Lactoferrin
Potent antiviral and antibiotic: Inhibits HSV, CMV, EBV, E coli, UTI bacteria (in mice), numerous other viruses and bacteria.
Improved sleep quality, reduced the occurrence of depressive-mood in a human RCT.
Improved intra-abdominal (visceral) fat, BMI and hip circumference in a human RCT.
Was used as part of a successful Myelofibrosis treatment (single case study).
In a Phase II clinical trial against advanced RCC, the treatment group got 21 months median survival on recombinant lactoferrin alone. This compares favorably with the RCC historical cohort, which have exhausted all other options.
Stimulated the immune system, extended lifespan, and reduced amyloid β peptide toxicity in C elegans.
Considered to be one of the key molecules responsible for the benefits of Mother’s milk (anticancer, antiviral, antibacterial).
Phase 2 trial of talactoferrin in previously treated patients with metastatic renal cell carcinoma (link)
Background: Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC).
Methods: Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival.
Results: TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months.
Conclusions: TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational.
Lactotransferrin Downregulation Drives the Metastatic Progression in Clear Cell Renal Cell Carcinoma, 2020
Clear cell renal cell carcinoma (ccRCC) is the main type of RCC, which is the most common type of malignant kidney tumor in adults. A subpopulation (>30%) of ccRCC patients develop metastasis; however, the molecular mechanism remains largely unknown. Here, we found that LTF, the gene encoding lactotransferrin, is dramatically downregulated in primary tumors compared to normal tissues derived from ccRCC patients deposited in The Cancer Genome Atlas (TCGA) database and is a favorable prognostic marker. Moreover, LTF downregulation appears to be more dominant in metastatic ccRCC. LTF overexpression suppresses migration ability in A498 ccRCC cells with high metastatic potential, whereas LTF knockdown fosters cellular migration in poorly metastatic ccRCC cells. Gene set enrichment analysis demonstrated that LTF expression inversely correlates with the progression of epithelial-mesenchymal transition (EMT) in ccRCC, which was further confirmed by RT-PCR experiments. Therapeutically, the administration of recombinant LTF protein significantly suppresses the cell migration ability and lung metastatic potential of ACHN cells, as well as LTF-silenced A498 cells. The gene knockdown of lipoprotein receptor-related protein 1 (LRP1) robustly blocked recombinant LTF protein-induced inhibition of cellular migration and gene expression of EMT markers in ACHN cells. LTF downregulation and LRP1 upregulation combined predicted a poor overall survival rate in ccRCC patients compared to that with either factor alone. Our findings uncover a new mechanism by which LTF may interact with LRP1 to inhibit metastatic progression in ccRCC and also reveal the therapeutic value of recombinant LTF protein in treating metastatic ccRCC.
Recombinant human lactoferrin in the treatment of renal cell carcinoma
Proc Amer Assoc Cancer Res, Volume 46, 2005
PURPOSE: Recombinant human lactoferrin (rhLF) is an immunomodulatory protein with anti-cancer activity. We evaluated rhLF in mice and patients with renal cell cancer (RCC), which is known to be immunosensitive. RESULTS: Oral rhLF inhibited renal tumor growth in syngeneic mice. Since rhLF has been described as lymphoproliferative, we looked for and found a significant (p<0.01) ex-vivo murine T-cell expansion on splenocyte co-culture with irradiated tumor cells. We evaluated oral rhLF monotherapy in a 5-patient pilot trial in metastatic RCC. RhLF showed an excellent safety profile without any drug-related SAEs. RCC is a heterogeneous disease with varying individual tumor biology, so we used tumor growth rates (TGR), with patients serving as their own control, to evaluate the effect of rhLF. All five patients (100%) showed a reduction in TGR following rhLF therapy. On average, target lesions decreased from growing 9.4% to shrinking 0.2% a month. This decrease in TGR correlated with an increased progression free survival (PFS) with median PFS (7.3 months) and PFS rates at 2, 6, 12 months (100%, 60%, 40%) all substantially higher than expected in this patient population. Two patients remain on drug and progression-free fifteen months after start of therapy, with one (20%) confirmed, sustained partial tumor response (63% tumor shrinkage by RECIST; over 85% by WHO). CONCLUSIONS: Oral rhLF appears to have activity against renal cancer in animals and humans. Although tested so far in only a few patients, these results are exciting since RCC patients have few effective options. A well-tolerated oral drug would be very attractive in this disease.
