lactoferrin and Anemia

Lactoferrin (LF) is abundant in human milk and plays an important role in the health of children. Bovine LF (bLF) has high homology with human LF and has been reported to have multiple biological functions. Several clinical studies have been conducted considering these properties, which reported the usefulness of bLF. This review was aimed to provide an overview of the clinical evidence in children. We searched clinical reports investigating the effects of bLF in children and identified 36 studies on the role of bLF in infections, iron metabolism, body growth, cerebral development, and fecal microbiome. Considering the accumulated evidence, bLF may contribute to the child health, particularly by suppressing or alleviating gastrointestinal and respiratory symptoms, and improving the iron status of children with anemia or those at high risk of anemia. The dose of bLF varies depending on the expected effect and target age, but may not necessarily have to be as high as human LF in human milk. Some of the beneficial effects of bLF have not been fully validated due to limited clinical evidence or being observed in the secondary analysis of some studies. Further clinical evidence would add significant value to the use of bLF in child health.

Topics: Anemia; Child; Child Health; Humans; Iron; Lactoferrin; Milk, Human

Iron is by far the most widespread and essential transition metal, possessing crucial biological functions for living systems. Despite chemical advantages, iron biology has forced organisms to face with some issues: ferric iron insolubility and ferrous-driven formation of toxic radicals. For these reasons, acquisition and transport of iron constitutes a formidable challenge for cells and organisms, which need to maintain adequate iron concentrations within a narrow range, allowing biological processes without triggering toxic effects. Higher organisms have evolved extracellular carrier proteins to acquire, transport and manage iron. In recent years, a renewed interest in iron biology has highlighted the role of iron-proteins dysregulation in the onset and/or exacerbation of different pathological conditions. However, to date, no resolutive therapy for iron disorders has been found. In this review, we outline the efficacy of Lactoferrin, a member of the transferrin family mainly secreted by exocrine glands and neutrophils, as a new emerging orchestrator of iron metabolism and homeostasis, able to counteract iron disorders associated to different pathologies, including iron deficiency and anemia of inflammation in blood, Parkinson and Alzheimer diseases in the brain and cystic fibrosis in the lung.

Topics: Anemia; Homeostasis; Humans; Iron; Iron Metabolism Disorders; Lactoferrin; Transferrin

Lactoferrin (Lf), an iron-binding multifunctional glycoprotein belonging to the transferrin family, is present in most biological secretions and reaches particularly high concentrations in colostrum and breast milk. A key function of lactoferrin is non-immune defence and it is considered to be a mediator linking innate and adaptive immune responses. Lf from bovine milk (bLf), the main Lf used in human medicine because of its easy availability, has been designated by the United States Food and Drug Administration as a food additive that is generally recognized as safe (GRAS). Among the numerous protective activities exercised by this nutraceutical protein, the most important ones demonstrated after its oral administration are: Antianemic, anti-inflammatory, antimicrobial, immunomodulatory, antioxidant and anticancer activities. All these activities underline the significance in host defence of bLf, which represents an ideal nutraceutical product both for its economic production and for its tolerance after ingestion. The purpose of this review is to summarize the most important beneficial activities demonstrated following the oral administration of bLf, trying to identify potential perspectives on its prophylactic and therapeutic applications in the future.

Topics: Administration, Oral; Anemia; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Dietary Supplements; Food Additives; Immunologic Factors; Lactoferrin; Milk

Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer's disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in

Topics: Anemia; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Biomarkers; Humans; Inflammation; Iron; Lactoferrin; Sepsis

Human lactoferrin (hLf), an iron-binding multifunctional cationic glycoprotein secreted by exocrine glands and by neutrophils, is a key element of host defenses. HLf and bovine Lf (bLf), possessing high sequence homology and identical functions, inhibit bacterial growth and biofilm dependently from iron binding ability while, independently, bacterial adhesion to and the entry into cells. In infected/inflamed host cells, bLf exerts an anti-inflammatory activity against interleukin-6 (IL-6), thus up-regulating ferroportin (Fpn) and transferrin receptor 1 (TfR1) and down-regulating ferritin (Ftn), pivotal actors of iron and inflammatory homeostasis (IIH). Consequently, bLf inhibits intracellular iron overload, an unsafe condition enhancing in vivo susceptibility to infections, as well as anemia of inflammation (AI), re-establishing IIH. In pregnant women, affected by AI, bLf oral administration decreases IL-6 and increases hematological parameters. This surprising effect is unrelated to iron supplementation by bLf (80 μg instead of 1-2 mg/day), but to its role on IIH. AI is unrelated to the lack of iron, but to iron delocalization: cellular/tissue overload and blood deficiency. BLf cures AI by restoring iron from cells to blood through Fpn up-expression. Indeed, anti-inflammatory activity of oral and intravaginal bLf prevents preterm delivery. Promising bLf treatments can prevent/cure transitory inflammation/anemia/oral pathologies in athletes.

