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Molecules (Basel, Switzerland) May 2022Numerous harmful factors that affect the human body from birth to old age cause many disturbances, e.g., in the structure of the genome, inducing cell apoptosis and... (Review)
Review
Numerous harmful factors that affect the human body from birth to old age cause many disturbances, e.g., in the structure of the genome, inducing cell apoptosis and their degeneration, which leads to the development of many diseases, including cancer. Among the factors leading to pathological processes, microbes, viruses, gene dysregulation and immune system disorders have been described. The function of a protective agent may be played by lactoferrin as a "miracle molecule", an endogenous protein with a number of favorable antimicrobial, antiviral, antioxidant, immunostimulatory and binding DNA properties. The purpose of this article is to present the broad spectrum of properties and the role that lactoferrin plays in protecting human cells at all stages of life.
Topics: Humans; Immune System; Lactoferrin; Viruses
PubMed: 35566292
DOI: 10.3390/molecules27092941 -
Nutrients Jul 2022Early adverse fetal environments can significantly disturb central nervous system (CNS) development and subsequently alter brain maturation. Nutritional status is a... (Review)
Review
Early adverse fetal environments can significantly disturb central nervous system (CNS) development and subsequently alter brain maturation. Nutritional status is a major variable to be considered during development and increasing evidence links neonate and preterm infant impaired brain growth with neurological and psychiatric diseases in adulthood. Breastfeeding is one of the main components required for healthy newborn development due to the many "constitutive" elements breastmilk contains. Maternal intake of specific nutrients during lactation may alter milk composition, thus affecting newborn nutrition and, potentially, brain development. Lactoferrin (Lf) is a major protein present in colostrum and the main protein in human milk, which plays an important role in the benefits of breastfeeding during postnatal development. It has been demonstrated that Lf has antimicrobial, as well as anti-inflammatory properties, and is potentially able to reduce the incidence of sepsis and necrotizing enterocolitis (NEC), which are particularly frequent in premature births. The anti-inflammatory effects of Lf can reduce birth-related pathologies by decreasing the release of pro-inflammatory factors and inhibiting premature cervix maturation (also related to commensal microbiome abnormalities) that could contribute to disrupting brain development. Pre-clinical evidence shows that Lf protects the developing brain from neuronal injury, enhances brain connectivity and neurotrophin production, and decreases inflammation in models of perinatal inflammatory challenge, intrauterine growth restriction (IUGR) and neonatal hypoxia-ischemia (HI). In this context, Lf can provide nutritional support for brain development and cognition and prevent the origin of neuropsychiatric diseases later in life. In this narrative review, we consider the role of certain nutrients during neurodevelopment linking to the latest research on lactoferrin with respect to neonatology. We also discuss new evidence indicating that early neuroprotective pathways modulated by Lf could prevent neurodegeneration through anti-inflammatory and immunomodulatory processes.
Topics: Adult; Brain; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Lactoferrin; Longevity; Milk, Human; Pregnancy; Premature Birth
PubMed: 35889882
DOI: 10.3390/nu14142923 -
Theranostics 2021Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death...
Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell line MDA-MB-231 and non-TNBC cell line MCF-7. Holo-Lf significantly increased the total iron content, promoted ROS generation, increased lipid peroxidation end product, malondialdehyde (MDA), and enhanced ferroptosis of MDA-MB-231 cells. By contrast, Apo-Lf upregulated SLC7a11 expression, increased GSH generation and inhibited ferroptosis of MDA-MB-231 cells. However, non-TNBC MCF-7 cells were resistant to Holo-Lf-induced ferroptosis because MCF-7 cells have a higher redox balance capacity than MDA-MB-231 cells. More importantly, Holo-Lf downregulated HIF-1α expression, ameliorated the hypoxia microenvironment in subcutaneous MDA-MB-231 tumors, and promoted radiation-induced DNA damage to hypoxic MDA-MB-231 cells. Finally, the efficacy of radiotherapy to MDA-MB-231 tumors was enhanced by Holo-Lf. Holo-Lf could induce ferroptosis in MDA-MB-231 cells and sensitize MDA-MB-231 tumors to radiotherapy.
