RESUMO
Iron is a fundament micronutrient, whose homeostasis is strictly regulated. Iron deficiency anemia is among the most widespread nutritional deficiencies and its therapy, based on dietary supplement and drugs, may lead to severe side effects. With the aim of improving iron bioavailability while reducing iron oral therapy side effects, novel dietary supplements based on innovative technologies-microencapsulation, liposomes, sucrosomes-have been produced and marketed. In the present work, six iron dietary supplements for different therapeutic targets were compared in terms of bioaccessibility, bioavailability, and safety by using an integrated in vitro approach. For general-purpose iron supplements, ME + VitC (microencapsulated) showed a fast, burst intestinal iron absorption kinetic, which maintained iron bioavailability and ferritin expression constant over time. SS + VitC (sucrosomes), on the other side, showed a slower, time-dependent iron absorption and ferritin expression trend. ME + Folate (microencapsulated) showed a behavior similar to that of ME + VitC, albeit with a lower bioavailability. Among pediatric iron supplements, a time-dependent bioavailability increase was observed for LS (liposome), while PIC (polydextrose-iron complex) bioavailability is severely limited by its poor bioaccessibility. Finally, except for SS + VitC, no adverse effects on intestinal mucosa vitality and barrier integrity were observed. Considering obtained results and the different therapeutic targets, microencapsulation-based formulations are endowed with better performance compared to the other formulations. Furthermore, performances of microencapsulated products were obtained with a lower iron daily dose, limiting the potential onset of side effects.
Assuntos
Anemia Ferropriva/dietoterapia , Suplementos Nutricionais/análise , Composição de Medicamentos/métodos , Ferritinas/farmacocinética , Ferritinas/uso terapêutico , Absorção Intestinal/fisiologia , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Humanos , Micronutrientes/uso terapêuticoRESUMO
Background: Iron deficiency is an enduring global health problem that requires new remedial approaches. Iron absorption from soybean-derived ferritin, an â¼550-kDa iron storage protein, is comparable to bioavailable ferrous sulfate (FeSO4). However, the absorption of ferritin is reported to involve an endocytic mechanism, independent of divalent metal ion transporter 1 (DMT-1), the transporter for nonheme iron. Objective: Our overall aim was to examine the potential of purified ferritin from peas (Pisum sativum) as a food supplement by measuring its stability under gastric pH treatment and the mechanisms of iron uptake into Caco-2 cells. Methods: Caco-2 cells were treated with native or gastric pH-treated pea ferritin in combination with dietary modulators of nonheme iron uptake, small interfering RNA targeting DMT-1, or chemical inhibitors of endocytosis. Cellular ferritin formation, a surrogate measure of iron uptake, and internalization of pea ferritin with the use of specific antibodies were measured. The production of reactive oxygen species (ROS) in response to equimolar concentrations of native pea ferritin and FeSO4 was also compared. Results: Pea ferritin exposed to gastric pH treatment was degraded, and the released iron was transported into Caco-2 cells by DMT-1. Inhibitors of DMT-1 and nonheme iron absorption reduced iron uptake by 26-40%. Conversely, in the absence of gastric pH treatment, the iron uptake of native pea ferritin was unaffected by inhibitors of nonheme iron absorption, and the protein was observed to be internalized in Caco-2 cells. Chlorpromazine (clathrin-mediated endocytosis inhibitor) reduced the native pea ferritin content within cells by â¼30%, which confirmed that the native pea ferritin was transported into cells via a clathrin-mediated endocytic pathway. In addition, 60% less ROS production resulted from native pea ferritin in comparison to FeSO4. Conclusion: With consideration that nonheme dietary inhibitors display no effect on iron uptake and the low oxidative potential relative to FeSO4, intact pea ferritin appears to be a promising iron supplement.