Topics: Anemia; Anemia, Iron-Deficiency; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Female; Glycoproteins; Homeostasis; Humans; Inflammation; Iron; Lactoferrin; Oral Health; Pregnancy; Premature Birth; Protein Binding; Structure-Activity Relationship

Iron is essential to all microorganisms. To obtain iron from the very low concentrations present in their environment, microorganisms have developed sophisticated mechanisms such as the siderophore system. As a primitive defense mechanism, humans have developed mechanisms to withhold iron from microorganisms. Iron-binding proteins such as transferrin, ferritin, and lactoferrin have a central role in human ferrokinetics. These iron-binding proteins also participate in the process of decreasing iron availability for the microorganisms. They do so by decreasing iron reutilization. Anemia of inflammation (previously called anemia of chronic disease) is seen in the setting of infectious, inflammatory, and neoplastic diseases. It results, in part, from changes in the intracellular metabolism of iron. Alterations of iron physiology seen in many clinical circumstances make excess iron available to microorganisms, thus enhancing their pathogenicity. Understanding the molecular basis of iron withholding by the human host, both in the absence of and during infection, and that of iron acquisition by microorganisms may provide us with new and innovative antimicrobial agents and vaccines.

Topics: Anemia; Bacteria; Bacterial Infections; Blood Transfusion; Carrier Proteins; Conalbumin; Deferoxamine; Diabetic Ketoacidosis; Ferritins; Hemochromatosis; Hemolysis; Humans; Inflammation; Iron; Iron-Binding Proteins; Lactoferrin; Transferrin; Transferrin-Binding Proteins

The pathogenesis, diagnosis and treatment of the anaemia of chronic disorders (ACD) in rheumatoid arthritis (RA) were reviewed. Causes of anaemia other than ACD frequently present in RA. Decreased iron absorption was shown to be the result of active RA rather than a cause of ACD or iron deficiency. It has been hypothesized that bone marrow iron availability decreases due to decreased iron release by the mononuclear phagocyte system or that the anaemia in ACD is due to ineffective erythropoiesis; these remain controversial theories. Studies considering a decreased erythropoietin responsiveness have not produced consistent results. Erythroid colony growth is suppressed in vitro by interleukins and tumour necrosis factor but their role in vivo in ACD is unknown. The diagnosis of ACD is made by exclusion. Iron deficiency is detected by transferrin, ferritin, and cellular indices after adaptation of their normal values. Treatment of the anaemia consists merely of antirheumatic treatment. Iron administration is counterproductive since iron chelators or exogenous erythropoietin administration might increase erythropoiesis.

Topics: Absorption; Anemia; Arthritis, Rheumatoid; Cell Survival; Diagnosis, Differential; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Hemolysis; Humans; Iron; Lactoferrin; Phagocytes; Stem Cells

Topics: Absorption; Anemia; Blood Cells; Chronic Disease; Hematopoiesis; Humans; Immunity; Iron; Lactoferrin; Lactoglobulins; Receptors, Cell Surface

