RESUMEN
Iron deficiency (ID) and iron-deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iron supplementation, typically using iron salts (e.g. FeSO4 ); however, dosing at several-fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental forms of iron are transported across the intestinal epithelium and whether these transport pathways are subject to regulation by the iron-regulatory hormone hepcidin.
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Anemia Ferropénica , Deficiencias de Hierro , Sobrecarga de Hierro , Adulto , Niño , Femenino , Humanos , Embarazo , Hierro/metabolismo , Anemia Ferropénica/terapia , Sobrecarga de Hierro/tratamiento farmacológicoRESUMEN
The mammalian multicopper ferroxidases (MCFs) ceruloplasmin (CP), hephaestin (HEPH) and zyklopen (ZP) comprise a family of conserved enzymes that are essential for body iron homeostasis. Each of these enzymes contains six biosynthetically incorporated copper atoms which act as intermediate electron acceptors, and the oxidation of iron is associated with the four electron reduction of dioxygen to generate two water molecules. CP occurs in both a secreted and GPI-linked (membrane-bound) form, while HEPH and ZP each contain a single C-terminal transmembrane domain. These enzymes function to ensure the efficient oxidation of iron so that it can be effectively released from tissues via the iron export protein ferroportin and subsequently bound to the iron carrier protein transferrin in the blood. CP is particularly important in facilitating iron release from the liver and central nervous system, HEPH is the major MCF in the small intestine and is critical for dietary iron absorption, and ZP is important for normal hair development. CP and HEPH (and possibly ZP) function in multiple tissues. These proteins also play other (non-iron-related) physiological roles, but many of these are ill-defined. In addition to disrupting iron homeostasis, MCF dysfunction perturbs neurological and immune function, alters cancer susceptibility, and causes hair loss, but, despite their importance, how MCFs co-ordinately maintain body iron homeostasis and perform other functions remains incompletely understood.
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Ceruloplasmina , Cobre , Animales , Ratones , Cobre/metabolismo , Ceruloplasmina/metabolismo , Ratones Noqueados , Oxidación-Reducción , Biología , Mamíferos/metabolismoRESUMEN
In order to supply adequate iron during pregnancy, the levels of the iron regulatory hormone hepcidin in the maternal circulation are suppressed, thereby increasing dietary iron absorption and storage iron release. Whether this decrease in maternal hepcidin is caused by changes in factors known to regulate hepcidin expression, or by other unidentified pregnancy factors, is not known. To investigate this, we examined iron parameters during pregnancy in mice. We observed that hepatic iron stores and transferrin saturation, both established regulators of hepcidin production, were decreased in mid and late pregnancy in normal and iron loaded dams, indicating an increase in iron utilization. This can be explained by a significant increase in maternal erythropoiesis, a known suppressor of hepcidin production, by mid-pregnancy, as indicated by an elevation in circulating erythropoietin and an increase in spleen size and splenic iron uptake. Iron utilization increased further in late pregnancy due to elevated fetal iron demand. By increasing maternal iron levels in late gestation, we were able to stimulate the expression of the gene encoding hepcidin, suggesting that the iron status of the mother is the predominant factor influencing hepcidin levels during pregnancy. Our data indicate that pregnancy-induced hepcidin suppression likely occurs because of reductions in maternal iron reserves due to increased iron requirements, which predominantly reflect stimulated erythropoiesis in mid-gestation and increased fetal iron requirements in late gestation, and that there is no need to invoke other factors, including novel pregnancy factor(s), to explain these changes.
