diseases such as Sjogren's syndrome. A rapid, portable test utilizing microfluidic technology has been developed to enable measurement of lactoferrin levels in human tear fluid at the point-of-care with the aim of improving diagnosis of Sjogren's syndrome and other forms of dry eye disease.
Lactotransferrin has been used in the synthesis of fluorescent gold quantum clusters, which has potential applications in nanotechnology.
- Sánchez L, Calvo M, Brock JH (1992). "Biological role of lactoferrin". Arch. Dis. Child. 67 (5): 657–61. doi:10.1136/adc.67.5.657. PMC 1793702. PMID 1599309.
- Levin RE, Kalidas S, Gopinadhan P, Pometto A (2006). Food biotechnology. Boca Raton, FL: CRC/Taylor & Francis. p. 1028. ISBN 0-8247-5329-1.
- Animal Breeding: Technology for the 21st Century (Modern Genetics,). Boca Raton: CRC. 1998. p. 191. ISBN 90-5702-292-3.
- M. Sorensen and S. P. L. Sorensen, Compf. rend. trav. lab. Carlsberg (1939) 23, 55, cited by Groves (1960)
- Groves ML (1960). "The Isolation of a Red Protein from Milk". Journal of the American Chemical Society 82 (13): 3345. doi:10.1021/ja01498a029.
- Johansson B, Virtanen AI, Tweit RC, Dodson RM (1960). "Isolation of an iron-containing red protein from human milk" (PDF). Acta Chem. Scand. 14 (2): 510–512. doi:10.3891/acta.chem.scand.14-0510.
- Naidu AS (2000). Lactoferrin: natural, multifunctional, antimicrobial. Boca Raton: CRC Press. pp. 1–2. ISBN 0-8493-0909-3.
- Jing-Fen Kang; Xiang-Long Li; Rong-Yan Zhou; Lan-Hui Li; Fu-Jun Feng; Xiu -Li Guo (2008). "Bioinformatics Analysis of Lactoferrin Gene for Several Species". Biochemical Genetics 46 (5–6): 312–322. doi:10.1007/s10528-008-9147-9. PMID 18228129.
- Seyfert HM, Tuckoricz A, Interthal H, Koczan D, Hobom G (1994). "Structure of the bovine lactoferrin-encoding gene and its promoter". Gene 143 (2): 265–9. doi:10.1016/0378-1119(94)90108-2. PMID 8206385.
- O'Halloran F, Bahar B, Buckley F, O'Sullivan O, Sweeney T, Giblin L (2009). "Characterisation of single nucleotide polymorphisms identified in the bovine lactoferrin gene sequences across a range of dairy cow breeds". Biochimie 91 (1): 68–75. doi:10.1016/j.biochi.2008.05.011. PMID 18554515.
- Birgens HS (1985). "Lactoferrin in plasma measured by an ELISA technique: evidence that plasma lactoferrin is an indicator of neutrophil turnover and bone marrow activity in acute leukaemia". Scand J Haematol 34 (4): 326–31. doi:10.1111/j.1600-0609.1985.tb00757.x. PMID 3858982.
- Baker HM, Anderson BF, Kidd RD, Shewry SC, Baker EN (2000). "Lactoferrin three-dimensional structure: a framework for interpreting function". In Shimazaki, Kei-ichi. Lactoferrin: structure, function, and applications: proceedings of the 4th International Conference on Lactoferrin: Structure, Function, and Applications, held in Sapporo, Japan, 18–22 May 1999. Amsterdam: Elsevier. ISBN 0-444-50317-X.
- Baker EN, Baker HM (2005). "Molecular structure, binding properties and dynamics of lactoferrin". Cell. Mol. Life Sci. 62 (22): 2531–9. doi:10.1007/s00018-005-5368-9. PMID 16261257.
- Håkansson A, Zhivotovsky B, Orrenius S, Sabharwal H, Svanborg C (1995). "Apoptosis induced by a human milk protein". Proc. Natl. Acad. Sci. U.S.A. 92 (17): 8064–8. doi:10.1073/pnas.92.17.8064. PMC 41287. PMID 7644538.
- Jameson GB, Anderson BF, Norris GE, Thomas DH, Baker EN (1998). "Structure of human apolactoferrin at 2.0 Å resolution. Refinement and analysis of ligand-induced conformational change". Acta Crystallogr. D 54 (Pt 6 Pt 2): 1319–35. doi:10.1107/S0907444998004417. PMID 10089508.
- Levay PF, Viljoen M (1995). "Lactoferrin: a general review". Haematologica 80 (3): 252–67. PMID 7672721.