The anemia of chronic disease (ACD) is defined as a mild anemia associated with a chronic inflammatory, infectious or neoplastic illness and with a characteristic disturbance of iron metabolism. Many of the findings in ACD can be accounted for by release of a monokine called leukocyte endogenous mediator (LEM), endogenous pyrogen, or interleukin-1. This substance is released from "activated" monocytes. Bacterial endotoxins, certain lymphokines and phagocytic challenges are among the factors stimulating its biosynthesis. LEM induces fever, leukocytosis, biosynthesis. LEM induces fever, leukocytosis, and a variety of biochemical changes, including hypoferremia and alterations in plasma protein synthesis, collectively known as the "acute phase response." It is proposed that ACD results from the long-term elaboration of LEM and that release of this material is the common pathogenetic factor found in the illnesses that are associated with ACD. Some suggestions are made for testing the hypothesis. The hypoferremia associated with ACD is probably caused by defective release of iron from cells--particularly from macrophages, but also from hepatocytes and intestinal epithelium. Two possible mechanisms for this abnormality have been proposed: liberation of lactoferrin from neutrophilic leukocytes and induction of apoferritin synthesis. Neither mechanism has been established. Erythrokinetic studies in ACD have detected a modest reduction of erythrocyte survival without an adequate compensatory increase in the rate of red cell production. The reduced erythrocyte survival is probably related to an increase in phagocytic activity by activated macrophages. Impaired bone marrow response is partly related to the restricted iron supply, but there is substantial evidence for an additional defect in erythropoietin secretion. In some malignant diseases, there is evidence of an additional abnormality: impaired marrow response to a normal amount of erythropoietin. The nature of the erythropoietic defects and the relation of LEM to them remain to be established.

Topics: Anemia; Animals; Apoferritins; Bone Marrow; Chronic Disease; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Ferritins; Hematopoietic Stem Cells; Humans; Interleukin-1; Iron; Lactoferrin; Macrophages; Mice; Neutrophils; Rabbits; Rats

The aim of this study was to explore the dose effect of bovine lactoferrin (bLF) fortification on the morbidity of diarrhea and respiratory tract infections in weaned infants with anemia.. A total of 108 infants with anemia, who were exclusively breast fed at 4 to 6 mo and weaned and formula fed at 6 to 9 mo, were recruited. The eligible infants were randomly assigned to fortified group 0 (FG0), fortified group 1 (FG1), or fortified group 2 (FG2) and were given formula fortified with 0 mg/100 g, 38 mg/100 g, and 76 mg/100 g of bLF, respectively, for 3 mo. The morbidity of diarrhea and respiratory tract infections (RTIs), the duration of respiratory and diarrhea-related illnesses, and the levels of fecal human beta-defensin 2 (HBD-2), cathelicidin LL-37 (LL-37), secretory IgA (sIgA), butyrate, and calprotectin were assessed.. After the exclusion of 12 dropouts, the primary outcome measures, including episodes and duration of diarrhea and RTIs during the intervention, were obtained from 96 infants (35, 33, and 28 in FG0, FG1, and FG2, respectively). Compared with infants in FG0, there was a lower morbidity of rhinorrhea, wheezing, and skin rash among infants in FG1 (P < 0.05) and a lower morbidity of respiratory-related illness and wheezing among infants in FG2 (P < 0.05). Furthermore, a lower morbidity of diarrhea-related illness, diarrhea, vomiting, and nausea was observed among infants in FG2 than those in the other two groups (P < 0.05). In addition, the FG1 infants had a lower morbidity of vomiting and nausea than the FG0 infants (P < 0.05). The HBD-2, LL-37, sIgA, and calprotectin levels were significantly higher whereas the butyrate level was significantly lower in the FG2 infants than in infants in the other two groups after 3 mo of intervention (P < 0.05).. The bLF-fortified formula was effective in reducing the morbidity of diarrhea and RTIs in infants with anemia, with the 76 mg/100 g bLF-fortified formula exhibiting a stronger effect. The bLF fortification could be a new strategy for the prevention of diarrhea and RTIs in infants with anemia.

Topics: Anemia; Diarrhea; Female; Humans; Infant; Lactoferrin; Respiratory Tract Infections; Weaning