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Hepcidinas , Deficiencias de Hierro , Femenino , Embarazo , Ratones , Animales , Hepcidinas/genética , Hepcidinas/metabolismo , Hierro/metabolismo , Hierro de la Dieta , Feto/metabolismo , EritropoyesisRESUMEN
BACKGROUND: Many women enter pregnancy with iron stores that are insufficient to maintain maternal iron balance and support fetal development and consequently, often require iron supplements. However, the side effects associated with many currently available iron supplements can limit compliance. OBJECTIVE: This study aimed to test the safety and efficacy of a novel nanoparticulate iron supplement, a dietary ferritin analog termed iron hydroxide adipate tartrate (IHAT), in pregnant mice. METHODS: Female C57BL/6 mice were maintained on either an iron-deficient or a control diet for 2 wk prior to timed mating to develop iron-deficient or iron-sufficient pregnancy models, respectively. Mice from each model were then gavaged daily with 10 mg iron/kg body weight as either IHAT or ferrous sulfate, or with water only, beginning on embryonic day (E) 4.5. Mice were killed on E18.5 and maternal iron and hematological parameters were measured. The expression of genes encoding iron transporters and oxidative stress markers in the duodenum and placenta were determined, along with hepatic expression of the gene encoding the iron regulatory hormone hepcidin and fetal iron. RESULTS: Oral IHAT and ferrous sulfate were equally effective at increasing maternal hemoglobin (20.2% and 16.9%, respectively) and hepatic iron (30.2% and 29.3%, respectively), as well as total fetal iron (99.7% and 83.8%, respectively), in iron-deficient pregnant mice compared with those gavaged with water only, with no change in oxidative stress markers seen with either treatment. However, there was a significant increase in the placental expression of the oxidative stress marker heme oxygenase 1 in iron-replete pregnant mice treated with ferrous sulfate when compared with iron-replete pregnant mice gavaged with IHAT (96.9%, P <0.05). CONCLUSIONS: IHAT has proved a safe and effective alternative to oral ferrous sulfate in mice, and it has potential for treating iron deficiency in human pregnancy.
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Anemia Ferropénica , Deficiencias de Hierro , Anemia Ferropénica/tratamiento farmacológico , Animales , Femenino , Ferritinas/uso terapéutico , Compuestos Ferrosos/uso terapéutico , Hemoglobinas/análisis , Humanos , Hierro , Ratones , Ratones Endogámicos C57BL , Placenta/química , Embarazo , AguaRESUMEN
OBJECTIVE: To investigate the effect of Hfe gene mutation on the distribution of iron and periodontal bone loss in periodontal tissues. BACKGROUND DATA: It remains unclear how tissue iron loading affects the periodontium architectures in a genetic animal model of hereditary haemochromatosis (HH). METHODS: Male C57BL/6 Hfe -/- (8 weeks old) and wild-type (WT) mice were utilized to examine the iron distribution in periodontal tissues, as well as periodontal tissues changes using micro-computed tomography and histomorphometric analysis. Furthermore, tissue inflammatory mediators, bone markers and periodontal pathogens were carried out in PFA-fixed paraffin-embedded tissues using ELISA, RT-qPCR and genomic DNA qPCR, respectively. RESULTS: Excessive iron deposition was found in the periodontal ligament, gingiva and alveolar bone in Hfe -/- mice relative to their WT counterparts. This, in turn, was associated with significant periodontal bone loss, increased cemento-enamel junction-alveolar bone crest distance and decreased expression of molecules involved in bone development and turnover. Furthermore, the pro-inflammatory cytokine - interleukin 6 and periodontal bacteria - Campylobacter rectus were significantly increased in Hfe -/- mice compared with WT controls. CONCLUSION: Our results suggest that the iron loading in a mouse model of HH decreases alveolar bone formation and leads to alterations in the inflammatory state in the periodontium. Periodontal health should be assessed during the clinical assessment of HFE-HH patients.
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Hemocromatosis , Animales , Modelos Animales de Enfermedad , Hemocromatosis/complicaciones , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Hierro/metabolismo , Hígado/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Microtomografía por Rayos XRESUMEN
Iron deficiency is one of the most common nutritional deficiencies worldwide and is often treated with oral iron supplements. However, commonly used supplements, including those based on ferrous iron salts, are associated with gastrointestinal side effects and unfavorable changes in the intestinal microbiome. Sucrosomial® iron is a novel iron formulation that is effective at treating iron deficiency, and with fewer gastrointestinal side effects, yet its effect on the gut microbiome has not been examined previously. Thus, we treated mice for two weeks with diets containing either Sucrosomial® iron or ferrous sulfate as the sole iron source and examined bacterial communities in the intestine using 16S Microbial Profiling of DNA extracted from feces collected both prior to and following dietary treatment. Mice treated with Sucrosomial® iron showed an increase in Shannon diversity over the course of the study. This was associated with a decrease in the abundance of the phylum Proteobacteria, which contains many pathogenic species, and an increase in short chain fatty acid producing bacteria such as Lachnospiraceae, Oscillibacter and Faecalibaculum. None of these changes were observed in mice treated with ferrous sulfate. These results suggest that Sucrosomial® iron may have a beneficial effect on the intestinal microbiome when compared to ferrous sulfate and that this form of iron is a promising alternative to ferrous iron salts for the treatment of iron deficiency.