Assuntos
Endocitose , Ferritinas/farmacocinética , Ácido Gástrico , Ferro/metabolismo , Pisum sativum/química , Proteínas de Plantas/farmacocinética , Estômago/química , Anemia Ferropriva/tratamento farmacológico , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Proteínas de Transporte de Cátions/metabolismo , Dieta , Proteínas Alimentares/isolamento & purificação , Proteínas Alimentares/metabolismo , Proteínas Alimentares/farmacocinética , Proteínas Alimentares/uso terapêutico , Suplementos Nutricionais , Ferritinas/isolamento & purificação , Ferritinas/metabolismo , Ferritinas/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/metabolismo , Proteínas de Plantas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Glycine max/químicaRESUMO
Ferritin, the principle cytosolic iron storage protein in the majority of living organisms, has important roles during immune process in invertebrates. Detailed information about ferritin in the ark shell Scapharca broughtonii, however, has been very limited. In this study, full-length ferritin (termed SbFer) was cloned by the rapid amplication of cDNA ends (RACE) method based upon the sequence from the transcriptome library. The cDNA contained a 182 bp 5'-untranslated region, a 519 bp open reading frame encoding a polypeptide of 172 amino acids, a 229 bp 3'-untranslated region, and three introns (902, 373 and 402 bp) embedded in four exons. There was an iron response element (IRE) in the 5'-untranslated region. The deduced amino acid sequence of SbFer possessed many characteristics of vertebrate H type ferritin, shared 63%-91% identity with mollusks and greater identity with vertebrate H type ferritin compared to the L type. The SbFer gene expression pattern examined by quantitative real-time PCR showed ferritin mRNA was expressed in all ark shell tissues examined. The highest levels of expression were found in hemocytes with decreasing levels of expression in foot, mantle, gill, adductor muscle and hepatopancreas. A challenge with Vibrio anguillarum resulted in time-dependent significant upregulation of SbFer mRNA, indicating SbFer participated actively in the bacterial defense process. Further analysis of the antibacterial activity indicated recombinant SbFer could function as an immune antibacterial agent to both Gram-positive and Gram-negative bacteria. Taken together, these results suggested strongly that ferritin of the ark shell is involved in immune defense against microbial infection and it is a constitutive and inducible acute-phase protein.
Assuntos
Ferritinas/genética , Ferritinas/imunologia , Scapharca/imunologia , Vibrio/imunologia , Proteínas de Fase Aguda/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , DNA Complementar/genética , Ferritinas/metabolismo , Ferritinas/farmacocinética , Proteínas Reguladoras de Ferro/genética , Scapharca/genética , Alinhamento de SequênciaRESUMO
BACKGROUND: Iron (Fe) deficiency anemia remains the largest nutritional deficiency disorder worldwide. How the gut acquires iron from nano Fe(III), especially at the apical surface, is incompletely understood. OBJECTIVE: We developed a novel Fe supplement consisting of nanoparticulate tartrate-modified Fe(III) poly oxo-hydroxide [here termed nano Fe(III)], which mimics the Fe oxide core of ferritin and effectively treats iron deficiency anemia in rats. METHODS: We determined transfer to the systemic circulation of nano Fe(III) in iron-deficient and iron-sufficient outbread Swiss mouse strain (CD1) mice with use of (59)Fe-labeled material. Iron deficiency was induced before starting the Fe-supplementation period through reduction of Fe concentrations in the rodent diet. A control group of iron-sufficient mice were fed a diet with adequate Fe concentrations throughout the study. Furthermore, we conducted a hemoglobin repletion study in which iron-deficient CD1 mice were fed for 7 d a diet supplemented with ferrous sulfate (FeSO4) or nano Fe(III). Finally, we further probed the mechanism of cellular acquisition of nano Fe(III) by assessing ferritin formation, as a measure of Fe uptake and utilization, in HuTu 80 duodenal cancer cells with targeted inhibition of divalent metal transporter 1 (DMT1) and duodenal cytochrome b (DCYTB) before exposure to the supplemented iron sources. Differences in gene expression were assessed by quantitative polymerase chain reaction. RESULTS: Absorption (means ± SEMs) of nano Fe(III) was significantly increased in iron-deficient mice (58 ± 19%) compared to iron-sufficient mice (18 ± 17%) (P = 0.0001). Supplementation of the diet with nano Fe(III) or FeSO4 significantly increased hemoglobin concentrations in iron-deficient mice (170 ± 20 g/L, P = 0.01 and 180 ± 20 g/L, P = 0.002, respectively). Hepatic hepcidin mRNA expression reflected the nonheme-iron concentrations of the liver and was also comparable for both nano Fe(III)- and FeSO4-supplemented groups, as were iron concentrations in the spleen and duodenum. Silencing of the solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2 (Slc11a2) gene (DMT1) significantly inhibited ferritin formation from FeSO4 (P = 0.005) but had no effect on uptake and utilization of nano Fe(III). Inhibiting DCYTB with an antibody also had no effect on uptake and utilization of nano Fe(III) but significantly inhibited ferritin formation from ferric nitrilotriacetate chelate (Fe-NTA) (P = 0.04). Similarly, cellular ferritin formation from nano Fe(III) was unaffected by the Fe(II) chelator ferrozine, which significantly inhibited uptake and utilization from FeSO4 (P = 0.009) and Fe-NTA (P = 0.005). CONCLUSIONS: Our data strongly support direct nano Fe(III) uptake by enterocytes as an efficient mechanism of dietary iron acquisition, which may complement the known Fe(II)/DMT1 uptake pathway.