The discovery of the ferroportin-hepcidin complex has led to a critical review on the treatment of anemia and anemia of inflammation (AI). Ferroportin, the only known mammalian iron exporter from cells to blood, is negatively regulated by hepcidin, a hormone peptide able to bind to ferroportin, leading to its degradation. Therefore, new efficient therapeutic interventions acting on hepcidin and ferroportin are imperative to manage anemia and AI. Bovine milk derivative lactoferrin (bLf), a glycoprotein able to chelate two ferric ions per molecule, is emerging as a natural anti-inflammatory substance able to modulate hepcidin and ferroportin synthesis through the down-regulation of interleukin-6 (IL-6). Here, an interventional study (ClinicalTrials.gov Identifier: NCT01221844) was conducted by orally administering 100 mg of 20-30% iron-saturated bLf (corresponding to 70-84 μg of elemental iron) twice a day. This treatment was compared with the Italian standard therapy, consisting in the oral administration of 329.7 mg of ferrous sulfate once a day (corresponding to 105 mg of elemental iron). Treatments were carried out on 29 anemic women with minor β-thalassemia (20 pregnant and 9 non-pregnant), 149 women with hereditary thrombophilia (HT) (70 pregnant and 79 non-pregnant) affected by AI and 20 anemic pregnant women suffering from various pathologies. In anemic pregnant and non-pregnant women with minor β-thalassemia, presenting undetectable hepcidin levels, differently from ferrous sulfate management, bLf decreased IL-6 (from 25 ± 8 to 6 ± 3 pg/ml) and increased total serum iron (TSI) (from 54 ± 17 to 80 ± 9 μg/dl). BLf was also more efficient than ferrous sulfate in AI treatment in HT pregnant and non-pregnant women by decreasing both serum IL-6 (from 89 ± 8 to 58 ± 6 pg/ml) and hepcidin (from 115 ± 23 to 65 ± 10 ng/ml), thus increasing hematological parameters, such as the number of red blood cells (RBCs), the concentration of hemoglobin, TSI and serum ferritin. BLf was also efficient in treating anemia in other pathological pregnancies. Taken together all the results, bLf, showing a greater benefit and efficacy than the standard ferrous sulfate management, can be considered as a promising compound in treating anemia and AI through its ability to down-regulate IL-6, thus restoring ferroportin-mediated iron export from cells to blood in a hepcidin-dependent or independent way.

Topics: Administration, Oral; Adult; Anemia; Animals; Cation Transport Proteins; Cattle; Down-Regulation; Female; Hepcidins; Humans; Interleukin-6; Italy; Lactoferrin; Pregnancy; Pregnancy Complications, Hematologic

Advanced-stage cancer patients often suffer from anemia that closely resembles the anemia of chronic inflammatory diseases characterized by specific changes in iron homeostasis and absorption. i.v. iron improves the efficacy of recombinant human erythropoietin (rHuEPO) in anemic cancer patients undergoing chemotherapy. We report the results of an open-label, randomized, prospective trial aimed at testing the efficacy and safety of treatment with oral lactoferrin versus i.v. iron, both combined with rHuEPO, for the treatment of anemia in a population of 148 advanced cancer patients undergoing chemotherapy. All patients received s.c. rHuEPO-beta, 30,000 UI once weekly for 12 weeks, and were randomly assigned to ferric gluconate (125 mg i.v. weekly) or lactoferrin (200 mg/day). Both arms showed a significant hemoglobin increase. No difference in the mean hemoglobin increase or the hematopoietic response, time to hematopoietic response, or mean change in serum iron, C-reactive protein, or erythrocyte sedimentation rate were observed between arms. In contrast, ferritin decreased in the lactoferrin arm whereas it increased in the i.v. iron arm. In conclusion, these results show similar efficacy for oral lactoferrin and for i.v. iron, combined with rHuEPO, for the treatment of anemia in advanced cancer patients undergoing chemotherapy.

Topics: Administration, Oral; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Ferric Compounds; Hemoglobins; Humans; Lactoferrin; Male; Neoplasms; Prospective Studies; Quality of Life; Recombinant Proteins; Treatment Outcome

Strongly pronounced argyrosis caused by adding AgCl to the feed of laboratory rats efficiently mimics the deficiency of ceruloplasmin (CP) ferroxidase activity. Bringing the concentration of AgCl in the feedstuff of lactating rats to 250 mg % and keeping their progeny (Ag-rats) for 3 months on the same silver-containing feed provided the serum iron content 1.4 times lower than that in the control group. Besides, the ferroxidase activity of CP dropped to zero. In CP purified from sera of Ag-rats two copper ions were substituted with two silver ions. Using rat models of both post-hemorrhagic and hemolytic anemia we showed that the deficiency of CP ferroxidase activity in Ag-rats affects the iron content in serum, though does not prevent the recovery of hemoglobin level accompanied by exhaustion of iron caches in liver and spleen. When apo-lactoferrin (apo-LF) was administered to Ag-rats suffering from either post-hemorrhagic or hemolytic anemia, both hemoglobin and serum iron were restored more rapidly than in the control animals. In independent experiments Ag-rats were compared with those fed on regular diet and the former displayed a prolonged 3-day stabilization of hypoxia-inducible factors 1 and 2 alpha (HIF-1a and HIF-2a) along with an increased serum concentration of erythropoietin. Introduction to Ag-rats of active CP separately or together with apo-LF reduced that effect to 1 day only. It is concluded that saturation of apo-LF with iron, provided by active CP, can strongly affect its protective capacity.

