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Lactoferrin from Milk: Nutraceutical and Pharmacological Properties

Francesco Giansanti, Gloria Panella, Loris Leboffe and 1 more

Pharmaceuticals · 2016 · Review · CC BY

doi:10.3390/ph9040061

Abstract

Lactoferrin is an iron-binding protein present in large quantities in colostrum and in breast milk, in external secretions and in polymorphonuclear leukocytes. Lactoferrin’s main function is non-immune protection. Among several protective activities shown by lactoferrin, those displayed by orally administered lactoferrin are: (i) antimicrobial activity, which has been presumed due to iron deprivation, but more recently attributed also to a specific interaction with the bacterial cell wall and extended to viruses and parasites; (ii) immunomodulatory activity, with a direct effect on the development of the immune system in the newborn, together with a specific antinflammatory effects; (iii) a more recently discovered anticancer activity. It is worth noting that most of the protective activities of lactoferrin have been found, sometimes to a greater extent, also in peptides derived from limited proteolysis of lactoferrin that could be generated after lactoferrin ingestion. Lactoferrin could therefore be considered an ideal nutraceutic product because of its relatively cheap production from bovine milk and of its widely recognized tolerance after ingestion, along with its well demonstrated protective activities. The most important protective activities shown by orally administered bovine lactoferrin are reviewed in this article.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introducing Lactoferrin

Lactoferrin (Lf, formerly known as lactotransferrin) is an iron-binding glycoprotein, belonging to the transferrin protein family, together with serum transferrin (sTf), ovotransferrin (Otrf), melanotransferrin and the inhibitor of carbonic anhydrase. Lf was first isolated by Sorensen and Sorensen from bovine milk in 1939 and after two decades it was determined to be the main iron- binding protein in human milk. Lf is produced and released by mucosal epithelial cells and neutrophils in various mammalian species, including humans, bovines, cows, goats, horses, dogs and several rodents. More recently González-Chávez et al. showed that Lf is also expressed in fishes.

Lf has been shown to be involved in several physiological and protective functions, including regulation of iron absorption in the bowel; antioxidant, anticancer, antinflammatory and antimicrobial activities, which are the most widely studied function to date. Interestingly, a great number of Lf activities are present also in ovotransferrin, an avian homologue of mammalian Lf, indicating that they have been conserved during evolution. Beside mammalian milk and colostrum, where Lf, present at a concentration of 7 g/L, is the second most abundant protein after caseins, Lf is primarily found in mucosal secretions; in particular it is present in tears, saliva, vaginal fluids, semen, nasal and bronchial secretions, bile, gastrointestinal fluids, and urine. It is also found in considerable amounts in secondary neutrophil granules (15 µg/106 neutrophils), where it plays a significant physiological role and it can also be found in bodily fluids such as blood plasma and amniotic fluid.

Lf is an 80 kDa glycosylated protein of about 700 aminoacids (711 aa for human Lf (hLf) and 689 aa for bovine Lf (bLf)) with high homology among species. Its three dimensional structure consists of a single polypeptide chain folded into two symmetrical lobes (N and C lobes), which are highly homologous with one another (33%–41% homology) (Figure 1).

A hinge region containing parts of an α-helix connects the two lobes. In hLf, the polypeptide chain includes amino acids 1–332 for the N lobe and 344–703 for the C lobe and it is made up of α-helix and β-sheet structures. Each lobe can be further divided into two subdomains (N1 and N2 in the N-lobe and C1 and C2 in the C-lobe) forming two clefts for each lobe, inside of which the iron is bound. In hLf, the subdomain N1 contains the residues 1–90 and 251–333, while N2 contains the residues 91–250). Each iron ion is bound to the protein together with two carbonate ions (CO32−) whose protonation leads to iron binding weaknesses. However, the binding site is not strictly restricted to iron, since Lf is able to bind other metals such as Cu2+, Zn2+ and Mn2+ ions. In biological fluids, Lf can be found either without bound iron (apo-lactoferrin) or in iron-bound form (holo-lactoferrin).

A large number of studies have demonstrated its tolerance in humans, and bLf has been approved by FDA (US) and European Food Safety Authority as a dietary supplement in food products. However, as Lf is susceptible to peptic digestion in the stomach, it cannot easily access to the digestive tract. To overcome this problem and to improve the therapeutic potential of Lf, the use of microparticles or liposomes has been tested. Liposomalization increased the Lf action by the improvement of stability against gastric degradation and facilitated the interaction with the intestinal membrane and with Lf-specific receptors.

2. Lactoferrin’s Antimicrobial Activity

Lf’s protection against microbial infection was the first activity discovered and it is currently the most widely studied function to date. There is a huge amount of literature data describing the in vitro and in vivo efficacy and animal-model benefits of Lf. The antimicrobial activity of Lf is due to two different mechanisms. Its primary role is to sequester free iron, thus removing an essential substrate required for bacterial growth and exerting a bacteriostatic effect. The other mechanism involves a direct interaction of the Lf with the infectious agent. Lf binds to the lipopolysaccharide of bacterial walls, and may also damage bacteria via formation of peroxides catalyzed by Lf-bound iron (III) ions, affecting membrane permeability and resulting in bacterial cell lysis. Since the pioneristic work of Bullen and co-workers on the protective effect of Lf towards E. coli 0111 infection in newborn guinea-pigs, there are several experimental observations that oral administration of Lf reduces bacterial and fungal infections mainly in the gastro-intestinal tract (see, for example,).

On the other hand, Lf promotes the growth of bacteria with low iron requirements such as Lactobacillus and Bifidobacteria, which are generally believed to be beneficial to the host. Orally administered recombinant human Lf (rhLf) was indeed demonstrated to be able to modulate the intestinal flora in piglets. Recently oral administration of bLf has had a significant increase of interest because of the demonstration of its probiotic activity both in adults and in infants, including prematurely born.

In addition to this well-known antibacterial function, Lf displays a potent antiviral activity of against both enveloped and naked viruses, like Cytomegalovirus (CMV), Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Human hepatitis C (HCV) and human hepatitis B (HBV) viruses. Therefore, the effects of Lf oral administration have been studied in several bacterial and viral infections in animals and humans and the beneficial effects of orally administered Lf have recently been found in viral infections including the common cold, influenza, and viral gastroenteritis.

An antiparasitic activity of Lf has been also demonstrated. This antiparasitic activity appears to involve interference with iron acquisition in some parasites, e.g., Pneumocystis carinii, on the other hand, Lf appears to act as a specific iron donor in other parasites such as Tritrichomonas foetus. Furthermore, Lf is able to inhibit the growth of Plasmodium berghei, binding directly to the plasmodial CS protein. Moreover, Lf has in vitro activity towards human pathogenic fungi, such as Candida albicans and several other Candida species.