Topics: Animals; Biomarkers, Pharmacological; Breast Neoplasms; Cell Death; Cell Line, Tumor; China; Female; Ferroptosis; Humans; Iron; Lactoferrin; Lipid Peroxidation; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Radiotherapy; Reactive Oxygen Species; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 33537080
DOI: 10.7150/thno.52028 -
The Journal of Pediatrics Oct 2023To evaluate the neurodevelopmental outcomes at 5.5 years of age in children who were previously randomized to cow milk-based infant formula (control) or similar formula... (Randomized Controlled Trial)
Randomized Controlled Trial
Improved Neurodevelopmental Outcomes at 5.5 Years of Age in Children Who Received Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula Through 12 Months: A Randomized Controlled Trial.
OBJECTIVE
To evaluate the neurodevelopmental outcomes at 5.5 years of age in children who were previously randomized to cow milk-based infant formula (control) or similar formula (milk fat globule membrane + lactoferrin) with added sources of bovine milk fat globule membrane and bovine lactoferrin through 12 months of age.
DESIGN
Children who completed study feeding were invited to participate in follow-up assessments: cognitive development across multiple domains (primary outcome; Wechsler Preschool & Primary Scale of Intelligence, 4 Edition), inhibitory control/rule learning (Stroop Task), flexibility/rule learning (Dimensional Change Card Sort), and behavior/emotion (Child Behavior Checklist).
RESULTS
Of 292 eligible participants (control: 148, milk fat globule membrane + lactoferrin: 144), 116 enrolled and completed assessments (control: 59, milk fat globule membrane + LF: 57). There were no group demographic differences except family income (milk fat globule membrane + lactoferrin significantly higher). Wechsler Preschool & Primary Scale of Intelligence, 4 Edition composite scores (mean ± standard error) for Visual Spatial (100.6 ± 1.7 vs 95.3 ± 1.7; P = .027), Processing Speed (107.1 ± 1.4 vs 100.0 ± 1.4; P < .001), and Full-Scale IQ (98.7 ± 1.4 vs 93.5 ± 1.5; P = .012) were significantly higher for milk fat globule membrane + lactoferrin versus control, even after controlling for demographic/socioeconomic factors. Stroop Task scores were significantly higher in milk fat globule membrane + lactoferrin versus control (P < .001). Higher Dimensional Change Card Sort scores (P = .013) in the border phase (most complex/challenging) were detected, and more children passed the border phase (32% vs 12%; P = .039) for milk fat globule membrane versus control. No group differences in Child Behavior Checklist score were detected.
CONCLUSIONS
Children who received infant formula to 12 months of age with added bovine milk fat globule membrane and bovine lactoferrin versus standard formula demonstrated improved cognitive outcomes in multiple domains at 5.5 years of age, including measures of intelligence and executive function.
TRIAL REGISTRATION
Clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT04442477.
Topics: Child; Child, Preschool; Female; Humans; Infant; Glycolipids; Glycoproteins; Infant Formula; Lactoferrin
PubMed: 37192722
DOI: 10.1016/j.jpeds.2023.113483 -
Theranostics 2023Myocardial infarction (MI) causes a severe injury response that eventually leads to adverse cardiac remodeling and heart failure. Lactoferrin (Ltf), as a secreted...