Topics: Acute Disease; Anemia; Animals; Ceruloplasmin; Diet; Female; Hemorrhage; Iron; Lactoferrin; Rats; Rats, Wistar; Silver Compounds

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.. 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.. Surprisingly, after 1 y, cachexia features improved, all MF symptoms were in remission, and inflammatory and oxidative stress parameters, hepcidin, and EPO were reduced.. 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.

Topics: Anemia; C-Reactive Protein; Cachexia; Carnitine; Celecoxib; Curcumin; Erythropoietin; Fatigue; Ferritins; Fever; Hepcidins; Humans; Interleukin-6; Iron; Lactoferrin; Male; Middle Aged; Oxidative Stress; Patient Compliance; Primary Myelofibrosis; Quality of Life; Reactive Oxygen Species; Recombinant Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha; Weight Loss

The effect of human lactoferrin on the arrest of experimental hemorrhagic anemia consequences was studied in rats. After six blood losses (days 1-4 and 7-8 of the experiment), the rats developed acute anemia: hemoglobin concentration decreased to 59% of the initial level, serum iron level decreased 3-fold. Intraperitoneal injections of lactoferrin (10 mg/day) for 4 days starting from day 7 led to an increase in hemoglobin level to 109% and of serum iron to 125% on day 14. In controls, hemoglobin level on day 14 was 70% and iron content 49% of the initial level. Ferroxidase activity of ceruloplasmin in blood serum decreased after 5 blood losses returned to normal only in rats receiving lactoferrin. The results indicate that lactoferrin modified ceruloplasmin activity in vivo, promoting normalization of iron metabolism.

Topics: Anemia; Animals; Ceruloplasmin; Chromatography, Ion Exchange; Erythrocyte Indices; Humans; Injections, Intraperitoneal; Iron; Lactoferrin; Male; Milk, Human; Rats; Rats, Wistar

This study was designed to examine whether lactoferrin, a glycoprotein contained in neutrophils which binds free iron, mediates the anemia associated with renal cell carcinoma. Preoperative hematocrit, urinalysis, serum iron, total iron binding capacity, and ferritin levels were obtained in 24 patients with hypernephroma. At the time of radical nephrectomy, a tumor specimen was obtained from all 24 patients and corresponding normal renal tissue was obtained from eight patients. Fifteen patients had low serum iron, whereas nine patients had normal serum iron. All tissue samples were snap frozen at the time of surgery and were subsequently sectioned into 3-microns slices using the cryostat. Then all the sectioned specimens were stained with FITC (fluorescein isothiocyanate) and peroxidase conjugated rabbit derived anti-human lactoferrin. Ten of the 15 patients with low serum iron had positive anti-lactoferrin staining in both the FITC and peroxidase systems. None of the tumors from patients with normal serum iron and none of the normal renal parenchyma exhibited positive anti-lactoferrin uptake. Stains for iron in the bone marrow of two patients with low serum iron showed increased iron stores. These studies suggest that lactoferrin mediates the anemia often seen in association with renal cell carcinoma.

Topics: Anemia; Bone Marrow; Carcinoma, Renal Cell; Humans; Immunoenzyme Techniques; Iron; Kidney Neoplasms; Lactoferrin; Lactoglobulins

Topics: Anemia; Anemia, Hypochromic; Humans; Infections; Intestine, Small; Iron; Lactoferrin; Lactoglobulins; Milk, Human; Neutrophils; Phagocytosis

The relation of biliary lactoferrin concentration and the iron status of the body was studied in normal, anaemic and iron-loaded rabbits. In anaemic rabbits lactoferrin concentrations rose to two to three times the original values. Loading with iron resulted in a return to normal values. Mobilization of iron with desferrioxamine also gave a rise in lactoferrin concentration in bile. Lactoferrin may have a regulatory function in situations of enhanced iron absorption or mobilization of iron from depots.

Topics: Anemia; Animals; Bile; Deferoxamine; Hemoglobins; Iron; Lactoferrin; Lactoglobulins; Male; Rabbits; Transferrin