3. Nutraceutical and Immunomodulation Protective Effects

Over the past decade, Lf has been reported to affect various immunological functions playing an important role in host defence against infection and excessive inflammation, appearing as a key element in the mammalian immune system. Indeed, Lf appears to be able to both up- and down-regulate the endogenous inflammatory response, possessing pro- and anti-inflammatory properties. The cellular and molecular mechanisms responsible for the immunomodulatory effects of Lf, are not fully elucidated, and in vitro and in vivo studies suggest the existence of multiple mechanisms. Lf acts on B-cells, which are well-known antigen presenters, to allow their subsequent interaction with T cells, which promotes elevation of the antibody response by promoting the maturation of T-cell precursors into competent helper cells and by the differentiation of immature B-cells into efficient antigen presenting cells. Both bovine and human Lf are able to bind surface receptors on the human T-cell line (Jurkat cell line) and the expression of Lf receptors has been recently reported in all T-cell subsets. At the cellular level, Lf modulates the migration, maturation and function of immune cells. There are also suggestions that Lf can play a role in the initiation of T-cell activation through the modulation of dendritic cell function. Several studies (mostly on animals but also on humans) have focused on the immunomodulatory effects of orally administered Lf: Mulder et al. found that oral administration of bLf to healthy human males increased the activation of total T-cell, helper T-cell and cytotoxic T-cell, increasing also hydrophilic antioxidant capacity (reviewed by Mayeur et al. in 2016).Saraiva et al. fed piglets with 3.6 g/L of bLF and showed higher IgG concentrations in serum and more IL-10, an immunomodulatory cytokine potentially limiting inflammation, was secreted by spleen cells into the culture media;Liu et al. administering orally bLf to piglets, and found an increase of the blood NK cell populations and NK Lf receptor expression without affecting NK cell cytotoxicity, suggesting that Lf could help protect the organism of infants from infections;Cooper et al. fed young pigs with transgenic cows’ milk containing rhLf. They showed favorable changes in systemic health in rhLf-milk fed pigs that had beneficial changes in circulating leukocyte populations with a decrease in neutrophils and increase in lymphocytes which is an indicator of decreased systemic inflammation. Moreover, favorable changes in intestinal villi architecture were also observed both in the duodenum and in the ileum of rhLf-milk fed pigs;Yang et al. showed that the percentage of piglets with symptoms of diarrhea during the first 38 days of life was decreased, if compared with the control group, from 54% to 15% by orally administered Lf at a dose level of 155 and 285 mg/kg/day, respectively. A significant delay in the onset of diarrhea by at least 1 week in the higher Lf dose group and 4 days in the lower Lf dose group, compared with the control group of piglets, was also observed;Wu et al. investigated the effect of enteral bLf supplementation on intestinal adaptation and barrier function in a rat model of short bowel syndrome (SBS) and they demonstrated a protective effect of Lf due to small-bowel luminal sIgA and TJ protein expression upregulation together with reduced intestinal permeability, supporting intestinal barrier integrity and providing better protection against bacterial infections;Arciniega-Martınez et al. analyzed the effects of bLf orally administered to healthy male BALB/c mice. They found that antibodies, antibody-secreting cells, and B and T responses in both Peyer’s patches and in lamina propria were higher in bLf-treated than bLf-untreated mice, suggesting a potential application of bLf as a nutraceutical to control inflammation in the distal small intestine;Kawashima et al. demonstrated the protective effect of Lf towards “Dry Eye Syndrome” caused by age-induced decrease in lacrimal gland secretory function. They attributed this activity to Lf anti-inflammatory properties since oral administration to aged mice of Lf alone or in combination with other antioxidants resulted in decreasing inflammatory cell infiltration in eyes. On the other hand they demonstrated also that Lactoferrin administration decreases MCP-1 and TNF-α expression levels and markers for oxidative damage while increases the volume of tear secretion. Moreover, a combined dietary supplement containing fish oil, lactoferrin, zinc, vitamin C, lutein, vitamin E, γ-aminobutanoic acid, and Enterococcus faecium WB2000 improves the symptoms of dry eye syndrome with no side effects.

Mulder et al. found that oral administration of bLf to healthy human males increased the activation of total T-cell, helper T-cell and cytotoxic T-cell, increasing also hydrophilic antioxidant capacity (reviewed by Mayeur et al. in 2016).

Saraiva et al. fed piglets with 3.6 g/L of bLF and showed higher IgG concentrations in serum and more IL-10, an immunomodulatory cytokine potentially limiting inflammation, was secreted by spleen cells into the culture media;

Liu et al. administering orally bLf to piglets, and found an increase of the blood NK cell populations and NK Lf receptor expression without affecting NK cell cytotoxicity, suggesting that Lf could help protect the organism of infants from infections;

Cooper et al. fed young pigs with transgenic cows’ milk containing rhLf. They showed favorable changes in systemic health in rhLf-milk fed pigs that had beneficial changes in circulating leukocyte populations with a decrease in neutrophils and increase in lymphocytes which is an indicator of decreased systemic inflammation. Moreover, favorable changes in intestinal villi architecture were also observed both in the duodenum and in the ileum of rhLf-milk fed pigs;

Yang et al. showed that the percentage of piglets with symptoms of diarrhea during the first 38 days of life was decreased, if compared with the control group, from 54% to 15% by orally administered Lf at a dose level of 155 and 285 mg/kg/day, respectively. A significant delay in the onset of diarrhea by at least 1 week in the higher Lf dose group and 4 days in the lower Lf dose group, compared with the control group of piglets, was also observed;

Wu et al. investigated the effect of enteral bLf supplementation on intestinal adaptation and barrier function in a rat model of short bowel syndrome (SBS) and they demonstrated a protective effect of Lf due to small-bowel luminal sIgA and TJ protein expression upregulation together with reduced intestinal permeability, supporting intestinal barrier integrity and providing better protection against bacterial infections;

Arciniega-Martınez et al. analyzed the effects of bLf orally administered to healthy male BALB/c mice. They found that antibodies, antibody-secreting cells, and B and T responses in both Peyer’s patches and in lamina propria were higher in bLf-treated than bLf-untreated mice, suggesting a potential application of bLf as a nutraceutical to control inflammation in the distal small intestine;

Kawashima et al. demonstrated the protective effect of Lf towards “Dry Eye Syndrome” caused by age-induced decrease in lacrimal gland secretory function. They attributed this activity to Lf anti-inflammatory properties since oral administration to aged mice of Lf alone or in combination with other antioxidants resulted in decreasing inflammatory cell infiltration in eyes. On the other hand they demonstrated also that Lactoferrin administration decreases MCP-1 and TNF-α expression levels and markers for oxidative damage while increases the volume of tear secretion. Moreover, a combined dietary supplement containing fish oil, lactoferrin, zinc, vitamin C, lutein, vitamin E, γ-aminobutanoic acid, and Enterococcus faecium WB2000 improves the symptoms of dry eye syndrome with no side effects.

However, despite the abundant evidence that orally administered Lf indeed has direct and indirect effects against inflammation, up to now it was not possible to understand the mechanisms of action of Lf that appear to be controversial in a lot of cases. In addition, several approaches have been used to study the way in which lactoferrin mediates neonatal immune development. One of these was to create transgenic animals that overexpress Lf in milk, which has been done in mice, goats, and cows as reviewed by Cooper et al..

