Abstract
Lactoferrin (lactotransferrin; Lf) is an iron-binding glycoprotein and one of the most important bioactivators in milk and other external secretions. It has numerous biological roles, including the regulation of iron absorption and modulation of immune responses, and has anti-microbial, anti-viral, antioxidant, anti-cancer, and anti-inflammatory activities. Lf regulates the quantity of iron absorbed in the intestine via its role in iron transport and can also chelate iron, directly or indirectly. Notably, it has been used as an adjuvant therapy for some intestinal diseases. It is now used in nutraceuticalsupplemented infant formula and other food products. This article reviews the content, distribution, physiologic functions and current applications of Lf, and aims to shed light on future prospects for additional applications of Lf.
Keywords: Lactoferrin (Lf), iron-binding activity, immunomodulatory function, anti-microbial effect, anti-viral effect, antioxidant effect, anti-cancer effect, application.
Graphical Abstract
[2]
Lönnerdal, B.; Iyer, S. Lactoferrin: Molecular structure and biological function. Annu. Rev. Nutr., 1995, 15, 93-110.
[3]
Redwan, E.M.; Uversky, V.N.; El-Fakharany, E.M.; Al-Mehdar, H. Potential lactoferrin activity against pathogenic viruses. C. R. Biol., 2014, 337, 581-595.
[4]
Yen, C.C.; Shen, C.J.; Hsu, W.H.; Chang, Y.H.; Lin, H.T.; Chen, H.L.; Chen, C.M. Lactoferrin: An iron-binding antimicrobial protein against Escherichia coli infection. Biometals, 2011, 24, 585-594.
[6]
Rastogi, N.; Singh, A.; Singh, P.K.; Tyagi, T.K.; Pandey, S.; Shin, K.; Kaur, P.; Sharma, S.; Singh, T.P. Structure of iron saturated C-lobe of bovine lactoferrin at pH 6.8 indicates a weakening of iron coordination. Proteins, 2016, 84, 591-599.
[7]
Mayeur, S.; Spahis, S.; Pouliot, Y.; Levy, E. Lactoferrin, a pleiotropic protein in health and disease. Antioxid. Redox Signal., 2016, 24, 813-836.
[8]
Giansanti, F.; Panella, G.; Leboffe, L.; Antonini, G. Lactoferrin from milk: Nutraceutical and pharmacological properties. Pharmaceuticals, 2016, 9, 61-76.
[9]
Gifford, J.L.; Ishida, H.; Vogel, H.J. Structural characterization of the interaction of human lactoferrin with calmodulin. PLoS One, 2012, 7, e51026.
[10]
Van der Strate, B.W.A.; Beljaars, L.; Molema, G.; Harmsen, M.C.; Meijer, D.K.F. Antiviral activities of lactoferrin. Antivir Res., 2001, 52, 225-239.
[11]
González-Chávez, S.A.; Arévalo-Gallegos, S.; Rascón-Cruz, Q. Lactoferrin: Structure, function and applications. Int. J. Antimicrob. Agents, 2009, 33, 301.e1-301.e8.
[12]
Kawakami, H.; Hiratsuka, M.; Dosako, S. Effects of iron-saturated lactoferrin on iron absorption. Agric. BioI. Chem., 1988, 52, 903-908.
[13]
Davidsson, L.; Kastenmayer, P.; Yuen, M.; Lönnerdal, B.; Hurrell, R.F. Influence of lactoferrin on iron absorption from human milk in infants. Pediatr. Res., 1994, 35, 117-124.
[14]
Hanson, L.H.; Sawicki, V.; Lewis, A.; Nuijens, J.H.; Neville, M.C.; Zhang, P. Does human lactoferrin in the milk of transgenic mice deliver iron to suckling neonates? Adv. Exp. Med. Biol., 2001, 501, 233-239.
[15]
Valenti, P.; Antonini, G. Lactoferrin: An important host defence against microbial and viral attack. Cell. Mol. Life Sci., 2005, 62, 2576-2587.
[16]
Sanchez, L.; Calvo, M.; Brock, J.H. Biological role of lactoferrin. Arch. Dis. Child., 1992, 67, 657-661.
[17]
Ochoa, T.J.; Sizonenko, S.V. Lactoferrin and prematurity: A promising milk protein? Biochem. Cell Biol., 2017, 95, 22-30.
[18]
Rahman, M.M.; Kim, W.S.; Ito, T.; Kumura, H.; Shimazaki, K.I. Growth promotion and cell binding ability of bovine lactoferrin to Bifidobacterium longum. Anaerobe, 2009, 15, 133-137.