- Mazurier J, Spik G (1980). "Comparative study of the iron-binding properties of human transferrins. I. Complete and sequential iron saturation and desaturation of the lactotransferrin". Biochim. Biophys. Acta 629 (2): 399–408. doi:10.1016/0304-4165(80)90112-9. PMID 6770907.
- Broc JHk; De Sousa M (1989). Iron in immunity, cancer, and inflammation. New York: Wiley. ISBN 0-471-92150-5.
- Shongwe MS, Smith CA, Ainscough EW, Baker HM, Brodie AM, Baker EN (1992). "Anion binding by human lactoferrin: results from crystallographic and physicochemical studies". Biochemistry 31 (18): 4451–8. doi:10.1021/bi00133a010. PMID 1581301.
- Bennett RM, Davis J (1982). "Lactoferrin interacts with deoxyribonucleic acid: a preferential reactivity with double-stranded DNA and dissociation of DNA-anti-DNA complexes". J. Lab. Clin. Med. 99 (1): 127–38. PMID 6274982.
- Bagby GC, Bennett RM (1982). "Feedback regulation of granulopoiesis: polymerization of lactoferrin abrogates its ability to inhibit CSA production". Blood 60 (1): 108–12. PMID 6979357.
- Mantel C, Miyazawa K, Broxmeyer HE (1994). "Physical characteristics and polymerization during iron saturation of lactoferrin, a myelopoietic regulatory molecule with suppressor activity". Adv. Exp. Med. Biol. Advances in, Experimental Medicine and Biology 357: 121–32. doi:10.1007/978-1-4615-2548-6_12. ISBN 978-0-306-44734-1. PMID 7762423.
- Furmanski P, Li ZP, Fortuna MB, Swamy CV, Das MR (1989). "Multiple molecular forms of human lactoferrin. Identification of a class of lactoferrins that possess ribonuclease activity and lack iron-binding capacity". J. Exp. Med. 170 (2): 415–29. doi:10.1084/jem.170.2.415. PMC 2189405. PMID 2754391.
- "Lactoferrin: a review" (PDF). Veterinarni Medicina 53 (9): 457. 2008.
- McCormick JJ, Larson LJ, Rich MA (1974). "RNase inhibition of reverse transcriptase activity in human milk". Nature 251 (5477): 737–40. doi:10.1038/251737a0. PMID 4139659.
- Das MR, Padhy LC, Koshy R, Sirsat SM, Rich MA (1976). "Human milk samples from different ethnic groups contain RNase that inhibits, and plasma membrane that stimulates, reverse transcription". Nature 262 (5571): 802–5. doi:10.1038/262802a0. PMID 60710.
- Liao Y, Lopez V, Shafizadeh TB, Halsted CH, Lönnerdal B (2007). "Cloning of a pig homologue of the human lactoferrin receptor: expression and localization during intestinal maturation in piglets". Comp Biochem Physiol a Mol Integr Physiol 148 (3): 584–90. doi:10.1016/j.cbpa.2007.08.001. PMC 2265088. PMID 17766154.
- The multifunctional glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a novel macrophage lactoferrin receptor. Pooja Rawat, Santosh Kumar, Navdeep Sheokand, Chaaya Iyengar Raje and Manoj Raje. Biochemistry and Cell Biology; 2012, 90(3): 329–338.
- Bharadwaj S, Naidu AG, Betageri GV, Prasadarao NV, Naidu AS (September 2009). "Milk ribonuclease-enriched lactoferrin induces positive effects on bone turnover markers in postmenopausal women". Osteoporos Int 20 (9): 1603–11. doi:10.1007/s00198-009-0839-8. PMID 19172341.
- Bharadwaj S, Naidu TA, Betageri GV, Prasadarao NV, Naidu AS (November 2010). "Inflammatory responses improve with milk ribonuclease-enriched lactoferrin supplementation in postmenopausal women". Inflamm. Res. 59 (11): 971–8. doi:10.1007/s00011-010-0211-7. PMID 20473630.
- Rosenmund A, Kuyas C, Haeberli A (1986). "Oxidative radioiodination damage to human lactoferrin". Biochem. J. 240 (1): 239–45. PMC 1147399. PMID 3827843.
- Farnaud S, Evans RW (2003). "Lactoferrin—a multifunctional protein with antimicrobial properties". Mol. Immunol. 40 (7): 395–405. doi:10.1016/S0161-5890(03)00152-4. PMID 14568385.
- Xanthou M (1998). "Immune protection of human milk". Biol. Neonate 74 (2): 121–33. doi:10.1159/000014018. PMID 9691154.
- Odell EW, Sarra R, Foxworthy M, Chapple DS, Evans RW (1996). "Antibacterial activity of peptides homologous to a loop region in human lactoferrin". FEBS Lett. 382 (1–2): 175–8. doi:10.1016/0014-5793(96)00168-8. PMID 8612745.