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMNs and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum ("first milk") has the highest concentration, followed by human milk, then cow milk (150 mg/L).[5]
Safety/Efficacy Study of Oral Recombinant Human Lactoferrin in Renal Cell Carcinoma (link) (link2)
This is an open label, multi-center Phase 2 study. Approximately 40 patients will be enrolled in a single study arm. RhLF, at a dose of 1.5 g [1 vial], twice a day (b.i.d.), will be administered orally for two cycles each of 12 consecutive weeks followed by 2 weeks off. A maximum of two additional cycles may be given if an objective response is obtained or if the patient has stable disease and no increase in the size of the target tumor(s) relative to either the Screening CT or the most recent CT measurement, measured according to RECIST prior to the additional cycle(s). Response and progression-free survival will be evaluated for the first 20 patients enrolled. If no patient has an objective response and less than 10% of the patients are alive and progression-free at 14 weeks from the start of Study Drug, then the study will be terminated. If in either Cycle 3 or Cycle 4, more than three out of the first ten patients or more than six out of the first twenty patients entering the cycle experience a Grade 3 or 4 Study-Drug-related adverse event, no further patients will advance into Cycle 3 or Cycle 4.
Effects of lactoferrin supplementation on sleep quality, mood states, and enteric environment in poor sleepers-Randomized, placebo-controlled, double-blind study-
January 2018, Japanese Pharmacology and Therapeutics
Abstract
Self-induced lifestyle problems, such as stress, negative emotions, or irregular sleep-wake schedule, cause sleep disturbance. Lactoferrin has been reported to improve sleep quality and enteric environment in rats and humans. Our previous randomized placebo-controlled double-blind trial has shown that lactoferrin supplementation for 4 weeks could increase immunoglobulin A (igA) secretion and improve sleep quality, daily mood, and enteric environment in sixty participants. In the present study, lactoferrin supplementation was evaluated in poor sleepers (total mood disturbance scores were more than the median). In all, thirty-one participants took LLF (liposomal lactoferrin: lactoferrin 270 mg/d) or a placebo for four weeks. Significant improvement in OSA sleep inventory for middle age and aged (OSA-MA) "sleepiness and fatigue on rising" and "initiation and maintenance of sleep", Profile of Mood States "depression-dejection", and stool consistency were found in the LLF group but not in the placebo group. The changes in subjective sleep quality had a significant linear correlation with the changes in the enteric environment. In conclusion, four-week lactoferrin supplementation may improve subjective sleepiness and fatigue on rising, nighttime sleep quality, daily depressed mood, and stool consistency.
Study on the Therapeutic Benefit on Lactoferrin in Patients with Colorectal Cancer Receiving Chemotherapy (link)
Bovine LF administration resulted in significant increase in serum LF, serum GST enzyme, INF-γ, WBCs count, platelet count, RBCs count, neutrophil count, and Hb level; also bLF administration resulted in significant decrease in BUN, creatinine, ALT, AST, and CEA as compared to all parameters values of patients in control group at significance level (Table 4).
Platelet (*103/mm3) +36.46 ± 12.26*
Lactoferrin for fat loss (link)
A role for lactoferrin in reducing adiposity was first discovered in fat cell culture studies. It was found that lactoferrin specifically inhibits fat accumulation in fat cells, as well as formation of new fat cells (a process called adipogenesis) 9, 10.
The potential anti-obesity effect of lactoferrin has been shown in obese mice, where a lactoferrin rich diet resulted in increased fat loss 11. Another study on mice found that a lactoferrin rich whey protein isolate prevents obesity by dose- dependently preventing fat gain and fatty liver formation during spontaneous feeding, and enhancing fat los during a calorie restricted diet 12.
Research is showing that lactoferrin might help with fat loss in humans as well. Higher blood levels of lactoferrin are associated with lower BMI (an obesity indicator), waist-to-hip ratio and fasting triglyceride and glucose concentrations 13, 14. A notable study supplemented healthy men and women, aged 22--60 years, with 300 mg lactoferrin (enteric coated) tablets per day for 8 weeks 15. n=26. Subjects were told to maintain their regular food habits. It was found that the lactoferrin supplement, compared to placebo, resulted in a 12.4% significant reduction in intra-abdominal (visceral) fat 15. The lacroferrin group also showed significant decreases in body weight (-3.3 lb), BMI (-0.6) and hip circumference (-1 inch), while the placebo group instead gained 0.45 lb body weight. In addition, there was a 1.7 inch reduction in waist circumference in the lacroferrin group. It was concluded that lacroferrin appears to be a promising supplement for counteracting intra-abdominal fat accumulation.