Myocardial infarction (MI) causes a severe injury response that eventually leads to adverse cardiac remodeling and heart failure. Lactoferrin (Ltf), as a secreted protein, bears multi-pharmacological properties. Present study aims to establish the cardioprotective function and corresponding mechanism of Ltf in MI process. We performed proteomic analysis in Tregs derived from MI heart, and identified Ltf as a remarkably upregulated secreted protein. However, Ltf was decreased in circulation and positively correlated with cardiac function both in mice and patients after MI. Ltf administration remarkably alleviated cardiac fibrosis and remodeling, improved cardiac function, and reduced incidence of heart failure in mice post-MI. , Ltf suppressed fibroblast to myofibroblast conversion induced by transforming growth factor-β (TGF-β). Mechanistically, phosphoproteomic landscape analysis revealed that Ltf repressed the activation of mTORC1/S6K/eIF-4B signaling pathway via interaction with CD74 receptor. Administration of mTORC1/S6K/eIF-4B axis agonist MHY1485 abolished the cardioprotective effects of Ltf. Besides, MHY1485 also markedly reversed the effects of Ltf on suppressing the transformation of fibroblast to myofibroblast mediated by TGF-β. Our study established the cardiac protective role of Ltf in attenuating cardiac remodeling and improving cardiac function by inhibiting the activation of myofibroblasts through suppressing mTORC1/S6K/eIF-4B signaling pathway post-MI. Treatment with Ltf may serve as a potential novel therapeutic intervention in patients with MI.
Topics: Mice; Animals; Lactoferrin; Myocardium; Ventricular Remodeling; Proteomics; Myocardial Infarction; Signal Transduction; Heart Failure; Transforming Growth Factor beta; Fibrosis
PubMed: 37351157
DOI: 10.7150/thno.85361 -
Biochemistry and Cell Biology =... Feb 2021Nearly all extracellular proteins undergo post-translational modification with sugar chains during their transit through the endoplasmic reticulum and the Golgi... (Review)
Review
Nearly all extracellular proteins undergo post-translational modification with sugar chains during their transit through the endoplasmic reticulum and the Golgi apparatus. These "sweet" modifications not only influence the activity of its carrier protein, but they themselves often have bioactivity, independent of the carrier function. Lactoferrin belongs to the group of glycoproteins and is modified with several different -glycans. 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. A 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. For this reason, the potential impact of the bovine-specific glycosylation patterns on the observed heterogeneous effects of lactoferrin in humans is discussed within this minireview.
Topics: Animals; Cattle; Endoplasmic Reticulum; Glycosylation; Golgi Apparatus; Humans; Lactoferrin; Polysaccharides; Protein Processing, Post-Translational
PubMed: 32464076
DOI: 10.1139/bcb-2020-0106 -
Indian Journal of Ophthalmology Jul 2022Lactoferrin (LF) is an iron-binding glycoprotein released from mucous secreting cells and neutrophils. LF can be used in a broad range of eye diseases related to the... (Review)
Review
Lactoferrin (LF) is an iron-binding glycoprotein released from mucous secreting cells and neutrophils. LF can be used in a broad range of eye diseases related to the retina, cornea, and optic nerve. The retina is particularly affected by oxidative stress inside the photoreceptor being constantly exposed to light which induces accumulation of reactive oxygen species (ROS) in the retinal pigmented epithelium (RPE) causing damage to photoreceptor recycling. Retinitis pigmentosa (RP) and macular degeneration are inherited retinopathies that consist of different disease-causing genes, that cause mutations with highly varied clinical consequences. Age-related macular degeneration is a chronic disease of the retina and one of the major causes of sight loss. This review provides an application of lactoferrin and LF-based nano-formulations or nanoparticles in the field of retinal diseases or corneal diseases such as retinitis pigmentosa, retinoblastoma, age-related macular degeneration (AMD), keratoconus and uveitis. Several studies have found that lactoferrin's antibacterial activity is not limited to its iron sequestration, but also its ability as a nanoparticle that acts as a carrier to deliver drugs by crossing the blood-retina barrier (BRB) and its involvement in cell cycle control, which is not possible by many transferrin proteins.