4. Anticancer Activity of Orally Administered Lactoferrin

The process of carcinogenesis includes the initial occurrence of genetic alterations which can lead to the inactivation of tumor suppressor genes and further accumulation of genetic alterations during tumor progression. Silencing or downregulation of the lactoferrin gene in cells is usually related to the occurrence of certain diseases, especially carcinomas.

Table 1 summarizes the identified anticancer activities of Lf and its derivative peptides, among which the lactoferricin (Lfcin) (see paragraph Lactoferrin peptides). Lf, and subsequently its peptides, is one of the most studied nutraceutical proteins, showing considerable potential for preventing the different stages of cancer, including initiation, promotion, and progression. Usually, alterations of the lactoferrin gene in cells are associated with an increased incidence of cancer. Several studies suggest that exogenous treatment with Lf and its derivatives can efficiently inhibit the growth of tumors and reduces susceptibility to cancer. The effect of apo- and holo-Lf in inhibiting tumor development and reducing growth and metastasis of solid tumors was also observed by Kanwar et al. and Tsuda et al..

Actually, Lf and its derivatives can be an effective anti-cancer treatment if combined with other therapeutic agents or if encapsulated in carriers after appropriate modifications. It is interesting to note that some studies have already begun to use these approaches to increase the cytotoxic effects of Lf and its derivatives. Oral Lf accelerated reconstitution of humoral and cellular immune responses during chemotherapy- induced immunosuppression in mice, suggesting it could be employed to overcome tamoxifen-induced immune suppression and indeed, Kanwar and coworwers showed that the oral administration of holo-bLf could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers. Orally administered holo-bLf improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice inducing significantly higher cancer cell death (apoptosis) and cytotoxicity in a dose-dependent manner in cancer cells than the normal intestinal cells.

As combination therapy becomes increasingly popular, it is likely that Lf will continue to be studied for its potential value as a primary or adjuvant agent in the treatment of cancer. Clinical trials involving the use of this protein in cancer therapy are ongoing and the relatively low cytotoxicity of Lf and its derivatives as compared with known anticancer drugs, along with the lack of data about the mechanisms of action, is likely to encourage the clinical use of Lf in cancer treatment.

5. Other Lactoferrin Activities

In addition, there is a potential use of Lf for the improvement of bone health. Dietary Lf supplementation preserved bone mass and microarchitecture in ovariectomized rats, improving both bone mineral density and bone strength. More importantly, in 38 healthy postmenopausal women, milk ribonuclease-enriched lactoferrin induces positive effects on bone turnover markers. Lf appeared therefore to be a promising candidate for the development of an anabolic therapeutic factor for osteoporosis, even though no more recent information is present in scientific literature.

Maternal iron-bLf supplementation stimulates human fetal growth in normal pregnancy. In addition, iron-bLf administration is able to decrease the onset of dexamethasone (DEX) induced IntraUterine Growth Restriction (IUGR) that alters levels of brain metabolites (γ-aminobutyric acid, glutamate, N-acetylaspartate, and N-acetylaspartylglutamate) and transcripts (brain-derived neurotrophic factor (BDNF), divalent metal transporter 1 (DMT-1), and glutamate receptors), leading to defective hippocampal development and later cognitive impairment.

6. Lactoferrin Peptides

An increasing number of functions are associated with the peptides of this protein. These peptides are produced by the action of proteolytic enzymes, and could be produced in the intestinal lumen after Lf oral ingestion. In particular, three peptides have been especially studied. They originate from the N-lobe of Lf, and have an antimicrobial activity by their hydrophobicity, cationic charge, and helical conformation, which render these peptides amphiphilic molecules.

These three peptides are Lf(1–11), Lfcin and lactoferrampin (Lfampin). In detail, Lf(1–11) is the oligopeptide that includes the first eleven aminoacidic residues of the Lf. The presence of the hydrophobic and hydrophilic residues lends to it a highly cationic nature. It has been demonstrated that Lf(1–11) interacts with the membrane of several bacteria.

Lfcin is an amphipathic, cationic peptide with anti-microbial and anti-cancer properties. Indeed it is the most studied anti-microbial peptide derived from milk proteins. It can be generated by the pepsin-mediated digestion of Lf (aminoacid residues 17–41). The peptide has an abundance of basic aminoacids including Lys and Arg, as well as hydrophobic residues like tryptophan and phenylalanine. Lfcin has several biological activities including antiviral, antibacterial, antifungal and anti-inflammatory activities.

Lfampin comprises residues 268–284 in the N1 domain of Lf, and was found to be located in closed proximity to Lfcin. Lfampin exhibits broad antimicrobial action against several Gram-positive and Gram-negative bacteria, yeast and parasites.

Lf- derived peptides showed often a considerably higher antimicrobial activity than the native protein with broad antibacterial spectrum and low minimum concentration. However, their activities are not limited to the antimicrobial properties but several protective activities have been found in Lf- derived peptides. These activities are summarized in Table 2.

7. Conclusions

Lf has been studied since long time for its various protective activities for which the protein has been evolved in a wide range of animals, including humans. The most beneficial activities are those related to the antimicrobial, antinflammatory and anticancer properties of the protein and of its peptides that may be possibly generated after ingestion. In addition, there is growing evidence of specific immunomodulatory activity of Lf in adults and newborns where, beyond the well-known nutritional immunity, Lf is of particular importance for the development of the immune system. These activities were shown after oral administration of bovine and human Lf and, together with its probiotic effect and the lack of any specific toxicity, allow Lf to be an ideal nutraceutical example.

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  43. 43.

    Welsh K.J., Hwang S.A., Boyd S., Kruzel M.L., Hunter R.L., Actor J.K. Influence of oral lactoferrin on Mycobacterium tuberculosis induced immunopathology. Tuberculosis. 2011;91:S105-S113.

    Not in our library10.1016/j.tube.2011.10.019

  44. 44.

    Velliyagounder K., Alsaedi W., Alabdulmohsen W., Markowitz K., Fine D.H. Oral lactoferrin protects against experimental candidiasis in mice. J. Appl. Microbiol. 2015;118:212-221.

    Not in our library10.1111/jam.12666

  45. 45.

    Sherman M.P., Bennett S.H., Hwang F.F., Yu C. Neonatal small bowel epithelia: Enhancing anti-bacterial defense with lactoferrin and Lactobacillus GG. Biometals. 2004;17:285-289.

    Not in our library10.1023/b:biom.0000027706.51112.62

  46. 46.

    Hu W., Zhao J., Wang J., Yu T., Wang J., Li N. Transgenic milk containing recombinant human lactoferrin modulates the intestinal flora in piglets. Biochem. Cell Biol. 2012;90:485-496.

    Not in our library10.1139/o2012-003

  47. 47.

    Sachdeva A., Rawat S., Nagpal J. Efficacy of fermented milk and whey proteins in Helicobacter pylori eradication: A review. World J. Gastroenterol. 2014;20:724-737.

