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Lactoferrin (Lf), a multifunctional cationic glycoprotein extracted from milk or colostrum, is able to chelate two ferric ions per molecule, inhibit the formation of reactive oxygen species, interact with the anionic components of bacteria or host cells, and enter inside host cell nucleus, thereby exerting antibacterial, anti-invasive, and anti-inflammatory activities. By virtue of Lf presence, bovine colostrum is expected to perform analogous functions to pure Lf, along with additional activities attributable to other bioactive constituents. The present research aims to compare the antibacterial, anti-invasive, and anti-inflammatory activities of bovine Lf purified from milk (mbLf) and colostrum (cbLf) in comparison to those exhibited by whole bovine colostrum (wbc). The results demonstrated a major efficacy of mbLf in inhibiting pathogenic bacteria and in exerting anti-invasive and anti-survival activities with respect to cbLf and wbc. Furthermore, mbLf lowered IL-6 levels to those of uninfected cells, while a less evident decrease was observed upon cbLf treatment. Conversely, wbc managed to slightly lower IL-6 levels compared to those synthesized by infected cells. These data demonstrate that, to obtain maximum effectiveness in such activities, Lf should be formulated/used without addition of other substances and should be sourced from bovine milk rather than colostrum. [ABSTRACT FROM AUTHOR]

Lactoferrin is an innate glycoprotein with broad antibacterial and antibiofilm properties. The autonomous antibiofilm activity of lactoferrin against Gram-positive bacteria is postulated to involve the cell wall and biofilm components. Thus, the prevention of biomass formation and eradication of preformed biofilms by lactoferrin was investigated using a methicillin-resistant Staphylococcus epidermidis (MRSE) strain. Additionally, the ability of lactoferrin to modulate the expression of the biofilm-associated protein gene (bap) was studied. The bap gene regulates the production of biofilm-associated proteins responsible for bacterial adhesion and aggregation. In the in vitro biofilm assays, lactoferrin prevented biofilm formation and eradicated established biofilms for up to 24 and 72 h, respectively. Extensive eradication of MRSE biofilm biomass was accompanied by the significant upregulation of bap gene expression. These data suggest the interaction of lactoferrin with the biofilm components and cell wall of MRSE, including the biofilm-associated protein. [ABSTRACT FROM AUTHOR]

Bovine lactoferrin (bLF) is a naturally occurring glycoprotein with antibacterial and antiviral activities. We evaluated whether bLF can prevent viral infections in the human intestinal epithelial cell line Caco-2. To assess antiviral responses, we measured the levels of interferon (IFN) expression, IFN-stimulated gene expression, and infection with a pseudotyped virus bearing either severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein or vesicular stomatitis virus (VSV)-G protein after treatment of cells with both bLF and polyinosinic-polycytidylic acid, an analog of double-stranded RNA that mimics viral infection. Combination treatment of cells with both bLF and polyinosinic-polycytidylic acid increased mRNA and protein expression of several IFN genes (IFNB, IFNL1, and IFNL2) and IFN-stimulated genes (ISG15, MX1, IFITM1, and IFITM3) in Caco-2 cells. However, treatment with bLF alone did not induce an antiviral response. Furthermore, combination treatment suppressed infection of the SARS-CoV-2 pseudotyped virus more efficiently than did bLF treatment alone, even though combination treatment increased the expression of mRNA encoding ACE2. These results indicate that bLF increases the antiviral response associated with the double-stranded RNA-stimulated signaling pathway. Our results also suggest that bLF and double-stranded RNA analogs can be used to treat viral infections, including those caused by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The article presents New insights into the systemic effects of oral lactoferrin: transcriptome profiling. Topics discussed include the immunomodulatory nature of lactoferrin (LF) derives from its ability to bridge innate and adaptive immunity in obtaining physiological equilibrium; and the aim of this study was to evaluate the systemic effects of orally and intravenously (IV) administered recombinant human LF (rhLF) on blood cell transcriptome profiling.

The article presents Effect of bovine lactoferrin on prevention of late-onset sepsis in infants, and pooled analysis of individual patient data from two randomized controlled trials. Topics discussed include the aim of this study was to determine the preventative effects of bLF on culture-proven or probable LOS in infants; and determine the effect of bLF in relation to intake of human milk, both trial designs had similar inclusion and exclusion criteria, the same dose of bLF.