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Anemia Ferropénica , Microbioma Gastrointestinal , Deficiencias de Hierro , Anemia Ferropénica/tratamiento farmacológico , Animales , Suplementos Dietéticos , Compuestos Ferrosos/farmacología , Hierro , Ratones , Sales (Química)/uso terapéuticoRESUMEN
The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane glycoprotein that is responsible for the cellular uptake of iron via iron-loaded transferrin (holo-transferrin) binding. It has been hypothesised that the HFE/TFR1 interaction serves as a sensor to the level of iron-loaded transferrin in circulation by means of a competition mechanism between HFE and iron-loaded transferrin association with TFR1. To investigate this, a series of peptides based on the helical binding interface between HFE and TFR1 were generated and shown to significantly interfere with the HFE/TFR1 interaction in an in vitro proximity ligation assay. The helical conformation of one of these peptides, corresponding to the α1 and α2 helices of HFE, was stabilised by the introduction of sidechain lactam "staples", but this did not result in an increase in the ability of the peptide to disrupt the HFE/TFR1 interaction. These peptides inhibitors of the protein-protein interaction between HFE and TFR1 are potentially useful tools for the analysis of the functional role of HFE in the regulation of hepcidin expression.
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Hemocromatosis , Hepcidinas , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Hepcidinas/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Hierro/metabolismo , Lactamas , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Péptidos/metabolismo , Péptidos/farmacología , Receptores de Transferrina/metabolismo , Transferrina/metabolismoRESUMEN
BACKGROUND: The ferroxidase zyklopen (Zp) has been implicated in the placental transfer of iron to the fetus. However, the evidence for this is largely circumstantial. OBJECTIVES: This study aimed to determine whether Zp is essential for placental iron transfer. METHODS: A model was established using 8- to 12-wk-old pregnant C57BL/6 mice on standard rodent chow in which Zp was knocked out in the fetus and fetal components of the placenta. Zp was also disrupted in the entire placenta using global Zp knockout mice. Inductively coupled plasma MS was used to measure total fetal iron, an indicator of the amount of iron transferred by the placenta to the fetus, at embryonic day 18.5 of gestation. Iron transporter expression in the placenta was measured by Western blotting, and the expression of Hamp1, the gene encoding the iron regulatory hormone hepcidin, was determined in fetal liver by real-time PCR. RESULTS: There was no change in the amount of iron transferred to the fetus when Zp was disrupted in either the fetal component of the placenta or the entire placenta. No compensatory changes in the expression of the iron transport proteins transferrin receptor 1 or ferroportin were observed, nor was there any change in fetal liver Hamp1 mRNA. Hephl1, the gene encoding Zp, was expressed mainly in the maternal decidua of the placenta and not in the nutrient-transporting syncytiotrophoblast. Disruption of Zp in the whole placenta resulted in a 26% increase in placental size (P < 0.01). CONCLUSIONS: Our data indicate that Zp is not essential for the efficient transfer of iron to the fetus in mice and is localized predominantly in the maternal decidua. The increase in placental size observed when Zp is knocked out in the entire placenta suggests that this protein may play a role in placental development.
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Ceruloplasmina , Placenta , Animales , Ceruloplasmina/genética , Femenino , Feto/metabolismo , Hierro/metabolismo , Ratones , Ratones Endogámicos C57BL , Placenta/metabolismo , Placentación , EmbarazoRESUMEN
BACKGROUND: Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease. RESULTS: Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane. CONCLUSION: These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.