Surprising results of a supportive integrated therapy in myelofibrosis - PubMed
https://pubmed.ncbi.nlm.nih.gov/25466670/
Objectives: Myelofibrosis (MF) is characterized by shortened survival and a greatly compromised quality of life. Weight loss and cachexia seem to be the most important factors influencing survival in patients with MF. The aim of this study was to assess the efficacy of an integrated supportive therapy in improving cachexia and MF-related symptoms.
Methods: We reported on a case of a patient with MF who presented with weight loss and cachexia associated with severe anemia, fatigue, fever, and bone pain. The circulating levels of inflammatory, oxidative stress parameters, hepcidin, and erythropoietin were evaluated and were above normal ranges. The patient was treated with a multitargeted approach specifically developed for cachexia including oral l-carnitine, celecoxib, curcumin, lactoferrin, and subcutaneous recombinant human erythropoietin (EPO)-α.
Results: Surprisingly, after 1 y, cachexia features improved, all MF symptoms were in remission, and inflammatory and oxidative stress parameters, hepcidin, and EPO were reduced.
Conclusions: Because our protocol was targeted at inflammation and the metabolic state, its effectiveness may emphasize the role of inflammation in the pathogenesis of MF symptoms and demonstrates a need for the study of new integrated therapeutic strategies.
Cachexia | MPNforum Magazine (link)
“We reported on a case of a patient with MF who presented with weight loss and cachexia associated with severe anemia, fatigue, fever, and bone pain. The circulating levels of inflammatory, oxidative stress parameters, hepcidin, and erythropoietin were evaluated and were above normal ranges. The patient was treated with a multitargeted approach specifically developed for cachexia including oral l-carnitine, celecoxib, curcumin, lactoferrin, and subcutaneous recombinant human erythropoietin (EPO)-α.”
RESULTS: “Surprisingly, after one year, cachexia features improved, all MF symptoms were in remission, and inflammatory and oxidative stress parameters, hepcidin, and EPO were reduced.”
Inhibition of Epstein-Barr Virus Infection by Lactoferrin, 2012
Lactoferrin (LF) is a multifunctional glycoprotein that plays an important role in native immune defense against infections, including human herpetic viruses, such as cytomegalovirus and herpes simplex virus types 1 and 2. However, its anti-Epstein-Barr virus (EBV, a γ-herpesvirus) function has not been reported in the literature. EBV is widespread in all human populations and is believed to be linked to tumorigenesis, such as lymphomas and nasopharyngeal carcinoma (NPC). We previously reported that LF expressed a significantly lower level in NPC tissues and was a likely tumor suppressor. Since EBV infection is a major carcinogen of NPC development, we investigated the effect of LF on EBV infection and found that LF could protect human primary B lymphocytes and nasopharyngeal epithelial cells from EBV infection, but had no effect on EBV genome DNA replication. LF prevented EBV infection of primary B cells mediated by its direct binding to the EBV receptor (CD21) on the B-cell surface. Tissue array immunohistochemistry revealed that LF expression was significantly downregulated in NPC specimens, in which high EBV viral capsid antigen-IgA levels were observed. These data suggest that LF may inhibit EBV infection and that its downregulation could contribute to NPC development.
Lactoferrin suppresses the Epstein–Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9, 2014
Epstein–Barr virus (EBV) infection contributes to tumorigenesis of various human malignancies including nasopharyngeal carcinoma (NPC). EBV triggers innate immune and inflammatory responses partly through Toll-like receptor (TLR) signaling. Lactoferrin (LF), with its anti-inflammatory properties, is an important component of the innate immune system. We previously reported that LF protects human B lymphocytes from EBV infection by its ability to bind to the EBV receptor CD21, but whether LF can suppress EBV-induced inflammation is unclear. Here, we report that LF reduced synthesis of IL-8 and monocyte chemoattractant protein-1 (MCP-1) induced by EBV in macrophages via its suppression of NF-κB activity. LF interacted with TLR2 and interfered with EBV-triggered TLR2-NF-κB activation. LF inhibited the ability of TLR9 to recognize dsDNA by binding to its co-receptor CD14, which blocked the interaction between CD14 and TLR9. EBV-induced inflammation was thus aggravated in the presence of CD14. In addition, LF expression levels were significantly downregulated in NPC specimens, and correlated inversely with IL-8 and MCP-1 expression. These findings suggest that LF may suppress the EBV-induced inflammatory response through interfering with the activation of TLR2 and TLR9.