The article presents synthetic mimic of the two antimicrobial domains of bovine lactoferrin. Topics discussed include this review describes how saliva has been the guideline for the design and characterization of a heterodimeric antimicrobial construct called LFchimera; and this construct mimics the helical parts of two antimicrobial domains in the crystal structure of bovine lactoferrin. I.

The article presents Antibiofilm activity of lactoferrin-derived synthetic peptides against Pseudomonas aeruginosa PAO1. Topics discussed include pathogenic bacteria can protect themselves from the effects of antibiotics and the host immune response system by forming biofilms; and Biofilms are polymer-entrapped bacterial cells, which adhere to each other and are often attached to a surface.

The article presents Dose escalation study of bovine lactoferrin in preterm infants. Topics discussed include Lactoferrin as a nutritional enteral supplement has emerged as a novel preventative therapy against serious infections in preterm infants, although neonatal studies have demonstrated variable results; and studies examining higher doses of lactoferrin, length of treatment, and potency of different products will aid in determining the optimal approach for the use of lactoferrin.

The article presents Biological activities of commercial bovine lactoferrin sources. Topics discussed include the purity and protein form of each Lf were examined by SDS–PAGE, Western blot, and proteomics analysis; and assays were conducted to evaluate uptake of Lfs and iron from Lfs by enterocytes as well as Lf bioactivities, including effects on intestinal cell proliferation and differentiation, IL-18 secretion, TGF-b1 transcription, and growth of enteropathogenic Escherichia coli (EPEC).

The article presents Binding of lactoferrin to the surface of low-density lipoproteins modified by myeloperoxidase prevents intracellular cholesterol accumulation by human blood monocytes. Topics discussed include Myeloperoxidase (MPO) is a unique heme-containing peroxidase that can catalyze the formation of hypochlorous acid (HOCl); and the strong interaction of MPO with low-density lipoproteins (LDL) promotes proatherogenic modification of LDL by HOCl.

The article presents evidence from systematic reviews of randomized trials on enteral lactoferrin supplementation in preterm neonates. Topics discussed include summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates; and meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections.

The article presents Comparative effect of bovine buttermilk, whey, and lactoferrin on the innate immunity receptors and oxidative status of intestinal epithelial cells. Topics discussed include Milk contains bioactive molecules with important functions as defensive proteins; among them are the whey protein lactoferrin and proteins of the milk fat globule membrane (MFGM) present in buttermilk; and the aim of this study has been to investigate the effects of lactoferrin, whey, and buttermilk.

The article presents Lactoferrin and hematoma detoxification after intracerebral hemorrhage. Topics discussed include discuss the role of lactoferrin (LTF) in detoxifying hematoma after intracerebral hemorrhage (ICH). Subsequent to ICH, neutrophils enter the ICH-affected brain; and LTF is an iron-binding glycoprotein that binds Fe3+ with high affinity.

The article presents N-glycans of lactoferrin. Topics discussed include this minireview summarizes several studies dealing with the diverse glycosylation patterns of lactoferrin from different origins, and the potential impact of these post-translational modifications on the functionality of lactoferrin; and special emphasis is placed on the differences between human and bovine lactoferrin, because the latter form is often selected for the development of novel therapeutic approaches in humans.

The article presents Lactoferrin levels in cervical fluid from in vitro fertilization (IVF) patients correlation with IVF parameters. Topics discussed include lactoferrin (LF) might have roles in the reproductive process and that its levels might change in the female tract as a response to various factors; and the aim of this investigation was to assess whether LF levels in cervical secretions correlate with reproductive parameters from in vitro fertilization (IVF) patients.

The article presents the effects of oral bovine lactoferrin on a mouse model of inflammation associated colon cancer. Topics discussed include Patients with ulcerative colitis or colonic Crohn's disease have a significantly increased risk of developing colorectal cancer; and Bovine lactoferrin (bLF) reportedly inhibited the development of colon cancer in rats and mice, and in a placebo controlled trial, ingestion of bLF inhibited the growth of intestinal polyps.

The article presents Lactoferrin, a versatile natural antimicrobial glycoprotein that modulates the host's innate immunity. Topics discussed include the antimicrobial activity of lactoferrin was the first to be discovered and was assumed to be solely dependent on its iron-chelating ability; and review the current understandings of the antimicrobial effect, interaction with host cells, and innate immune modulation of lactoferrin.