    Not in our library10.3748/wjg.v20.i3.724

  48. 48.

    Vongbhavit K., Underwood M.A. Prevention of necrotizing enterocolitis through manipulation of the intestinal microbiota of the premature Infant. Clin. Ther. 2016;38:716-732.

    Not in our library10.1016/j.clinthera.2016.01.006

  49. 49.

    Pammi M., Abrams S.A. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst. Rev. 2011;10:CD007138.

    Not in our library10.1002/14651858.cd007138.pub3

  50. 50.

    Harmsen M.C., Swart P.J., de Béthune M.P., Pawels R., De Clercq E., The T.H., Meijer D.K.F. Antiviral effects of plasma and milk proteins: Lactoferrin shows a potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. J. Infect. Dis. 1995;172:280-388.

    Not in our library10.1093/infdis/172.2.380

  51. 51.

    Andersen J.H., Osbakk S.A., Vorland L.H., Traavik T., Gutteberg T.J. Lactoferrin and cyclic lactoferricin inhibit the entry of human cytomegalovirus into human fibroblasts. Antivir. Res. 2001;51:141-149.

    Not in our library10.1016/s0166-3542(01)00146-2

  52. 52.

    Marchetti M., Longhi C., Conte M.P., Pisani S., Valenti P., Seganti L. Lactoferrin inhibits herpes simplex virus type 1 adsorption to Vero cells. Ativir. Res. 1996;29:221-231.

    Not in our library10.1016/0166-3542(95)00840-3

  53. 53.

    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. 1998;11:89-94.

    Not in our library10.1023/a:1009217709851

  54. 54.

    Siciliano R., Rega B., Marchetti M., Seganti L., Antonini G., Valenti P. Bovine lactoferrin peptidic fragments involved in inhibition of herpes simplex virus type 1 infection. Biochem. Biophys. Res. Commun. 1999;264:19-23.

    Not in our library10.1006/bbrc.1999.1318

  55. 55.

    Swart P.J., Kuipers M.E., Smith C., Pawels R., de Béthune M.P., De Clerck E., Meijer D.K.F., Huisman J.G. Antiviral effects of milk proteins: Acylation results in polyanionic compounds with potent activity against human immunodeficiency virus types 1 and 2 in vitro. AIDS Res. Human Retrov. 1996;12:769-775.

    Not in our library10.1089/aid.1996.12.769

  56. 56.

    Puddu P., Borghi P., Gessani S., Valenti P., Belardelli F., Seganti L. Antiviral effects of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection. Int. J. Biochem. Cell Biol. 1998;30:1055-1062.

    Not in our library10.1016/s1357-2725(98)00066-1

  57. 57.

    Berkhout B., Floris R., Recio I., Visser S. The antiviral activity of the milk protein lactoferrin against the human immunodeficiency virus type 1. Biometals. 2004;17:291-294.

    Not in our library10.1023/b:biom.0000027707.82911.be

  58. 58.

    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. Biochem. Biophys. Res. Commun. 1998;245:549-553.

    Not in our library10.1006/bbrc.1998.8481

  59. 59.

    Hara K., Ikeda M., Saito S., Matsumoto S., Numata K., Kato N. Lactoferrin inhibits hepatitis B virus infection in cultured human hepatocytes. Hepatol. Res. 2002;24:228-236.

    Not in our library10.1016/s1386-6346(02)00088-8

  60. 60.

    Tanaka K., Ikeda M., Nozaki A., Kato N., Tsuda H., Saito S., Sekihara H. Lactoferrin inhibits hepatitis C virus viremia in patients with chronic hepatitis C: A pilot study. Jpn. J. Cancer Res. 1999;90:367-371.

    Not in our library10.1111/j.1349-7006.1999.tb00756.x

  61. 61.

    Ueno H., Sato T., Yamamoto S., Tanaka K., Ohkawa S., Takagi H., Yokosuka O., Furuse J., Saito H., Sawaki A., et al. Randomized, double-blind, placebo-controlled trial of bovine lactoferrin in patients with chronic hepatitis C. Cancer Sci. 2006;97:1105-1110.

    Not in our library10.1111/j.1349-7006.2006.00274.x

  62. 62.

    Pietrantoni A., Dofrelli E., Tinari A., Ammendolia M.G., Puzelli S., Fabiani C., Donatelli I., Superti F. Bovine lactoferrin inhibits influenza A virus induced programmed cell death in vitro. Biometals. 2010;23:465-475.

    Not in our library10.1007/s10534-010-9323-3

  63. 63.

    Wakabayashi H., Oda H., Yamauchi K., Abe F. Lactoferrin for prevention of common viral infections. J. Infect. Chemother. 2014;20:666-671.

    Not in our library10.1016/j.jiac.2014.08.003

  64. 64.

    Weinberg G.A. Iron chelators as therapeutic agents against Pneumocystis carinii. Antimicrob. Agents Chemother. 1994;38:997-1003.

    Not in our library10.1128/aac.38.5.997

  65. 65.

    Cirioni O., Giacometti A., Barchiesi F., Scalise G. Inhibition of growth of Pneumocystis carinii by lactoferrins alone and in combination with pyrimethamine, clarithromycin and minocycline. J. Antimicrob. Chemother. 2000;46:577-582.

    Not in our library10.1093/jac/46.4.577

  66. 66.

    Tachezy J., Kulda J., Bahnikova I., Suchan P., Razga J., Schrevel J. Tritrichomonas foetus: Iron acquisition from lactoferrin and transferrin. Exp. Parasitol. 1996;83:216-228.

    Not in our library10.1006/expr.1996.0068

  67. 67.

    Shakibaei M., Frevert U. Dual interaction of the malaria circumsporozoite protein with the low density lipoprotein receptor-related protein (LRP) and heparan sulfate proteoglycans. J. Exp. Med. 1996;184:1699-1711.

    Not in our library10.1084/jem.184.5.1699

  68. 68.

    Giansanti F., Leboffe L., D’Elia I., Antonini G. An update on the antifungal activities of Lactoferrin: New promising applications in diagnostic, therapeutics and biotechnology. Anti-Infect. Agents. 2013;11:155-158.

    Not in our library10.2174/2211352511311020009

  69. 69.

    Puddu P., Valenti P., Gessani S. Immunomodulatory effects of lactoferrin on antigen presenting cells. Biochimie. 2009;91:11-18.

    Not in our library10.1016/j.biochi.2008.05.005

  70. 70.

    Embleton N.D., Berrington J.E., McGuire W., Stewart C.J., Cummings S.P. Lactoferrin: Antimicrobial activity and therapeutic potential. Semin. Fetal Neonat. Med. 2013;18:143-149.

    Not in our library10.1016/j.siny.2013.02.001

  71. 71.

    Legrand D., Mazurier J. A critical review of the roles of host lactoferrin in immunity. Biometals. 2010;23:365-376.

    Not in our library10.1007/s10534-010-9297-1

  72. 72.