[IL-1β, TNF-α, IL-6, IL-8, VEGF, PDGF, TGF-β and IFNs are Cytokines frequently implicated in MPN.]
Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections (link)
Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly cationic charge. Noteworthy, Lf also exhibits immunomodulatory activities performing up- and down-regulation of innate and adaptive immune cells, contributing to the homeostasis in mucosal surfaces exposed to myriad of microbial agents, such as the gastrointestinal and respiratory tracts. Although the inflammatory process is essential for the control of invasive infectious agents, the development of an exacerbated or chronic inflammation results in tissue damage with life-threatening consequences. In this review, we highlight recent findings in in vitro and in vivo models of the gut, lung, oral cavity, mammary gland, and liver infections that provide experimental evidence supporting the therapeutic role of human and bovine Lf in promoting some parameters of inflammation and protecting against the deleterious effects of bacterial, viral, fungal and protozoan-associated inflammation. Thus, this new knowledge of Lf immunomodulation paves the way to more effective design of treatments that include native or synthetic Lf derivatives, which may be useful to reduce immune-mediated tissue damage in infectious diseases.
A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid β peptide toxicity in Caenorhabditis elegans (link)
Lactoferrin is a highly multifunctional glycoprotein involved in many physiological functions, including regulation of iron absorption and immune responses. Moreover, there is increasing evidence for neuroprotective effects of lactoferrin. We used Caenorhabditis elegans as a model to test the protective effects, both on phenotype and transcriptome, of a nutraceutical product based on lactoferrin liposomes. In a dose‐dependent manner, the lactoferrin‐based product protected against acute oxidative stress and extended lifespan of C. elegans N2. Furthermore, Paralysis of the transgenic C. elegans strain CL4176, caused by Aβ1‐42 aggregates, was clearly ameliorated by treatment. Transcriptome analysis in treated nematodes indicated immune system stimulation, together with enhancement of processes involved in the oxidative stress response. The lactoferrin‐based product also improved the protein homeostasis processes, cellular adhesion processes, and neurogenesis in the nematode. In summary, the tested product exerts protection against aging and neurodegeneration, modulating processes involved in oxidative stress response, protein homeostasis, synaptic function, and xenobiotic metabolism. This lactoferrin‐based product is also able to stimulate the immune system, as well as improving reproductive status and energy metabolism. These findings suggest that oral supplementation with this lactoferrin‐based product could improve the immune system and antioxidant capacity. Further studies to understand the molecular mechanisms related with neuronal function would be of interest.
An abundant iron-binding protein in milk.
The potent iron-binding properties of lactoferrin can locally create iron deficiency, and this is an important factor in host defense as it prevents bacteria from growing and forming biofilms.
Has direct antiviral, antifungal, and even some anticancer activities.
Promote wound healing and bone growth, or it can act as an iron carrier.
Displays a cytokine-like “alarmin” activity, and it activates the immune system. Simultaneously, it can bind endotoxin (lipopolysaccharide), and in doing so, it modulates the activity of the host immune response.
https://cdnsciencepub.com/doi/10.1139/o2012-016
Lactoferrin is a protein produced in milk and bodily secretions like saliva. It’s also produced by some immune system cells.
Research shows that lactoferrin is active against a wide assortment of viruses.
Its antiviral activity has been shown to aid in the battle against viruses that cause the common cold, flu, stomach flu, and other illnesses.
Oral lactoferrin may reduce both the incidence and severity of disease caused by viruses.
Effective against E Coli and effective against UTI in mice.