The article presents Lactoferrin receptors in Gram-negative bacteria: an evolutionary perspective. Topics discussed include these events led to the appearance of the lactoferrin gene, which has since been exploited into adopting countless new functions, including the provision of highly bactericidal degradation products; and parallel to lactoferrin's evolution, evolving bacterial receptors have countered the bactericidal properties of this innate immunity protein.

The article presents prospective on multiple biological activities of lactoferrin contributing to piglet welfare. Topics discussed include this review examines the following known beneficial effects of lactoferrin: improves the digestion and capacity for absorption in the intestinal tract; and promotes the absorption of iron and reduces the incidence of iron deficiency anemia.

The article presents Bovine lactoferrin and lactoferrin peptides affect endometrial and cervical cancer cell lines. Topics discussed include the bLF and LF peptides inhibited the proliferation of uterine cancer cells and caused cellular morphological changes and damage to cell monolayers; and bLF induced apoptosis, LFcin17–30 and LFampin265–284 induced apoptosis and necrosis, and LF chimera induced necrosis.

The article presents ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions. Topics discussed include results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC); and the Enteral Lactoferrin in Neonates (ELFIN) study, performed in the Grate Britain, aimed to further address this issue with a well powered double-blind placebo controlled trial.

The article presents Lactoferrin reduces mycobacterial M1-type inflammation induced with trehalose 6,6'-dimycolate and facilitates the entry of fluoroquinolone into granulomas. Topics discussed include Primary infection with Mycobacterium tuberculosis (Mtb) results in the formation of a densely packed granulomatous response that essentially limits the entry and efficacy of immune effector cells; and the physical nature of the granuloma does not readily permit the entry of therapeutic agents.

The article presents Lactoferrin and oral pathologies. Topics discussed include the oral cavity is a non-uniform, extraordinary environment characterized by mucosal, epithelial, abiotic surfaces and secretions as saliva; and commensals exert an important role in host defenses, while pathogenic microorganisms can nullify this protective function causing oral and systemic diseases.

The article presents Antiviral effects of bovine lactoferrin on human norovirus. Topics discussed include Human noroviruses cause significant morbidity and mortality worldwide, but lack approved antivirals or vaccines to treat or prevent infections; and the recent development of two cell culture systems in human transformed B cells (BJABs) and non-transformed human intestinal enteroid cultures overcomes a main limitation in identifying molecules with anti-norovirus activities.

The article presents ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions. Topics discussed include results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC); and the Enteral Lactoferrin in Neonates (ELFIN) study, performed in the Grate Britain, aimed to further address this issue with a well powered double-blind placebo controlled trial.

Lactoferrin supplementation may help prevent infections in preterm infants, but the efficacy has varied with different doses and products. We assessed the absorption and excretion of bovine lactoferrin (bLF) in 31 infants receiving 100, 200, or 300 mg·kg–1·day–1 of enteral bLF for 30 days. bLF and human lactoferrin (hLF) in infant saliva, blood, urine, and stool, as well as expressed (EBM) or donor breast milk (DBM) that were collected (i) before the treatment was initiated, (ii) at study day 22, and (iii) one week after treatment cessation, were measured using ELISA. During treatment, bLF was absorbed from the gastrointestinal tract and detected in plasma, saliva, and urine, as well as excreted in stool. Levels of bLF in the saliva and stool began to decline within 12 h after dosing, and bLF was undetectable in all samples one week after treatment. The concentrations of hLF exceeded those of bLF across sample types and time-points. Infants receiving EBM demonstrated higher levels of hLF in the saliva and stool than those receiving DBM. Neither bLF nor hLF levels varied by patient characteristics, bLF dosage, or infection status. This is the first study demonstrating bLF absorption into the bloodstream and distribution to saliva and urine in preterm infants. Future studies should further explore LF pharmacokinetics because higher and more frequent dosing may improve the clinical benefit of LF supplementation. [ABSTRACT FROM AUTHOR]

Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks gestation) reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC). The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the UK, aimed to further address this issue with a well powered double-blind placebo controlled trial of >2200 preterm infants. The results from ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. Of the 1093 infants, 316 (29%) in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group, with an adjusted risk ratio of 0.95 (95% CI = 0.86–1.04; p = 0.233). Reasons for the differences in ELFIN trial results and other studies may include population differences, the routine use of antifungal prophylaxis in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in the different trials. The UK National Institutes for Health Research funded "Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials" (MAGPIE) study is further exploring the use of lactoferrin, and the results should be available soon. [ABSTRACT FROM AUTHOR]