- Kuwata H, Yip TT, Yip CL, Tomita M, Hutchens TW (1998). "Bactericidal domain of lactoferrin: detection, quantitation, and characterization of lactoferricin in serum by SELDI affinity mass spectrometry". Biochem. Biophys. Res. Commun. 245 (3): 764–73. doi:10.1006/bbrc.1998.8466. PMID 9588189.
- Sojar HT, Hamada N, Genco RJ (1998). "Structures involved in the interaction of Porphyromonas gingivalis fimbriae and human lactoferrin". FEBS Lett. 422 (2): 205–8. doi:10.1016/S0014-5793(98)00002-7. PMID 9490007.
- Andrés MT, Fierro JF (2010). "Antimicrobial mechanism of action of transferrins: Selective inhibition of H+-ATPase". Antimicrob. Agents Chemother. 54 (10): 4335–42. doi:10.1128/AAC.01620-09. PMC 2944611. PMID 20625147.
- of Pharmacist's letter; Prescriber's letter, eds. (2007). Natural medicines comprehensive database (10th ed.). Therapeutic Research Faculty. p. 915. ISBN 0978820533.
- van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK (2001). "Antiviral activities of lactoferrin". Antiviral Res. 52 (3): 225–39. doi:10.1016/S0166-3542(01)00195-4. PMID 11675140.
- Fujihara T, Hayashi K (1995). "Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea". Arch. Virol. 140 (8): 1469–72. doi:10.1007/BF01322673. PMID 7661698.
- Giansanti F, Rossi P, Massucci MT, Botti D, Antonini G, Valenti P, Seganti L (2002). "Antiviral activity of ovotransferrin discloses an evolutionary strategy for the defensive activities of lactoferrin". Biochem. Cell Biol. 80 (1): 125–30. doi:10.1139/o01-208. PMID 11908636.
- Harmsen MC, Swart PJ, de Béthune MP, Pauwels R, De Clercq E, The TH, Meijer DK (1995). "Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro". J. Infect. Dis. 172 (2): 380–8. doi:10.1093/infdis/172.2.380. PMID 7622881.
- Puddu 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 1 infection". Int. J. Biochem. Cell Biol. 30 (9): 1055–62. doi:10.1016/S1357-2725(98)00066-1. PMID 9785469.
- Azzam HS, Goertz C, Fritts M, Jonas WB (2007). "Natural products and chronic hepatitis C virus". Liver Int. 27 (1): 17–25. doi:10.1111/j.1478-3231.2006.01408.x. PMID 17241377.
- Nozaki A, Ikeda M, Naganuma A, Nakamura T, Inudoh M, Tanaka K, Kato N (2003). "Identification of a lactoferrin-derived peptide possessing binding activity to hepatitis C virus E2 envelope protein". J. Biol. Chem. 278 (12): 10162–73. doi:10.1074/jbc.M207879200. PMID 12522210.
- Arnold D, Di Biase AM, Marchetti M, Pietrantoni A, Valenti P, Seganti L, Superti F (2002). "Antiadenovirus activity of milk proteins: lactoferrin prevents viral infection". Antiviral Res. 53 (2): 153–8. doi:10.1016/S0166-3542(01)00197-8. PMID 11750941.
- Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, Leung BP, Melendez AJ (2005). "Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome". BMC Immunol. 6: 2. doi:10.1186/1471-2172-6-2. PMC 546205. PMID 15655079.
- Wakabayashi H, Uchida K, Yamauchi K, Teraguchi S, Hayasawa H, Yamaguchi H (2000). "Lactoferrin given in food facilitates dermatophytosis cure in guinea pig models". J. Antimicrob. Chemother. 46 (4): 595–602. doi:10.1093/jac/46.4.595. PMID 11020258.
- Lupetti A, Paulusma-Annema A, Welling MM, Dogterom-Ballering H, Brouwer CP, Senesi S, Van Dissel JT, Nibbering PH (2003). "Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species". Antimicrob. Agents Chemother. 47 (1): 262–7. doi:10.1128/AAC.47.1.262-267.2003. PMC 149030. PMID 12499200.
- Viejo-Díaz M, Andrés MT, Fierro JF (2004). "Modulation of in vitro fungicidal activity of human lactoferrin against Candida albicans by extracellular cation concentration and target cell metabolic activity". Antimicrob. Agents Chemother. 48 (4): 1242–8. doi:10.1128/AAC.48.4.1242-1248.2004. PMC 375254. PMID 15047526.