[19]
Van der Kraan, M.I.A.; Groenink, J.; Nazmi, K.; Veerman, E.C.I.; Bolscher, J.G.M.; Amerongen, A.V.N. Lactoferrampin: A novel antimicrobial peptide in the N1-domain of bovine lactoferrin. Peptides, 2004, 25, 177-183.
[20]
Chen, H.L.; Yen, C.C.; Lu, C.Y.; Yu, C.H.; Chen, C.M. Synthetic porcine lactoferricin with a 20-residue peptide exhibits antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans. J. Agric. Food Chem., 2006, 54, 3277-3282.
[21]
Flores-Villasenor, H.; Canizalez-Román, A.; Reyes-Lopez, M.; Nazmi, K.; de la Garza, M.; Zazueta-Beltrán, J.; León-Sicairos, N.; Bolscher, J.G.M. Bactericidal effect of bovine lactoferrin, LFcin, LFampin and LFchimera on antibiotic-resistant Staphylococcus aureus and Escherichia coli. Biometals, 2010, 23, 569-578.
[22]
Leon-Sicairos, N.; Canizalez-Roman, A.; de la Garza, M.; Reyes-Lopez, M.; Zazueta-Beltran, J.; Nazmi, K.; Gomez-Gil, B.; Bolscher, J.G. Bactericidal effect of lactoferrin and lactoferrin chimera against halophilic Vibrio parahaemolyticus. Biochimie, 2009, 91, 133-140.
[23]
Kim, W.S.; Tanaka, T.; Kumura, H.; Shimazaki, K. Lactoferrin-binding proteins in Bifidobacterium bifidum. Biochem. Cell Biol., 2002, 80, 91-94.
[24]
Kim, W.S.; Ohashi, M.; Tanaka, T.; Kumura, H.; Kim, G.Y.; Kwon, I.K.; Goh, J.S.; Shimazaki, K.I. Growth-promoting effects of lactoferrin on L. acidophilus and Bifidobacterim spp. Biometals, 2004, 17, 279-283.
[25]
Ochoa, T.J.; Noguera-Obenza, M.; Ebel, F.; Guzman, C.A.; Gomez, H.F.; Cleary, T.G. Lactoferrin impairs type III secretory system function in enteropathogenic Escherichia coli. Infect. Immun., 2003, 71, 5149-5155.
[26]
Yen, C.C.; Lin, C.Y.; Chong, K.Y.; Tsai, T.C.; Shen, C.J.; Lin, M.F.; Su, C.Y.; Chen, H.L.; Chen, C.M. Lactoferrin as a natural regimen for selective decontamination of the digestive tract: recombinant porcine lactoferrin expressed in the milk of transgenic mice protects neonates from pathogenic challenge in the gastrointestinal tract. J. Infect. Dis., 2009, 199, 590-598.
[27]
Rybarczyk, J.; Kieckens, E.; De Zutter, L.; Remon, J.P.; Vanrompay, D.; Cox, E. Effects of lactoferrin treatment on Escherichia coli O157:H7 rectal colonization in cattle. Vet. Microbiol., 2017, 202, 38-46.
[28]
Latorre, D.; Berlutti, F.; Valenti, P.; Gessani, S.; Puddu, P. LF immunomodulatory strategies: Mastering bacterial endotoxin. Biochem. Cell Biol., 2012, 90, 269-278.
[29]
Legrand, D. Lactoferrin, a key molecule in immune and inflammatory processes. Biochem. Cell Biol., 2012, 90, 252-268.
[30]
Actor, J.K.; Hwang, S.A.; Kruzel, M.L. Lactoferrin as a natural immune modulator. Curr. Pharm. Des., 2009, 15, 1956-1973.
[31]
De la Rosa, G.; Yang, D.; Tewary, P.; Varadhachary, A.; Oppenheim, J.J. Lactoferrin acts as an alarmin to promote the recruitment and activation of APCs and antigen-spedific immune responses. J. Immunol., 2008, 180, 6868-6876.
[33]
Harmsen, M.C.; Swart, P.J.; de Béthune, M.P.; Pauwels, R.; Clercq, E.D.; The, T.B.; Meijer, D.K.F. 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., 1995, 172, 380-388.
[34]
Hung, C.M.; Wu, S.C.; Yen, C.C.; Lin, M.F.; Lai, Y.W.; Tung, Y.T.; Chen, H.L.; Chen, C.M. Porcine lactoferrin as feedstuff additive elevates avian immunity and potentiates vaccination. Biometals, 2010, 23, 579-587.