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The short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is an important innate material in the upper airway, and lactoferrin (LF) aids the innate functions in humans. In this study, a nasal epithelial model was used to investigate how LF modulates SPLUNC1 to reduce the inflammatory process mediated by lipopolysaccharide (LPS). The inflammation of human RPMI-2650 cells was induced with LPS to evaluate SPLUNC1 expression after treating the cells with bovine LF (bLF). The interaction pathway between LF and SPLUNC1 in LPS-induced inflammation was further investigated. Our study reveals that the addition of bLF results in the recovery of SPLUNC1 expression in nasal epithelial cells under LPS-induced inflammation. MAPK is involved in the main pathway for the SPLUNC1 and bLF interaction. Decreased SPLUNC1 function could be recovered by addition of bLF. The MEK1/2-MAPK signaling pathway is crucial for the SPLUNC1 and bLF interaction. Therefore, LF could support SPLUNC1 in the innate immunity recovery process. [ABSTRACT FROM AUTHOR]

Lactoferrin (Lf), an iron-chelating glycoprotein of innate immunity, produced by exocrine glands and neutrophils in infection/inflammation sites, is one of the most abundant defence molecules in airway secretions. Lf, a pleiotropic molecule, exhibits antibacterial and anti-inflammatory functions. These properties may play a relevant role in airway infections characterized by exaggerated inflammatory response, as in Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) subjects. To verify the Lf role in Pseudomonas aeruginosa lung infection, we evaluated the efficacy of aerosolized bovine Lf (bLf) in mouse models of P. aeruginosa acute and chronic lung infections. C57BL/6NCrl mice were challenged with 106 CFUs of P. aeruginosa PAO1 (acute infection) or MDR-RP73 strain (chronic infection) by intra-tracheal administration. In both acute and chronic infections, aerosolized bLf resulted in nonsignificant reduction of bacterial load but significant decrease of the neutrophil recruitment and pro-inflammatory cytokine levels. Moreover, in chronic infection the bLf-treated mice recovered body weight faster and to a higher extent than the control mice. These findings add new insights into the benefits of bLf as a mediator of general health and its potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Giardia intestinalis is the most common infectious protozoan parasite in children. Despite the effectiveness of some drugs, the disease remains a major worldwide problem. Consequently, the search for new treatments is important for disease eradication. Biological molecules with antimicrobial properties represent a promising alternative to combat pathogens. Bovine lactoferrin (bLF) is a key component of the innate host defense system, and its peptides have exhibited strong antimicrobial activity. Based on these properties, we evaluated the parasiticidal activity of these peptides on G. intestinalis. Trophozoites were incubated with different peptide concentrations for different periods of time, and the growth or viability was determined by carboxyfluorescein-succinimidyl-diacetate-ester (CFDA) and propidium iodide (PI) staining. Endocytosis of peptides was investigated by confocal microscopy, damage was analyzed by transmission and scanning electron microscopy, and the type of programmed cell death was analyzed by flow cytometry. Our results showed that the LF peptides had giardicidal activity. The LF peptides interacted with G. intestinalis and exposure to LF peptides correlated with an increase in the granularity and vacuolization of the cytoplasm. Additionally, the formation of pores, extensive membrane disruption, and programmed cell death was observed in trophozoites treated with LF peptides. Our results demonstrate that LF peptides exhibit potent in vitro antigiardial activity. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF) is a multifunctional cationic protein (p I 8.2-8.9) in mammalian milk. We previously reported that enteric-LF prevented hypercholesterolemia and atherosclerosis in a diet-induced atherosclerosis model using Microminipig, although the underlying mechanisms remain unclear. Because LF is assumed to electrostatically interact with bile acids to inhibit intestinal cholesterol absorption, LF could promote cholesterol excretion. In this study, we assessed the interaction between LF and taurocholate in vitro, and the effect of LF on cholesterol excretion in rats. The binding rate of taurocholate to LF was significantly higher than that to transferrin (p I 5.2-6.3). When rats were administered a high-cholesterol diet (HCD) containing 5% LF, LF was detected using ELISA in the upper small intestine from 7.5 to 60 min after the administration. Rats were fed one of the following diets: control, HCD, or HCD + 5% LF for 21 days. Fecal neutral steroids and hepatic cholesterol levels in the HCD group were significantly higher than those in the control group. The addition of LF to a HCD significantly increased fecal neutral steroids levels (22% increase, p < 0.05) and reduced hepatic cholesterol levels (17% decrease, p < 0.05). These parameters were inversely correlated ( R = −0.63, p < 0.05). These results suggest that LF promotes cholesterol excretion via interactions with bile acids. [ABSTRACT FROM AUTHOR]