- Takakura N, Wakabayashi H, Ishibashi H, Teraguchi S, Tamura Y, Yamaguchi H, Abe S (2003). "Oral lactoferrin treatment of experimental oral candidiasis in mice". Antimicrob. Agents Chemother. 47 (8): 2619–23. doi:10.1128/AAC.47.8.2619-2623.2003. PMC 166093. PMID 12878528.
- Masci JR (October 2000). "Complete response of severe, refractory oral candidiasis to mouthwash containing lactoferrin and lysozyme". AIDS 14 (15): 2403–4. doi:10.1097/00002030-200010200-00023. PMID 11089630.
- Kuipers ME, de Vries HG, Eikelboom MC, Meijer DK, Swart PJ (1999). "Synergistic fungistatic effects of lactoferrin in combination with antifungal drugs against clinical Candida isolates". Antimicrob. Agents Chemother. 43 (11): 2635–41. PMC 89536. PMID 10543740.
- Human lactoferrin induces apoptosis-like cell death in Candida albicans: critical role of K+-channel-mediated K+ efflux. Andrés MT, Viejo-Díaz M, Fierro JF. Antimicrob Agents Chemother. 2008 Nov;52(11):4081-8. doi: 10.1128/AAC.01597-07
- Tsuda H, Sekine K, Fujita K, Ligo M (2002). "Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies". Biochem. Cell Biol. 80 (1): 131–6. doi:10.1139/o01-239. PMID 11908637.
- Chandra Mohan KV, Kumaraguruparan R, Prathiba D, Nagini S (September 2006). "Modulation of xenobiotic-metabolizing enzymes and redox status during chemoprevention of hamster buccal carcinogenesis by bovine lactoferrin". Nutrition 22 (9): 940–6. doi:10.1016/j.nut.2006.05.017. PMID 16928475.
- Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (2007). "A novel host defense system of airways is defective in cystic fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83. doi:10.1164/rccm.200607-1029OC. PMC 2720149. PMID 17082494.
- Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP (2000). "Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms". Nature 407 (6805): 762–4. doi:10.1038/35037627. PMID 11048725.
- Singh PK, Parsek MR, Greenberg EP, Welsh MJ (2002). "A component of innate immunity prevents bacterial biofilm development". Nature 417 (6888): 552–5. doi:10.1038/417552a. PMID 12037568.
- Rogan MP, Taggart CC, Greene CM, Murphy PG, O'Neill SJ, McElvaney NG (2004). "Loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis". J. Infect. Dis. 190 (7): 1245–53. doi:10.1086/423821. PMID 15346334.
- Antibiotic tolerance induced by lactoferrin in clinical Pseudomonas aeruginosa isolates from cystic fibrosis patients. Andrés MT, Viejo-Diaz M, Pérez F, Fierro JF. Antimicrob Agents Chemother. 2005 Apr;49(4):1613-6.
- Rogan MP, Geraghty P, Greene CM, O'Neill SJ, Taggart CC, McElvaney NG (2006). "Antimicrobial proteins and polypeptides in pulmonary innate defence". Respir. Res. 7 (1): 29. doi:10.1186/1465-9921-7-29. PMC 1386663. PMID 16503962.
- "Public summary of positive opinion for orphan designation of hypothiocyanite/lactoferrin for the treatment of cystic fibrosis" (PDF). Pre-authorisation Evaluation of Medicines for Human Use. European Medicines Agency. 2009-09-07. Retrieved 2010-01-23.
- "Meveol: orphan drug status granted by the FDA for the treatment of cystic fibrosis". United States Food and Drug Administration. 2009-11-05. Retrieved 2010-01-23.
- Ohashi, Yoshiki; Reiko Ishida; Takashi Kojima; Eiki Goto; Yukihiro Matsumoto; Katsuhiko Watanabe; Naruhiro Ishida; Katsuhiko Nakata; Tsutomu Takeuchi; Kazuo Tsubota (August 2003). "Abnormal Protein Profiles in Tears with Dry Eye Syndrome". American Journal of Ophthalmology 136 (2): 291–9. doi:10.1016/S0002-9394(03)00203-4. PMID 12888052.
- Karns, Kelly; Herr, Amy E (November 2011). "Human Tear Protein Analysis Enabled by an Alkaline Microfluidic Homogeneous Immunoassay". Analytical Chemistry 83 (21): 8115–22. doi:10.1021/ac202061v. PMID 21910436.
- Xavier PL, Chaudhari K, Verma PK, Pal SK, Pradeep T (2010). "Luminescent quantum clusters of gold in transferrin family protein, lactoferrin exhibiting FRET" (PDF). Nanoscale 12 (12): 2769–76. doi:10.1039/C0NR00377H. PMID 20882247.
- LTF on the National Center for Biotechnology Information
- FDA Lactoferrin Considered Safe to Fight E. Coli.