Assuntos
Duodeno/citologia , Duodeno/efeitos dos fármacos , Ferritinas/administração & dosagem , Nanopartículas/química , Anemia Ferropriva/tratamento farmacológico , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Suplementos Nutricionais , Duodeno/metabolismo , Enterócitos/metabolismo , Compostos Férricos/metabolismo , Ferritinas/farmacocinética , Compostos Ferrosos/administração & dosagem , Compostos Ferrosos/farmacocinética , Hemoglobinas , Hepcidinas/genética , Hepcidinas/metabolismo , Ferro da Dieta/administração & dosagem , Ferro da Dieta/farmacocinética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Recent studies in humans suggest that ferritin iron in soybeans has high bioavailability. However, direct evidence for this is lacking because the soybeans were intrinsically labeled; thus, iron bound to other ligands, such as phytate, was also labeled. OBJECTIVE: The objectives of the study were to evaluate the absorption of iron from extrinsically labeled, purified ferritin (horse spleen) reconstituted with either high-phosphate iron mineral (plant-type) or low-phosphate iron mineral (animal-type) and to compare it with iron absorption from ferrous sulfate. DESIGN: Nonanemic, healthy young women were fed a standard breakfast meal supplemented with (59)Fe-labeled ferritin or ferrous sulfate, in randomized order. Fifteen subjects received ferritin with the low-phosphate iron mineral, and 15 subjects received ferritin with the high-phosphate iron mineral. Iron absorption was measured in a whole-body counter after 14 and 28 d and by red blood cell incorporation after 28 d. RESULTS: There was no significant difference in iron absorption between ferritin and ferrous sulfate: low-phosphate iron mineral ferritin (x +/- SD: 21.4 +/- 14.7%) compared with ferrous sulfate (21.9 +/- 14.6%), or high-phosphate iron mineral ferritin (22.2 +/- 19.2%) compared with ferrous sulfate (16.7 +/- 7.1%). Results obtained by using whole-body retention of iron and red blood cell incorporation differed with the type of iron, which suggests that pathways for iron uptake and utilization differed for the 2 forms. CONCLUSIONS: Iron is equally well absorbed from ferritin and ferrous sulfate independent of the phosphate content of the ferritin iron mineral. Thus, dietary ferritin iron is likely to be a good source of iron.
Assuntos
Eritrócitos/química , Ferritinas/farmacocinética , Compostos Ferrosos/farmacocinética , Ferro da Dieta/farmacocinética , Análise de Variância , Disponibilidade Biológica , Estudos Cross-Over , Contagem de Eritrócitos , Feminino , Ferritinas/sangue , Ferritinas/metabolismo , Compostos Ferrosos/metabolismo , Hemoglobinas/análise , Humanos , Absorção Intestinal , Radioisótopos de Ferro , Ferro da Dieta/sangue , Ferro da Dieta/metabolismo , Estado Nutricional , Glycine max/químicaRESUMO
Ferritin, a major form of endogenous iron in food legumes such as soybeans, is a novel and natural alternative for iron supplementation strategies where effectiveness is limited by acceptability, cost, or undesirable side effects. A member of the nonheme iron group of dietary iron sources, ferritin is a complex with Fe3+ iron in a mineral (thousands of iron atoms inside a protein cage) protected from complexation. Ferritin illustrates the wide range of chemical and biological properties among nonheme iron sources. The wide range of nonheme iron receptors matched to the structure of the iron complexes that occurs in microorganisms may, by analogy, exist in humans. An understanding of the chemistry and biology of each type of dietary iron source (ferritin, heme, Fe2+ ion, etc.), and of the interactions dependent on food sources, genes, and gender, is required to design diets that will eradicate global iron deficiency in the twenty-first century.
Assuntos
Ferritinas/farmacocinética , Deficiências de Ferro , Ferro da Dieta/farmacocinética , Fenômenos Fisiológicos da Nutrição , Animais , Disponibilidade Biológica , Suplementos Nutricionais , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Ferro da Dieta/administração & dosagem , RatosRESUMO
Iron amino acid chelate is being increasingly considered in programs for iron fortification of foods. The bioavailability of iron bis-glycinate chelate given in water was studied using a double-isotopic method in a group of 14 women. Iron absorption from aqueous solutions of 15 mg/L of elemental iron as either iron bis-glycine chelate or ferrous ascorbate was not significantly different (34.6% and 29.9% respectively). Standardized iron absorption of the iron bis-glycinate was 46.3% (standardized to 40% absorption of the reference dose). There was a significant correlations between (ln) iron absorption of iron bis-glycinate chelate with (ln) serum ferritin (r = -0.60, p < 0.03) and with (ln) iron absorption from ferrous ascorbate (r = 0.71, p < 0.006), suggesting that iron bis-glycinate chelate absorption is indeed regulated by the iron stores of the body.