[35]
Hung, C.M.; Yeh, C.C.; Chen, H.L.; Lai, C.W.; Kuo, M.F.; Yeh, M.H.; Lin, W.; Tu, M.Y.; Cheng, H.C.; Chen, C.M. Porcine lactoferrin administration enhances peripheral lymphocyte proliferation and assists infectious bursal disease vaccination in native chickens. Vaccine, 2010, 28, 2895-2902.
[36]
Appelmelk, B.J.; An, Y.Q.; Geerts, M.; Thijs, B.G.; De Boer, H.A.; MacLaren, D.M.; De Graaff, J.; Nuijens, J.H. Lactoferrin is a lipid a-binding protein. Infect. Immun., 1994, 62, 2628-2632.
[37]
Elass-Rochard, E.; Roseanu, A.; Legrand, D.; Trif, M.; Salmon, V.; Motas, C. Montreuil, J.; Spik, G. Lactoferrin-lipopolysaccharide interaction: involvement of the 28-34 loop region of human lactoferrin in the high-affinity binding to Escherichia coli 055B5 lipopolysaccharide. Biochem. J., 1995, 312, 839-845.
[38]
Beutler, B. LPS in microbial pathogenesis: Promise and fulfilment. J. Endotoxin Res., 2002, 8, 329-335.
[39]
Beutler, B.; Moresco, E.M. The forward genetic dissection of afferent innate immunity. Curr. Top. Microbiol. Immunol., 2008, 321, 3-26.
[40]
Clark, S.R.; Ma, A.C.; Tavener, S.A.; McDonald, B.; Goodarzi, Z.; Kelly, M.M.; Patel, K.D. Chakrabarti, S.; McAvoy, E.; Sinclair, G.D.; Keys, E.M.; Allen-Vercoe, E.; Devinney, R.; Doig, C.J.; Green, F.H.; Kubes, P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med., 2007, 13, 463-469.
[42]
Okubo, K.; Kamiya, M.; Urano, Y.; Nishi, H.; Herter, J.M.; Mayadas, T.; Hirohama, D.; Suzuki, K.; Kawakami, H.; Tanaka, M.; Kurosawa, M.; Kagaya, S.; Hishikawa, K.; Nangaku, M.; Fujita, T.; Hayashi, M.; Hirahashi, J. Lactoferrin suppresses neutrophil extracellular traps release in inflammation. EBioMedicine, 2016, 10, 204-215.
[43]
Debbabi, H.; Dubarry, M.; Rautureau, M. Tomé, D. Bovine lactoferrin induces both mucosal and systemic immune response in mice. J. Dairy Res., 1998, 65, 283-293.
[44]
Prasad, A.S. Zinc: An antioxidant and anti-inflammatory agent: Role of zinc in degenerative disorders of aging. J. Trace Elem. Med. Biol., 2014, 28, 364-371.
[45]
Gong, J.; Xiao, M. Selenium and antioxidant status in dairy cows at different stages of lactation. Biol. Trace Elem. Res., 2016, 171, 89-93.
[46]
Fujita, K.; Matsuda, E.; Sekine, K. Iigo, M.; Tsuda, H. Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats. Carcinogenesis, 2004, 25, 1961-1966.
[47]
Burrow, H.; Kanwar, R.K.; Kanwar, J.R. Antioxidant enzyme activities of iron-saturated bovine lactoferrin (Fe-bLf) in human gut epithelial cells under oxidative stress. Med. Chem., 2011, 7, 224-230.
[48]
Ogasawara, Y.; Imase, M.; Oda, H.; Wakabayashi, H.; Ishii, K. Lactoferrin directly scavenges hydroxyl radicals and undergoes oxidative self-degradation: a possible role in protection against oxidative DNA damage. Int. J. Mol. Sci., 2014, 15, 1003-1013.
[49]
Park, Y.G.; Jeong, J.K.; Lee, J.H.; Lee, Y.J.; Seol, J.W.; Kim, S.J.; Hur, T.Y.; Jung, Y.H.; Kang, S.J.; Park, S.Y. Lactoferrin protects against prion protein-induced cell death in neuronal cells by preventing mitochondrial dysfunction. Int. J. Mol. Med., 2013, 31, 325-330.
[50]
Baveye, S.; Elass, E.; Mazurier, J.; Legrand, D. Lactoferrin inhibits the binding of lipopolysaccharides to L-selectin and subsequent production of reactive oxygen species by neutrophils. FEBS Lett., 2000, 469, 5-8.