    Actor J.K., Hwang S.A., Kruzel M.L. Lactoferrin as a natural immune modulator. Curr. Pharm. Des. 2009;15:1956-1973.

    Not in our library10.2174/138161209788453202

  73. 73.

    Turin C.G., Zea-Vera A., Pezo A., Cruz K., Zegarra J., Bellomo S., Cam L., Llanos R., Castañeda A., Tucto L., et al. Lactoferrin for prevention of neonatal sepsis. Biometals. 2014;27:1007-1016.

    Not in our library10.1007/s10534-014-9754-3

  74. 74.

    Kruzel M.L., Actor J.K., Boldogh I., Zimecki M. Lactoferrin in health and disease. Postepy Hig. Med. Dosw. 2007;61:261-267.

    Not in our library

  75. 75.

    Kawasaki Y., Sato K., Shinmoto H., Dosako S. Role of basic residues of human lactoferrin in the interaction with B lymphocytes. Biosci. Biotechnol. Biochem. 2000;64:14-18.

    Not in our library10.1271/bbb.64.314

  76. 76.

    Dhennin-Duthille I., Masson M., Damiens E., Fillebeen C., Spik G., Mazurier J. Lactoferrin upregulates the expression of CD4 antigen through the stimulation of the mitogen- activated protein kinase in the human lymphoblastic T Jurkat cell line. J. Cell. Biochem. 2000;79:583-593.

    Not in our library10.1002/1097-4644(20001215)79:4<583::aid-jcb70>3.0.co;2-9

  77. 77.

    Siqueiros-Cendón T., Arévalo-Gallegos S., Iglesias-Figueroa BF., García-Montoya IA., Salazar-Martínez J., Rascón-Cruz Q. Immunomodulatory effects of lactoferrin. Acta Pharmacol. Sin. 2014;35:57-66.

    Not in our library10.1038/aps.2013.200

  78. 78.

    Legrand D., Elass E., Carpentier M., Mazurier J. Lactoferrin: A modulator of immune and inflammatory responses. Cell. Mol. Life Sci. 2005;62:2549-2559.

    Not in our library10.1007/s00018-005-5370-2

  79. 79.

    Hwang S.A., Kruzel M.L., Actor J.K. Lactoferrin augments BCG vaccine efficacy to generate T helper response and subsequent protection against challenge with virulent Mycobacterium tuberculosis. Int. Immunopharmacol. 2005;5:591-599.

    Not in our library10.1016/j.intimp.2004.11.006

  80. 80.

    Mulder A.M., Connellan P.A., Oliver C.J., Morris C.A., Stevenson L.M. Bovine lactoferrin supplementation supports immune and antioxidant status in healthy human males. Nutr. Res. 2008;28:583-589.

    Not in our library10.1016/j.nutres.2008.05.007

  81. 81.

    Mayeur S., Spahis S., Pouliot Y., Levy E. Lactoferrin, a Pleiotropic Protein inHealth and Disease. Antioxid. Redox Signal. 2016;24:813-836.

    Not in our library10.1089/ars.2015.6458

  82. 82.

    Saraiva M., O’Garra A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 2010;10:70-81.

    Not in our library10.1038/nri2711

  83. 83.

    Liu K.Y., Comstock S.S., Shunk J.M., Monaco M.H., Donovan S.M. Natural killer cell populations and cytotoxic activity in pigs fed mother’s milk, formula, or formula supplemented with bovine lactoferrin. Pediatr. Res. 2013;74:402-407.

    Not in our library10.1038/pr.2013.125

  84. 84.

    Cooper C.A., Nelson K.M., Maga E.A., Murray J.D. Consumption of transgenic cows’ milk containing human lactoferrin results in beneficial changes in the gastrointestinal tract and systemic health of young pigs. Transgenic. Res. 2013;22:571-578.

    Not in our library10.1007/s11248-012-9662-7

  85. 85.

    Yang C., Zhu X., Liu N., Chen Y., Gan H., Troy F.A., Wang B. Lactoferrin up-regulates intestinal gene expression of brain-derived neurotrophic factors BDNF, UCHL1 and alkaline phosphatase activity to alleviate early weaning diarrhea in postnatal piglets. J. Nutr. Biochem. 2014;25:834-842.

    Not in our library10.1016/j.jnutbio.2014.03.015

  86. 86.

    Wu J., Chen J., Wu W., Shi J., Zhong Y., van Tol E.A.F., Tang Q., Cai W. Enteral supplementation of bovine lactoferrin improves gut barrier function in rats after massive bowel resection. Br. J. Nutr. 2014;112:486-492.

    Not in our library10.1017/s000711451400107x

  87. 87.

    Arciniega-Martínez I.M., Campos-Rodríguez R., Drago-Serrano M.E., Sánchez-Torres L.E., Cruz-Hernández T.R., Reséndiz-Albor A.A. Modulatory Effects of Oral Bovine Lactoferrin on the IgA Response at Inductor and Effector Sites of Distal Small Intestine from BALB/c Mice. Arch. Immunol. Ther. Exp. (Warsz). 2016;64:57-63.

    Not in our library10.1007/s00005-015-0358-6

  88. 88.

    Kawashima M., Kawakita T., Inaba T., Okada N., Ito M., Shimmura S., Watanabe M., Shinmura K., Tsubota K. Dietary Lactoferrin Alleviates Age-Related Lacrimal Gland Dysfunction in Mice. PLoS ONE. 2012;7:e33148.

    Not in our library10.1371/journal.pone.0033148

  89. 89.

    Kawashima M., Nakamura S., Izuta Y., Inoue S., Tsubota K. Dietary Supplementation with a Combination of Lactoferrin, Fish Oil, and Enterococcus faecium WB2000 for Treating Dry Eye: A Rat Model and Human Clinical Study. Ocul. Surf. 2016;14:255-263.

    Not in our library10.1016/j.jtos.2015.12.005

  90. 90.

    Cooper C.A., Maga E.A., Murray J.D. Production of human lactoferrin and lysozyme in the milk of transgenic dairy animals: Past, present, and future. Transgenic Res. 2015;24:605-614.

    Not in our library10.1007/s11248-015-9885-5

  91. 91.

    de Mejia E.G., Dia V.P. The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells. Cancer Metastasis Rev. 2010;29:511-528.

    Not in our library10.1007/s10555-010-9241-4

  92. 92.

    Teng C., Gladwell W., Raphiou I., Liu E. Methylation and expression of the lactoferrin gene in human tissues and cancer cells. Biometals. 2004;17:317-323.

    Not in our library10.1023/b:biom.0000027711.13818.8a

  93. 93.

    Shaheduzzaman S., Vishwanath A., Furusato B., Cullen J., Chen Y., Bañez L., Nau M., Ravindranath L., Kim K.H., Mohammed A., et al. Silencing of Lactotransferrin expression by methylation in prostate cancer progression. Cancer Biol. Ther. 2007;6:1088-1095.

    Not in our library10.4161/cbt.6.7.4327

  94. 94.