Topics: Humans; Iron; Lactoferrin; Macular Degeneration; Retina; Retinitis Pigmentosa
PubMed: 35791114
DOI: 10.4103/ijo.IJO_303_22 -
International Journal of Molecular... Apr 2017Lactoferrin is a multifunctional glycoprotein found in the milk of most mammals. In addition to its well-known role of binding iron, lactoferrin carries many important... (Review)
Review
Lactoferrin is a multifunctional glycoprotein found in the milk of most mammals. In addition to its well-known role of binding iron, lactoferrin carries many important biological functions, including the promotion of cell proliferation and differentiation, and as an anti-bacterial, anti-viral, and anti-parasitic protein. These functions differ among lactoferrin homologs in mammals. Although considerable attention has been given to the many functions of lactoferrin, its primary nutritional contribution is presumed to be related to its iron-binding characteristics, whereas the role of glycosylation has been neglected. Given the critical role of glycan binding in many biological processes, the glycan moieties in lactoferrin are likely to contribute significantly to the biological roles of lactoferrin. Despite the high amino acid sequence homology in different lactoferrins (up to 99%), each exhibits a unique glycosylation pattern that may be responsible for heterogeneity of the biological properties of lactoferrins. An important task for the production of biotherapeutics and medical foods containing bioactive glycoproteins is the assessment of the contributions of individual glycans to the observed bioactivities. This review examines how the study of lactoferrin glycosylation patterns can increase our understanding of lactoferrin functionality.
Topics: Animals; Glycoproteins; Glycosylation; Humans; Lactoferrin; Mass Spectrometry; Milk Proteins; Polysaccharides; Protein Isoforms; Protein Processing, Post-Translational; Protein Stability
PubMed: 28425960
DOI: 10.3390/ijms18040870 -
American Journal of Perinatology Aug 2021Very low birth weight preterm infants are at risk for life-threatening infections in the NICU. Breast milk protects against infections but carries the risk of infection...
OBJECTIVE
Very low birth weight preterm infants are at risk for life-threatening infections in the NICU. Breast milk protects against infections but carries the risk of infection by cytomegalovirus (CMV) shed in mother's milk. Lactoferrin is a breast milk and saliva protein with potent neutralizing activity against CMV.
STUDY DESIGN
VLBW, maternal breast milk fed infants in the NICU and their lactating mothers were enrolled and followed for 3 months/discharge. Breast milk and infant saliva samples were collected biweekly. Maternal CMV status was determined on breast milk. CMV was measured using quantitative polymerase chain reaction and lactoferrin by enzyme-linked immunosorbent assay.
RESULTS
In an in vitro neutralization assay, the IC of purified human lactoferrin against CMV was 2.08 ng/mL. Bovine lactoferrins were more potent, ICs > 10-fold higher. Lactoferrin was detected in all breast milk (median: 3.3 × 10 ng/mL) and saliva (median: 84.4 ng/swab) samples. Median CMV load in breast milk was 893 copies/mL. There was no correlation between breast milk lactoferrin concentration and CMV load. Five infants acquired postnatal CMV. There was no difference in saliva or breast milk lactoferrin concentration for mother-infant pairs and postnatal CMV acquisition.
CONCLUSION
Lactoferrin neutralizes CMV in vitro, but concentrations in breast milk and saliva are likely too low for effective neutralization in vivo.
Topics: Breast Feeding; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Infectious Disease Transmission, Vertical; Lactoferrin; Male; Milk, Human; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Saliva
PubMed: 32069486
DOI: 10.1055/s-0040-1701609 -
Biochemistry and Cell Biology =... Feb 2017Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and... (Review)
Review
Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and iron homeostasis. Oral Lf supplementation in human preterm infants has been shown to reduce the incidence of sepsis and necrotizing enterocolitis. In preclinical models of antenatal stress and perinatal brain injury, bovine Lf protected the developing brain from neuronal loss, improved connectivity, increased neurotrophic factors, and decreased inflammation. It also supported brain development and cognition. Further, Lf can prevent preterm delivery by reducing proinflammatory factors and inhibiting premature cervix maturation. We review here the latest research on Lf in the field of neonatology.
Topics: Animals; Anti-Infective Agents; Cattle; Humans; Infant, Premature; Lactoferrin
PubMed: 28085488
DOI: 10.1139/bcb-2016-0066