[51]
Iigo, M.; Alexander, D.B.; Long, N.; Xu, J.; Fukamachi, K.; Futakuchi, M.; Takase, M.; Tsuda, H. Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine. Biochimie, 2009, 91, 86-101.
[52]
Xu, X.X.; Jiang, H.R.; Li, H.B.; Zhang, T.N.; Zhou, Q.; Liu, N. Apoptosis of stomach cancer cell SGC-7901 and regulation of Akt signaling way induced by bovine lactoferrin. J. Dairy Sci., 2010, 93, 2344-2350.
[53]
Duarte, D.C.; Nicolau, A.; Teixeira, J.A.; Rodrigues, L.R. The effect of bovine milk lactoferrin on human breast cancer cell lines. J. Dairy Sci., 2011, 94, 66-76.
[54]
Tsuda, H.; Sekine, K.; Fujita, K.; Ligo, M. Cancer prevention by bovine lactoferrin and underlying mechanisms - A review of experimental and clinical studies. Biochem. Cell Biol., 2002, 80, 131-136.
[55]
Habib, H.M.; Ibrahim, W.H.; Schneider-Stock, R.; Hassan, H.M. Camel milk lactoferrin reduces the proliferation of colorectal cancer cells and exerts antioxidant and DNA damage inhibitory activities. Food Chem., 2013, 141, 148-152.
[56]
Damiens, E.; E.I Yazidi, I.; Mazurier, J.; Duthille, I.; Spik, G.; Boilly-Marer, Y. Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells. J. Cell. Biochem., 1999, 74, 486-498.
[57]
Zhang, Y.L.; Lima, C.F.; Rodrigues, L.R. In vitro evaluation of bovine lactoferrin potential as an anticancer agent. Int. Dairy J., 2015, 40, 6-15.
[58]
Sherman, M.P.; Pritzl, C.J.; Xia, C.; Miller, M.M.; Zaghouani, H.; Hahm, B. Lactoferrin acts as an adjuvant during influenza vaccination of neonatal mice. Biochem. Biophys. Res. Commun., 2015, 467, 766-770.
[59]
Carvalho, C.A.M.; Sousa, I.P.; Silva, J.L.; Oliveira, A.C.; Gonçalves, R.B.; Gomes, A.M.O. Inhibition of Mayaro virus infection by bovine lactoferrin. Virology, 2014, 452-453, 297-302.
[60]
Waarts, B.L.; Aneke, O.J.; Smit, J.M.; Kimata, K.; Bittman, R.; Meijer, D.K.; Wilschut, J. Antiviral activity of human lactoferrin: Inhibition of alphavirus interaction with heparan sultate. Virology, 2005, 333, 284-292.
[61]
Viani, R.M.; Gutteberg, T.J.; Lathey, J.L.; Spector, S.A. Lactoferrin inhibits HIV-1 replication in vitro and exhibits synergy when combined with zidovudine. AIDS, 1999, 13, 1273-1274.
[62]
Marchetti, M.; Superti, F.; Ammendolia, M.G.; Rossi, P.; Valenti, P.; Seganti, L. Inhibition of poliovirus type 1 infection by iron-, manganese- and zinc-saturated lactoferrin. Med. Microbiol. Immunol. , 1999, 187, 199-204.
[63]
Ikeda, M.; Sugiyama, K.; Tanaka, T. Nozaki, A.; Naganuma, A.; Tanaka, K.; Sekihara, H.; Shimotohno, K.; Saito, M.; Kato, N. Antiviral activity of lactoferrin against HCV infection in human cultured cells. 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. 2000: 225-232.
[64]
hen, K.; Zhang, L.; Li, H.; Zhang, Y.; Xie, H.; Shang, J.; Tian, W.; Yang, P.; Chai, L.; Mao, M. Iron metabolism in infants: Influence of bovine
lactoferrin from iron-fortified formula. Nutrition, 2015, 31, 304-309
[65]
Ziegler, E.E. Consumption of cow’s milk as a cause of iron deficiency in infants and toddlers. Nutr. Rev., 2011, 69(Suppl. 1), S37-S42.
[66]
Eidelman, A.I.; Schanler, R.J. Breastfeeding and the use of human milk. Pediatrics, 2012, 129, e827-e841.
[67]
Wang, X.; Liu, S.; Xu, H.; Yan, W. Effects of recombinant human lactoferrin on improving the iron status of IDA rats. Wei Sheng Yan Jiu, 2012, 41, 13-17.