https://www.lifeextension.com/magazine/2020/6/lactoferrin-protects-against-viruses
Lactoferrin Defends Against a Wide Range of Viruses
Lactoferrin has been shown in laboratory, animal, and preclinical research to help protect against a huge list of viruses, including:
Various viruses that cause the common cold,4
Various viruses that cause flu, including several different strains of influenza A (even the H1N1 subtype that caused a global outbreak in 2009),4,11
Various viruses that cause gastroenteritis (stomach flu) 4
Herpes simplex virus,4,12
Human immunodeficiency virus (HIV), which causes AIDS,1,2,4
Hepatitis B virus,1,3,8
Hepatitis C virus,1,2,8
Cytomegalovirus (CMV),1,4
Poliovirus,4,8
Respiratory syncytial virus (RSV),1,11
Hantavirus,1,11
Dengue virus, the cause of dengue fever,7,8
Enteroviruses,2,8
Echovirus,1,7,8
Coxsackieviruses,10 and
Epstein-Barr virus (EBV).12
Lactoferrin: an iron-binding antimicrobial protein against Escherichia coli infection, 2011
Escherichia coli (E. coli) are the most common aerobic gram-negative bacilli in a normal intestinal tract. They cause most of the intra-abdominal infections, wound infections associated with abdominal surgery, and septicemia. Most of these infections are of endogenous intestinal origin. Lactoferrin (LF) is an iron-binding glycoprotein found in milk and various external secretions. This protein has been found to have a number of biological functions, including antimicrobial, anti-cancer, antioxidant, and immunomodulatory effects. Partial degradation of LF by pepsin can give rise to peptides termed lactoferricin (LFcin) with more potent antimicrobial activity. LF and LFcin have been shown to inhibit the growth of a number of pathogenic bacteria (including E. coli and antibiotic-resistant strains), fungi, and even viruses in both in vitro and in vivo studies. We previously demonstrated that both recombinant porcine LF (pLF) produced from yeast and a synthetic 20-residue porcine LFcin peptide exhibit antimicrobial activity in vitro. In one of our recent studies, we performed pathogen challenges, including pathogenic E. coli, Staphylococcus aureus and Candida albicans, of the digestive tract of a transgenic milk-fed animal model. The results showed that LF has broad spectrum antimicrobial activity in the digestive tract and protects the mucosa of the small intestine from injury. Our following study also revealed that pLF as a feedstuff additive enhances avian immunity, including antibody formation and cell-mediated immunity. All of these results suggest that LF could be a novel natural protein in the treatment and prevention of infections with E. coli or antibiotic-resistant bacteria strains.
Lactoferrin prevents invasion and inflammatory response following E. coli strain LF82 infection in experimental model of Crohn's disease
Background: Crohn's disease is a multifactorial disease in which an aberrant immune response to commensal intestinal microbiota leads to chronic inflammation. The small intestine of patients with Crohn's disease is colonized by a group of adherent-invasive Escherichia coli strongly able to adhere and invade intestinal epithelial cells lactoferrin is an iron-binding glycoprotein known to have anti-bacterial and anti-inflammatory activities.
Aims: We explore the ability of bovine lactoferrin to modulate the interactions between the adherent-invasive E. coli strain LF82 and intestinal epithelial cells as well as the inflammatory response.
Methods: Bacterial adhesion and invasion assays were used to assess the antimicrobial activity of lactoferrin. Electron microscopy was used to characterize bacteria-cell interactions. The mRNA expression of pro-inflammatory cytokines was measured both in cultured cells and in biopsies taken from intestine of patients affected by Crohn's disease.
Results: Lactoferrin inhibited bacterial invasion through minimally affecting adhesion. This divergence was due to a mannose-dependent lactoferrin binding to the bacterial type 1 pili and consequent bacterial aggregation on the intestinal epithelial cell surface. Expression of pro-inflammatory cytokines, such as TNF-alpha, IL-8, and IL-6, was markedly inhibited by lactoferrin both in cultured and Crohn-derived intestinal cells.
Augmentation of Urinary Lactoferrin Enhances Host Innate Immune Clearance of Uropathogenic Escherichia coli, 2019
Urinary tract infection (UTI) is a prominent global health care burden. Although UTI is readily treated with antibiotics in healthy adults, complicated cases in immune-compromised individuals and the emerging antibiotic resistance of several uropathogens have accelerated the need for new treatment strategies. Here, we surveyed the composition of urinary exosomes in a mouse model of uropathgenic Escherichia coli (UPEC) UTI to identify specific urinary tract defense constituents for therapeutic development. We found an enrichment of the iron-binding glycoprotein lactoferrin in the urinary exosomes of infected mice. In subsequent in vitro studies, we identified human bladder epithelial cells as a source of lactoferrin during UPEC infection. We further established that exogenous treatment with human lactoferrin (hLf) reduces UPEC epithelial adherence and enhances neutrophil antimicrobial functions including bacterial killing and extracellular trap production. Notably, a single intravesicular dose of hLf drastically reduced bladder bacterial burden and neutrophil infiltration in our murine UTI model. We propose that lactoferrin is an important modulator of innate immune responses in the urinary tract and has potential application in novel therapeutic design for UTI.
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