Lactoferrin (Lf) is an iron-binding glycoprotein that is present at high concentrations in milk. Bovine lactoferricin (LfcinB) is a peptide fragment generated by pepsin proteolysis of bovine lactoferrin (bLf). LfcinB consists of amino acid residues 17-41 proximal to the N-terminus of bLf and a disulfide bond between residues 19 and 36, forming a loop. Both bLf and LfcinB have been demonstrated to have antitumor activities. Colorectal cancer is the second most common cause of cancer death in developed countries. We hypothesized that bLf and LfcinB exert antitumor activities on colon cancer cells (HT-29) by triggering various signaling pathways. bLf and LfcinB significantly induced apoptosis in HT-29 cells but not in normal human intestinal epithelial cells, as revealed by the ApoTox-Glo Triplex Assay. The LIVE/DEAD cell viability assay showed that both bLf and LfcinB reduced the viability of HT-29 cells. Transcriptome analysis indicated that bLf, cyclic LfcinB, and linear LfcinB exerted antitumor activities by differentially activating diverse signaling pathways, including p53, apoptosis, and angiopoietin signaling. Immunoblotting results confirmed that both bLf and LfcinBs increased expression of caspase-8, p53, and p21, critical proteins in tumor suppression. These results provide valuable information regarding bLf and LfcinB for potential clinical applications in colon cancer therapy. [ABSTRACT FROM AUTHOR]

We examined the in-vitro effects of bovine lactoferrin (LF) on the production of interferon-λ (IFN-λ), an antiviral cytokine important for the defense of enterocytes, using the human intestinal epithelial cell line HT-29. HT-29 cell cultures were treated with LF for 1 h, and the cultures were stimulated with polyinosinic-polycytidylic acid (poly I:C). LF increased the concentration of IFN-λ in the culture supernatant after stimulation in a dose-dependent manner. A similar increase in the concentration of IFN-λ was observed in the supernatant of cells washed between treatment with LF and stimulation with poly I:C. At 6 and 24 h after stimulation with poly I:C (early and late phases, respectively) treated cultures contained significantly higher concentrations of IFN-λ1 in the culture supernatant, and significantly higher IFN-λ1 and IFN-λ2 mRNA levels, than controls. These results suggest that LF activates the innate cellular immunity of the enterocytes to double-stranded RNA and increases the production of IFN-λ. [ABSTRACT FROM AUTHOR]

Lactoferrin exerts its biological activities by interacting with receptors on target cells, including LDL receptor-related protein-1 (LRP-1/CD91), intelectin-1 (omentin-1), and Toll-like receptor 4 (TLR4). However, the effects mediated by these receptors are not sufficient to fully explain the many functions of lactoferrin. C-X-C-motif cytokine receptor 4 (CXCR4) is a ubiquitously expressed G-protein coupled receptor for stromal cell-derived factor-1 (SDF-1/CXCL12). Lactoferrin was found to be as capable as SDF-1 in blocking infection by an HIV variant that uses CXCR4 as a co-receptor (X4-tropic HIV), suggesting that lactoferrin interacts with CXCR4. We addressed whether CXCR4 acts as a lactoferrin receptor using HaCaT human keratinocytes and Caco-2 human intestinal cells. We found that bovine lactoferrin interacted with CXCR4-containing lipoparticles, and that this interaction was not antagonized by SDF-1. In addition, activation of Akt in response to lactoferrin was abrogated by AMD3100, a small molecule inhibitor of CXCR4, or by a CXCR4-neutralizing antibody, suggesting that CXCR4 functions as a lactoferrin receptor able to mediate activation of the PI3K-Akt signaling pathway. Lactoferrin stimulation mimicked many aspects of SDF-1-induced CXCR4 activity, including receptor dimerization, tyrosine phosphorylation, and ubiquitination. Cycloheximide chase assays indicated that turnover of CXCR4 was accelerated in response to lactoferrin. These results indicate that CXCR4 is a potent lactoferrin receptor that mediates lactoferrin-induced activation of Akt signaling. [ABSTRACT FROM AUTHOR]