[68]
Hernell, O.; Lönnerdal, B. Iron status of infants fed low-iron formula: no effect of added bovine lactoferrin or nucleotides. Am. J. Clin. Nutr., 2002, 76, 858-864.
[69]
Moreno-Navarrete, J.M.; Ortega, F.J.; Bassols, J.; Castro, A.; Ricart, W.; Fernández-Real, J.M. Association of circulating lactoferrin concentration and 2 nonsynonymous LTF gene polymorphisms with dyslipidemia in men depends on glucose-tolerance status. Clin. Chem., 2008, 54, 301-309.
[70]
Moreno-Navarrete, J.M.; Ortega, F.J.; Bassols, J.; Ricart, W.; Fernández-Real, J.M. Decreased circulating lactoferrin in insulin resistance and altered glucose tolerance as a possible marker of neutrophil dysfunction in type 2 diabetes. J. Clin. Endocrinol. Metab., 2009, 94, 4036-4044.
[71]
Ma, N.; Tian, Y.; Wu, Y.; Ma, X. Contributions of the interaction between dietary protein and gut microbiota to intestinal health. Curr. Protein Pept. Sci., 2017, 18, 795-808.
[72]
Guo, P.; Li, Y.; Eslamfamc, S.; Ding, W.; Ma, X. Discovery of novel genes mediating glucose and lipid metabolisms. Curr. Protein Pept. Sci., 2017, 18, 609-618.
[73]
Talukder, J.R.; Griffin, A.; Jaima, A.; Boyd, B.; Wright, J. Lactoferrin ameliorates prostaglandin E2-mediated inhibition of Na+ -glucose cotransport in enterocytes. Can. J. Physiol. Pharmacol., 2014, 92, 9-20.
[74]
Moreno-Navarrete, J.M.; Serrano, M.; Sabater, M.; Ortega, F.; Serino, M.; Pueyo, N.; Luche, E.; Waget, A.; Rodriguez-Hermosa, J.I.; Ricart, W.; Burcelin, R.; Fernández-Real, J.M. Study of lactoferrin gene expression in human and mouse adipose tissue, human preadipocytes and mouse 3T3-L1 fibroblasts. Association with adipogenic and inflammatory markers. J. Nutr. Biochem., 2013, 24, 1266-1275.
[75]
Ono, T.; Murakoshi, M.; Suzuki, N.; Iida, N.; Ohdera, M.; Iigo, M.; Yoshida, T.; Sugiyama, K.; Nishino, H. Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br. J. Nutr., 2010, 104, 1688-1695.
[76]
Ochoa, T.J.; Pezo, A.; Cruz, K.; Chea-Woo, E.; Cleary, T.G. Clinical studies of lactoferrin in children. Biochem. Cell Biol., 2012, 90, 457-467.
[77]
King, J.C.; Cummings, G.E.; Guo, N.; Trivedi, L.; Readmond, B.X.; Keane, V.; Feigelman, S.; de Waard, R. A double-blind, placebo-controlled, pilot study of bovine lactoferrin supplementation in bottle-fed infants. J. Pediatr. Gastroenterol. Nutr., 2007, 44, 245-251.
[78]
Ochoa, T.J.; Chea-Woo, E.; Campos, M.; Pecho, I.; Prada, A.; McMahon, R.J.; Cleary, T.G. Impact of lactoferrin supplementation on growth and prevalence of Giardia colonization in children. Clin. Infect. Dis., 2008, 46, 1881-1883.
[79]
Artym, J.; Zimecki, M.; Paprocka, M.; Kruzel, M.L. Orally administered lactoferrin restores humoral immune response in immunocompromised mice. Immunol. Lett., 2003, 89, 9-15.
[80]
Huang, R.; Ke, W.; Liu, Y.; Jiang, C.; Pei, Y. The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain. Biomaterials, 2008, 29, 238-246.
[81]
Meng, F.; Asghar, S.; Gao, S.; Su, Z.; Song, J.; Huo, M.; Meng, W.; Ping, Q.; Xiao, Y. A novel LDL-mimic nanocarrier for the targeted delivery of curcumin into the brain to treat Alzheimer’s disease. Colloids Surf. B Biointerfaces, 2015, 134, 88-97.
[82]
Wakabayashi, H.; Yamauchi, K.; Takase, M. Lactoferrin research, technology and applications. Int. Dairy J., 2006, 16, 1241-1251.
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