    Wang J., Li Q., Li K., Ou Y., Han Z., Gao D., Li J. Effects of adenovirus vectors mediated human lactoferrin cDNA on mice bearing EMT6 breast carcinoma. Die Pharm. 2011;66:704-709.

    Not in our library

  95. 95.

    Li W.Y., Li Q.W., Han Z.S., Jiang Z.L., Yang H., Li J., Zhang X.B. Growth suppression effects of recombinant adenovirus expressing human lactoferrin on cervical cancer in vitro and in vivo. Cancer Biother. Radiopharm. 2011;26:477-483.

    Not in our library10.1089/cbr.2010.0937

  96. 96.

    Freiburgahus C., Janicke B., Lindmark-Mansson H., Oredsson S.M., Paulsson M.A. Lactoferricin treatment decreases the rate of cell proliferation of a human colon cancer cell line. J. Dairy Sci. 2009;92:2477-2484.

    Not in our library10.3168/jds.2008-1851

  97. 97.

    Lönnerdal B., Jiang R., Du X. Bovine lactoferrin can be taken up by the human intestinal lactoferrin receptor and exert bioactivities. J. Pediatr. Gastroenterol. Nutr. 2011;53:606-614.

    Not in our library10.1097/mpg.0b013e318230a419

  98. 98.

    Kuhara T., Iigo M., Itoh T., Ushida Y., Sekine K., Terada N., Okamura H., Tsuda H. Orally administered lactoferrin exerts an antimetastatic effect and enhances production of IL-18 in the intestinal epithelium. Nutr. Cancer. 2000;38:192-199.

    Not in our library10.1207/s15327914nc382_8

  99. 99.

    Iigo M., Shimamura M., Matsuda E., Fujita K., Nomoto H., Satoh J., Kojima S., Alexander D.B., Moore M.A., Tsuda H. Orally 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. 2004;25:36-44.

    Not in our library10.1016/j.cyto.2003.09.009

  100. 100.

    Pan W.R., Chen P.W., Chen Y.L., Hsu H.C., Lin C.C., Chen W.J. Bovine lactoferricin B induces apoptosis of human gastric cancer cell line AGS by inhibition of autophagy at a late stage. J. Dairy Sci. 2013;96:7511-7520.

    Not in our library10.3168/jds.2013-7285

  101. 101.

    Deng M., Zhang W., Tang H., Ye Q., Liao Q., Zhou Y., Wu M., Xiong W., Zheng Y., Guo X., et al. Lactotransferrin acts as a tumor suppressor in nasopharyngeal carcinoma by repressing AKT through multiple mechanisms. Oncogene. 2013;32:4273-4283.

    Not in our library10.1038/onc.2012.434

  102. 102.

    Letchoumy P.V., Mohan K.V., Stegeman J.J., Gelboin H.V., Hara Y., Nagini S. In vitro antioxidative potential of lactoferrin and black tea polyphenols and protective effects in vivo on carcinogen activation, DNA damage, proliferation, invasion, and angiogenesis during experimental oral carcinogenesis. Oncol. Res. 2008;17:193-203.

    Not in our library10.3727/096504008786111365

  103. 103.

    Wolf J. S., Li G., Varadhachary A., Petark K., Schneyer M., Li D., Ongkasuwan J., Zhang X., Taylor R.J., Strome S.E., et al. Oral lactoferrin results in T cell-dependent tumor inhibition of head and neck squamous cell carcinoma in vivo. Clin. Cancer Res. 2007;13:1601-1610.

    Not in our library10.1158/1078-0432.ccr-06-2008

  104. 104.

    Xiao Y., Monitto C.L., Minhas K.M., Sidransky D. Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells. Clin. Cancer Res. 2004;10:8683-8686.

    Not in our library10.1158/1078-0432.ccr-04-0988

  105. 105.

    Sakai T., Banno Y., Kato Y., Nozawa Y., Kawaguchi M. Pepsin-digested lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells. J. Pharm. Sci. 2005;98:41-48.

    Not in our library10.1254/jphs.fpj04047x

  106. 106.

    Richardosn A., de Antueno R., Duncan R., Hoskin D.W. Intracellular delivery of bovine lactoferricin’s antimicrobial core (RRWQWR) kills T-leukemia cells. Biochem. Biophys. Res. Commun. 2009;388:736-741.

    Not in our library10.1016/j.bbrc.2009.08.083

  107. 107.

    Mader J.S., Salsman J., Conrad D.M., Hoskin D.W. Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. Mol. Cancer Ther. 2005;4:612-624.

    Not in our library10.1158/1535-7163.mct-04-0077

  108. 108.

    Lu Y., Zhang T.F., Shi Y., Zhou H.W., Chen Q., Wei B.Y., Wang X., Yang T.X., Chinn Y.E., Kang J., et al. PFR peptide, one of the antimicrobial peptides identified from the derivatives of lactoferrin, induces necrosis inleukemia cells. Sci. Rep. 2016;6:20823.

    Not in our library10.1038/srep20823

  109. 109.

    Lee S.H., Hwang H.M., Pyo C.W., Hahm D.H., Choi S.Y. E2F1-directed activation of Bcl-2 is correlated with lactoferrin-induced apoptosis in Jurkat leukemia T lymphocytes. Biometals. 2010;23:507-514.

    Not in our library10.1007/s10534-010-9341-1

  110. 110.

    Matsuda Y., Saoo K., Hosokawa K., Yamakawa K., Yokohira M., Zeng Y., Takeuchi H., Imaida K. Post-initiation chemopreventive effects of dietary bovine lactoferrin on 4-(methynitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in female A/J mice. Cancer Lett. 2007;246:41-46.

    Not in our library10.1016/j.canlet.2006.01.034

  111. 111.

    Son H.J., Lee S.H., Choi S.Y. Human lactoferrin controls the level of retinoblastoma protein and its activity. Biochem. Cell Biol. 2006;84:345-350.

    Not in our library10.1139/o06-048

  112. 112.

    Wang S., Tu J., Zhou C., Li J., Huang L., Tao L., Zhao L. The effect of Lfcin-B on non-small cell lung cancer H460 cells is mediated by inhibiting VEGF expression and inducing apoptosis. Arch. Pharm. Res. 2015;38:261-271.

    Not in our library10.1007/s12272-014-0373-x

  113. 113.

    Eliassen L.T., Berge G., Leknessund A., Wikman M., Lindin I., Løkke C., Ponthan F., Johnsen J.I., Sveinbjørnsson B., Kogner P., et al. The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo. Int. J. Cancer. 2006;119:493-500.

    Not in our library10.1002/ijc.21886

  114. 114.

    Arcella A., Oliva M.A., Staffieri S., Aalberti S., Grillea G., Madonna M., Bartolo M., Pavone L., Giangaspero F., Cantore G., et al. In vitro and in vivo effect of human lactoferrin on glioblastoma growth. J. Neurosurg. 2015;123:1026-1035.

    Not in our library10.3171/2014.12.jns14512

  115. 115.