Assuntos
Compostos Ferrosos/farmacocinética , Glicina/análogos & derivados , Glicina/farmacocinética , Quelantes de Ferro/farmacocinética , Água , Adulto , Antioxidantes/farmacocinética , Ácido Ascórbico/farmacocinética , Disponibilidade Biológica , Ingestão de Líquidos , Feminino , Ferritinas/sangue , Ferritinas/farmacocinética , Compostos Ferrosos/sangue , Alimentos Fortificados , Glicina/sangue , Humanos , Isótopos de Ferro , Pessoa de Meia-IdadeRESUMO
ICL670A (formerly CGP 72 670) or 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]- benzoic acid is a tridentate iron-selective synthetic chelator of the bis-hydroxyphenyl-triazole class of compounds. The present studies used selective radioiron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to define the source of iron chelated in vivo by ICL670A and its mode of excretion, to examine its ability to remove iron directly from iron-loaded myocardial cells, and to examine its ability to interact with other chelators through a possible additive or synergistic effect. Results indicate that ICL670A given orally is 4 to 5 times more effective than parenteral deferoxamine (DFO) in promoting the excretion of chelatable iron from hepatocellular iron stores. The pattern of iron excretion produced by ICL670A is quite different from that of DFO and all iron excretion is restricted to the bile regardless of whether it is derived from RE or hepatocellular iron stores. Studies in heart cell cultures have shown a favorable interaction between DFO and ICL670A manifested in improved chelating efficiency of ICL670A, which is most probably explained by an exchange of chelated iron between ICL670A and DFO. These unique chelating properties of ICL670A may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.
Assuntos
Benzoatos/uso terapêutico , Hepatócitos/metabolismo , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Radioisótopos de Ferro/farmacocinética , Sistema Fagocitário Mononuclear/metabolismo , Reação Transfusional , Triazóis/uso terapêutico , Animais , Benzoatos/química , Benzoatos/farmacocinética , Bile/metabolismo , Células Cultivadas , Deferasirox , Desferroxamina/farmacocinética , Desferroxamina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Transfusão de Eritrócitos , Eritrócitos Anormais , Fezes/química , Feminino , Ferritinas/farmacocinética , Coração/efeitos dos fármacos , Temperatura Alta , Injeções Intravenosas , Quelantes de Ferro/química , Quelantes de Ferro/farmacocinética , Sobrecarga de Ferro/metabolismo , Radioisótopos de Ferro/urina , Fígado/metabolismo , Camundongos , Estrutura Molecular , Miocárdio/citologia , Miocárdio/metabolismo , Especificidade de Órgãos , Ratos , Ratos Wistar , Distribuição Tecidual , Triazóis/química , Triazóis/farmacocinética , Urina/químicaRESUMO
Hypotransferrinemic (Hp) mice have a point mutation or small deletion in the transferrin (Tf) gene, resulting in defective splicing of precursor Tf mRNA. Hp animals produce < 1% of normal Tf levels and require supplemental serum or purified Tf for survival. Because of the lack of endogenous brain Tf, we examined regional and cellular distributions of iron and iron regulatory proteins (Tf and ferritin) in selected brain regions of Hp mice. The regional distribution of iron, Tf, and ferritin in Hp brain was similar to normal except for the pattern of iron staining in hippocampus. The cellular distribution of iron, ferritin, and Tf was similar between Hp and normal animals. The predominant cell type staining for Tf and iron was oligodendrocytes. Qualitative observations suggest that the number of cells staining for iron was similar between Hp and normal mice, whereas the number of Hp Tf-positive cells was reduced. Ferritin immunostaining was similar in both cases. However, ferritin-positive cells were predominantly astrocytes, an observation unique to mice among species studied previously. Western blot analysis revealed that Tf present in Hp brain was of exogenous origin (from supplemental injections). Presumably, Tf transports the iron found in Hp oligodendrocytes. These data demonstrate that, despite reduced endogenous Hp brain Tf, iron and plasma Tf migrate or are transported to the appropriate cells (oligodendrocytes), bringing into question the role of endogenous brain Tf in extracellular iron transport.