Myeloperoxidase (MPO) is a unique heme-containing peroxidase that can catalyze the formation of hypochlorous acid (HOCl). The strong interaction of MPO with low-density lipoproteins (LDL) promotes proatherogenic modification of LDL by HOCl. The MPO-modified LDL (Mox-LDL) accumulate in macrophages, resulting in the formation of foam cells, which is the pathognomonic symptom of atherosclerosis. A promising approach to prophylaxis and atherosclerosis therapy is searching for remedies that prevent the modification or accumulation of LDL in macrophages. Lactoferrin (LF) has several application points in obesity pathogenesis. We aimed to study LF binding to Mox-LDL and their accumulation in monocytes transformed into macrophages. Using surface plasmon resonance and ELISA techniques, we observed no LF interaction with intact LDL, whereas Mox-LDL strongly interacted with LF. The affinity of Mox-LDL to LF increased with the degree of oxidative modification of LDL. Moreover, an excess of MPO did not prevent interaction of Mox-LDL with LF. LF inhibits accumulation of cholesterol in macrophages exposed to Mox-LDL. The results obtained reinforce the notion of LF potency as a remedy against atherosclerosis.

As shown recently, oleic acid (OA) in complex with lactoferrin (LF) causes the death of cancer cells, but no mechanism(s) of that toxicity have been disclosed. In this study, constitutive parameters of the antitumor effect of LF/OA complex were explored. Complex LF/OA was prepared by titrating recombinant human LF with OA. Spectral analysis was used to assess possible structural changes of LF within its complex with OA. Structural features of apo-LF did not change within the complex LF:OA = 1:8, which was toxic for hepatoma 22a cells. Cytotoxicity of the complex LF:OA = 1:8 was tested in cultured hepatoma 22a cells and in fresh erythrocytes. Its anticancer activity was tested in mice carrying hepatoma 22a. In mice injected daily with LF-8OA, the same tumor grew significantly slower. In 20% of animals, the tumors completely resolved. LF alone was less efficient, i.e., the tumor growth index was 0.14 for LF-8OA and 0.63 for LF as compared with 1.0 in the control animals. The results of testing from 48 days after the tumor inoculation showed that the survival rate among LF-8OA-treated animals was 70%, contrary to 0% rate in the control group and among the LF-treated mice. Our data allow us to regard the complex of LF and OA as a promising tool for cancer treatment.

Our previous study showed that not only bovine lactoferrin (LF), the protein of milk and neutrophils, but also the human species forms complexes with oleic acid (OA) that inhibit tumor growth. Repeated injections of human LF in complex with OA (LF/8OA) to hepatoma-carrying mice decelerated tumor growth and increased animals’ longevity. However, whether the effect of the LF/8OA complex is directed exclusively against malignant cells was not studied. Hence, its effect on normal blood cells was assayed, along with its possible modulation of ceruloplasmin (CP), the preferred partner of LF among plasma proteins. The complex LF/8OA (6 μM) caused hemolysis, unlike LF alone or BSA/8OA (250 μM). The activation of neutrophils with exocytosis of myeloperoxidase (MPO), a potent oxidant, was induced by 1 μM LF/8OA, whereas BSA/8OA had a similar effect at a concentration increased by an order. The egress of heme-containing proteins, i.e., MPO and hemoglobin, from blood cells affected by LF/8OA was followed by a pronounced oxidative/halogenating stress. CP, which is the natural inhibitor of MPO, added at a concentration of 2 mol per 1 mol of LF/8OA abrogated its cytotoxic effect. It seems likely that CP can be used effectively in regulating the LF/8OA complex’s antitumor activity.

Our previous study showed antitumor activity of the complex formed by iron-free recombinant human lactoferrin (apo-recHLF) and oleic acid (OA) (1:8 molar ratio) in a model of murine hepatoma 22a inoculated to C3HA mice. Taken alone, apo-recHLF was less efficient; i.e., the tumor growth index was 0.14 for recHLF-8OA and 0.63 for recHLF as compared with 1.0 in the control animals. In the present study, we evaluated antitumor activity of iron-saturated recHLF per se and of the complexes formed by OA with apo-recHLF and holo-recHLF. Balb/c mice with solid myeloma Sp2/0 were subjected to the 10-day treatment with daily intraperitoneal (i/p) injections of 10 mg iron-saturated recHLF with OA (1:8) per animal (0.4 g/kg). In 15 days, the tumor growth was substantially inhibited. Mean tumor mass was 93% lower as compared with the control value ( p < 0.01). I/p injections of apo-recHLF/OA complex did not inhibit the tumor growth. Holo-recHLF used without OA had less pronounced antitumor effect as compared with their complex.

Objective. We aimed to analyze the alterations of activity of iron metabolism members i.e. ceruloplasmin (Cp) and transferrin (Tf), in relation to the percentage of glycated hemoglobin. The latter is one of biochemical criteria of chronic hyperglycemia compensation in case of type 2 diabetes mellitus. Materials and methods. Concentration and activity of Cp and Tf, concentration of iron, copper and lipoprotein cholesterol were measured by biochemical methods in blood serum samples obtained from healthy donors and patients with type 2 diabetes mellitus divided in three groups according to glycated hemoglobin level. Results. The significant decrease in serum copper, ferroxidase activity of Cp and iron-binding capacity of Tf, as well as an increase of Tf concentration, in groups with compensated and uncompensated type 2 diabetes mellitus was found. Conclusion. Our data demonstrate a statistical link between the degree of type 2 diabetes mellitus compensation and alteration of iron metabolism members activity. Thus, an increase of hyperglycemia is associated with a decrease of both Cp ferroxidase activity and the degree of Tf saturation with iron. These alterations may explain the efficiency of treatment with iron chelators of such type 2 diabetes mellitus complications as trophic ulcers. The said disease condition is directly connected with the changes in iron efflux.

The review summarizes data on the effect of the protein present in exocrine secretions and neutrophils, lactoferrin, on components of metabolic syndrome pathogenesis. The molecular mechanisms of lactoferrin participation in the regulation of carbohydrate and lipid metabolism, such as that of lipoproteins, glycated proteins, fatty and bile acids, are contemplated. The influence of lactoferrin on the development of insulin resistance and hypertension, on proliferation of adipocytes, on inflammatory processes and endocrine control is considered. An analysis of population-based studies on the link between lactoferrin gene expression level and metabolic syndrome evidences is carried out. The results of numerous experiments focused on the effects of lactoferrin in metabolic syndrome and obesity animal models are presented. The results of the first international clinical trials aimed to correct obesity and type 2 diabetes mellitus in volunteers are discussed.