    Hoedt E., Hardivillé S., Mariller C., Elass E., Perraudin J.P., Pierce A. Discrimination and evaluation of lactoferrin and delta-lactoferrin gene expression levels in cancer cells and under inflammatory stimuli using TaqMan real-time PCR. Biometals. 2010;23:441-452.

    Not in our library10.1007/s10534-010-9305-5

  116. 116.

    Benaïssa M., Peyrat J.P., Hornez L., Mariller C., Mazurier J., Pierce A. Expression and prognostic value of lactoferrin mRNA isoforms in human breast cancer. Int. J. Cancer. 2005;114:299-306.

    Not in our library10.1002/ijc.20728

  117. 117.

    Kanwar J.R., Palmano K.P., Sun X., Kanwar R.K., Gupta R., Haggarty N., Rowan A., Ram S., Krissansen G.W. ‘Iron-saturated’ lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy. Immunol. Cell Boil. 2008;86:277-288.

    Not in our library10.1038/sj.icb.7100163

  118. 118.

    Kanwar J.R., Mahidhara G., Kanwar R.K. Novel alginate-enclosed chitosan-calcium phosphate-loaded iron-saturated bovine lactoferrin nanocar-riers for oral delivery in colon cancer therapy. Nanomedicine. 2012;7:1521-1550.

    Not in our library10.2217/nnm.12.29

  119. 119.

    Tsuda H., Kozu T., Iinuma G., Ohashi Y., Saito Y., Saito D., Akasu T., Alexander D.B., Futakuchi M., Fukamachi K., et al. Cancer prevention by bovine lactoferrin: From animal studies to human trial. Biometals. 2010;23:399-409.

    Not in our library10.1007/s10534-010-9331-3

  120. 120.

    Furlong S.J., Mader J.S., Hoskin D.W. Lactoferricin-induced apoptosis in estrogen- nonresponsive MDA-MB-435 breast cancer cells is enhanced by C6 ceramide or tamoxifen. Oncol. Rep. 2006;15:1385-1390.

    Not in our library10.3892/or.15.5.1385

  121. 121.

    Massodi I., Thomas E., Raucher D. Application of thermally responsive elastin-like polypeptide fused to a lactoferrin-derived peptide for treatment of pancreatic cancer. Molecules. 2009;14:1999-2015.

    Not in our library10.3390/molecules14061999

  122. 122.

    Roseanu A., Florian P.E., Moisei M., Sima L.E., Evans R.W., Trif M. Liposomalization of lactoferrin enhanced its anti-tumoral effects on melanoma cells. Biometals. 2010;23:485-492.

    Not in our library10.1007/s10534-010-9312-6

  123. 123.

    Artym J., Zimecki M., Kruzel M.L. Effect of lactoferrin on the methotrexate- induced suppression of the cellular and humoral immune response in mice. Anticancer Res. 2004;24:3831-3836.

    Not in our library

  124. 124.

    Artym J., Zimecki M., Kuryszko J., Kruzel M.L. Lactoferrin accelerates reconstitution of the humoral and cellular immune response during chemotherapy-induced immunosuppression and bone marrow transplant in mice. Stem. Cells Dev. 2005;14:548-555.

    Not in our library10.1089/scd.2005.14.548

  125. 125.

    Sun X., Jiang R., Przepiorski A., Reddy S., Palmano K.P., Krissansen G.W. “Iron-saturated” bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice. BMC Cancer. 2012;12:591.

    Not in our library10.1186/1471-2407-12-591

  126. 126.

    Guo H.Y., Jiang L., Ibrahim S.A., Zhang L., Zhang H., Zhang M., Ren F.Z. Orally administered lactoferrin preserves bone mass and microarchitecture in ovariectomized rats. J. Nutr. 2009;139:958-964.

    Not in our library10.3945/jn.108.100586

  127. 127.

    Bharadwaj S., Naidu A.G., Betageri G.V., Prasadarao N.V., Naidu A.S. Milk ribonuclease-enriched lactoferrin induces positive effects on bone turnover markers in postmenopausal women. Osteoporos. Int. 2009;20:1603-1611.

    Not in our library10.1007/s00198-009-0839-8

  128. 128.

    Cornish J., Naot D. Lactoferrin as an effector molecule in the skeleton. Biometals. 2010;23:425-430.

    Not in our library10.1007/s10534-010-9320-6

  129. 129.

    Georgieff M.K. The role of iron in neurodevelopment: Fetal iron deficiency and the developing hippocampus. Biochem. Soc. Trans. 2008;36:267-271.

    Not in our library10.1042/bst0361267

  130. 130.

    Somm E., Larvaron P., van de Looij Y., Toulotte A., Chatagner A., Faure M., Métairon S., Mansourian R., Raymond F., Gruetter R., et al. Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism. Pediatr. Res. 2014;75:51-61.

    Not in our library10.1038/pr.2013.199

  131. 131.

    Szwajkowska M., Wolanciuk A., Barłowska J., Król J., Litwińczuk Z. Bovine milk proteins as the source of bioactive peptides influencing the consumers’ immune system. Anim. Sci. Pap. Rep. 2011;29:269-280.

    Not in our library

  132. 132.

    Brouwer C.P., Welling M.M. Various routes of administration of (99m) Tc-labeled synthetic lactoferrin antimicrobial peptide hLF 1–11 enables monitoring and effective killing of multidrug-resistant Staphylococcus aureus infections in mice. Peptides. 2008;29:1109-1117.

    Not in our library10.1016/j.peptides.2008.03.003

  133. 133.

    Gifford J.L., Hunter H.N., Vogel H.J. Lactoferricin: A lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cell Mol. Life Sci. 2005;62:2588-2598.

    Not in our library10.1007/s00018-005-5373-z

  134. 134.

    Flores-Villaseñor H., Canizalez-Román A., Reyes-Lopez M., Nazmi K., de la Garza M., Zazueta-Beltrán J., León-Sicairos N., Bolscher J.G. Bactericidal effect of bovine lactoferrin, LFcin, LFampin and LFchimera on antibiotic-resistant Staphylococcus aureus and Escherichia coli. Biometals. 2010;23:569-578.

    Not in our library10.1007/s10534-010-9306-4

  135. 135.

    Wakabayashi H., Bellamy W., Takase M., Tomita M. Inactivation of Listeria monocytogenes by lactoferricin, a potent antimicrobial peptide derived from cow’s milk. J. Food Prot. 1992;55:238-240.

    Not in our library10.4315/0362-028x-55.4.238

  136. 136.

    Dijkshoorn L., Brouwer C.P., Bogaards S.J., Nemec A., van den Broek P.J., Nibbering P.H. The synthetic N-terminal peptide of human lactoferrin, hLF(1–11), is highly effective against experimental infection caused by multidrug-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2004;48:4919-4921.

    Not in our library10.1128/aac.48.12.4919-4921.2004

  137. 137.

    Federico B., Pinto L., Quintieri L., Carito A., Calabrese N., Caputo L. Efficacy of lactoferricin B in controlling ready-to-eat vegetable spoilage caused by Pseudomonas spp. Int. J. Food Microbiol. 2015;215:179-186.

    Not in our library10.1016/j.ijfoodmicro.2015.09.017

  138. 138.

    Sánchez-Gómez S., Ferrer-Espada R., Stewart P.S., Pitts B., Lohner K., Martínez de Tejada G. Antimicrobial activity of synthetic cationic peptides and lipopeptides derived from human lactoferricin against Pseudomonas aeruginosa planktonic cultures and biofilms. BMC Microbiol. 2015;15:137.

    Not in our library10.1186/s12866-015-0473-x

  139. 139.

    León-Calvijo M.A., Leal-Castro A.L., Almanzar-Reina G.A., Rosas-Pérez J.E., García-Castañeda J.E., Rivera-Monroy Z.J. Antibacterial activity of synthetic peptides derived from lactoferricin against Escherichia coli ATCC 25922 and Enterococcus faecalis ATCC 29212. Biomed. Res. Int. 2015;2015:453826.

    Not in our library10.1155/2015/453826

  140. 140.

    Tang Z., Zhang Y., Stewart A.F., Geng M., Tang X., Tu Q., Yin Y. High-level expression, purification and antibacterial activity of bovine lactoferricin and lactoferrampin in Photorhabdus luminescens. Protein Expr. Purif. 2010;73:132-139.

    Not in our library10.1016/j.pep.2010.05.013

  141. 141.

    Cruz J., Ortiz C., Guzmán F., Cárdenas C., Fernandez-Lafuente R., Torres R. Design and activity of novel lactoferrampin analogues against O157:H7 enterohemorrhagic Escherichia coli. Biopolymers. 2014;101:319-328.

    Not in our library10.1002/bip.22360

  142. 142.

    van der Kraan M.I., Nazmi K., van ’t Hof W., Amerongen A.V., Veerman E.C., Bolscher J.G. Distinct bactericidal activities of bovine lactoferrin peptides LFampin 268–284 and LFampin 265–284: Asp-Leu-Ile makes a difference. Biochem. Cell. Biol. 2006;84:358-362.

    Not in our library10.1139/o06-042

  143. 143.

    Wang W.Y., Wong J.H., Ip D.T., Wan D.C., Cheung R.C., Ng T.B. Bovine Lactoferrampin, Human Lactoferricin, and Lactoferrin 1–11 Inhibit Nuclear Translocation of HIV Integrase. Appl. Biochem. Biotechnol. 2016;179:1202-1212.

    Not in our library10.1007/s12010-016-2059-y

  144. 144.

    Ng T.B., Cheung R.C., Wong J.H., Wang Y., Ip D.T., Wan D.C., Xia J. Antiviral activities of whey proteins. Appl. Microbiol. Biotechnol. 2015;99:6997-7008.

    Not in our library10.1007/s00253-015-6818-4

  145. 145.

    Tsou Y.A., Huang H.J., Lin W.W., Chen C.Y. Investigation of anti-infection mechanism of lactoferricin and splunc-1. Evid. Based Complement. Alternat. Med. 2014;2014:907028.

    Not in our library10.1155/2014/907028

  146. 146.

    Jenssen H., Sandvik K., Andersen J.H., Hancock R.E., Gutteberg T.J. Inhibition of HSV cell-to-cell spread by lactoferrin and lactoferricin. Antivir. Res. 2008;79:192-198.

    Not in our library10.1016/j.antiviral.2008.03.004

  147. 147.

    Mistry N., Drobni P., Näslund J., Sunkari V.G., Jenssen H., Evander M. The anti-papillomavirus activity of human and bovine lactoferricin. Antivir. Res. 2007;75:258-265.

    Not in our library10.1016/j.antiviral.2007.03.012

  148. 148.

    Lupetti A., Brouwer C.P., Bogaards S.J., Welling M.M., de Heer E., Campa M., van Dissel J.T., Friesen R.H., Nibbering P.H. Human lactoferrin-derived peptide’s antifungal activities against disseminated Candida albicans infection. J. Infect. Dis. 2007;196:1416-1424.

    Not in our library10.1086/522427

  149. 149.

    Sengupta J., Saha S., Khetan A., Sarkar S.K., Mandal S.M. Effects of lactoferricin Bagainst keratitis-associated fungal biofilms. J. Infect. Chemother. 2012;18:698-703.

    Not in our library10.1007/s10156-012-0398-3

  150. 150.

    Vylkova S., Sun J.N., Edgerton M. The role of released ATP in killing Candida albicans and other extracellular microbial pathogens by cationic peptides. Purinergic Signal. 2007;3:91-97.

    Not in our library10.1007/s11302-006-9040-0

  151. 151.

    Tang X.S., Shao H., Li T.J., Tang Z.R., Huang R.L., Wang S.P., Kong X.F., Wu X., Yin Y.L. Dietary supplementation with bovine lactoferrampin-lactoferricin produced by Pichia pastoris fed-batch fermentation affects intestinal microflora in weaned piglets. Appl. Biochem. Biotechnol. 2012;168:887-898.

    Not in our library10.1007/s12010-012-9827-0

  152. 152.

    Haney E.F., Nazmi K., Lau F., Bolscher J.G., Vogel H.J. Novel lactoferrampin antimicrobial peptides derived from human lactoferrin. Biochimie. 2009;91:141-154.

    Not in our library10.1016/j.biochi.2008.04.013

  153. 153.

    Leitch G.J., Ceballos C. A role for antimicrobial peptides in intestinal microsporidiosis. Parasitology. 2009;136:175-181.

    Not in our library10.1017/s0031182008005313

  154. 154.

    López-Soto F., León-Sicairos N., Nazmi K., Bolscher J.G., de la Garza M. Microbicidal effect of the lactoferrin peptides lactoferricin17–30, lactoferrampin265–284, and lactoferrin chimera on the parasite Entamoeba histolytica. Biometals. 2010;23:563-568.

    Not in our library10.1007/s10534-010-9295-3

  155. 155.

    Eliassen L.T., Berge G., Sveinbjørnsson B., Svendsen J.S., Vorland L.H., Rekdal Ø. Evidence for a direct antitumor mechanism of action of bovine lactoferricin. Anticancer Res. 2002;22:2703-2710.

    Not in our library

  156. 156.

    Chen H.Y., Mollstedt O., Tsai M.H., Kreider R.B. Potential clinical applications of multi-functional milk proteins and peptides in cancer management. Curr. Med. Chem. 2014;21:2424-2437.

    Not in our library10.2174/0929867321666140205135739

  157. 157.

    Yin C.M., Wong J.H., Xia J., Ng T.B. Studies on anticancer activities of lactoferrin and lactoferricin. Curr. Protein Pept. Sci. 2013;14:492-503.

    Not in our library10.2174/13892037113149990066

  158. 158.

    Zheng Y., Chen P., Guo X., Ma J., Li G. New function of lactoferrin: Protection against cancer development and metastasis. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2012;37:1284-1289.

    Not in our library10.3969/j.issn.1672-7347.2012.12.019

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