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Fibrosis Quística , Ferroptosis , Muerte Celular , Células Epiteliales , Humanos , Peroxidación de LípidoRESUMEN
Microglia-mediated neuroinflammation is one of the most significant features in a variety of central nervous system (CNS) disorders such as traumatic brain injury, stroke, and many neurodegenerative diseases. Microglia become polarized upon stimulation. The two extremes of the polarization are the neuron-destructive proinflammatory M1-like and the neuron-regenerative M2-like phenotypes. Thus, manipulating microglial polarization toward the M2 phenotype is a promising therapeutic approach for CNS repair and regeneration. It has been reported that nanoparticles are potential tools for regulating microglial polarization. Gold nanoclusters (AuNCs) could penetrate the blood-brain barrier and have neuroprotective effects, suggesting the possibility of utilizing AuNCs to regulate microglial polarization and improve neuronal regeneration in CNS. In the current study, AuNCs functionalized with dihydrolipoic acid (DHLA-AuNCs), an antioxidant with demonstrated neuroprotective roles, were prepared, and their effects on polarization of a microglial cell line (BV2) were examined. DHLA-AuNCs effectively suppressed proinflammatory processes in BV2 cells by inducing polarization toward the M2-like phenotype. This was associated with a decrease in reactive oxygen species and reduced NF-kB signaling and an improvement in cell survival coupled with enhanced autophagy and inhibited apoptosis. Conditioned medium from DHLA-AuNC-treated BV2 cells was able to enhance neurogenesis in both the neuronal cell line N2a and in an ex vivo brain slice stroke model. The direct treatment of brain slices with DHLA-AuNCs also ameliorated stroke-related tissue injury and reduced astrocyte activation (astrogliosis). This study suggests that by regulating neuroinflammation to improve neuronal regeneration, DHLA-AuNCs could be a potential therapeutic agent in CNS disorders.
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Polaridad Celular/efectos de los fármacos , Oro , Nanopartículas del Metal/química , Microglía/metabolismo , Neurogénesis/efectos de los fármacos , Neuronas/metabolismo , Ácido Tióctico/análogos & derivados , Animales , Línea Celular Tumoral , Oro/química , Oro/farmacología , Ratones , Ácido Tióctico/química , Ácido Tióctico/farmacologíaRESUMEN
INTRODUCTION: Significant disparities are apparent in geographic areas and among racial/ethnic minority groups in Wisconsin. Cancer disparities are complex and multifactorial and require collaborative, multilevel efforts to reduce their impact. Our objective was to understand cancer disparities and identify opportunities to collaborate across community and research sectors to address them. METHODS: From May 2017 through October 2018, we assembled groups of community members and researchers and conducted 10 listening sessions and 29 interviews with a total of 205 participants from diverse backgrounds. Listening sessions and interviews were scheduled on the basis of participant preference and consisted of a brief review of maps illustrating the breast and lung cancer burden across Wisconsin, and a semistructured set of questions regarding causes, solutions, and opportunities. Interviews followed the same structure as listening sessions, but were conducted between a facilitator and 1 or 2 individuals. Major themes were summarized from all sessions and coded. We used the Model for Analysis of Population Health and Health Disparities to identify areas for collaboration and to highlight differences in emphasis between community participants and researchers. RESULTS: Participants identified the need to address individual behavioral risks and medical mistrust and to build equitable multilevel partnerships. Communities provided insights on the impact of environment and location on cancer disparities. Researchers shared thoughts about societal poverty and policy issues, biologic responses, genetic predisposition, and the mechanistic influence of lifestyle factors on cancer incidence and mortality. CONCLUSION: Listening sessions and interviews provided insight into contributors to cancer disparities, barriers to improving outcomes, and opportunities to improve health. The unique perspectives of each group underscored the need for multisector teams to tackle the complex issue of cancer disparities.
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Neoplasias de la Mama/mortalidad , Disparidades en Atención de Salud , Neoplasias Pulmonares/mortalidad , Demografía , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Masculino , Investigación Cualitativa , Wisconsin/epidemiologíaRESUMEN
Iron-loading disorders, such as hereditary hemochromatosis, are associated with inappropriately low expression of the iron regulatory hormone, hepcidin. A recent study has demonstrated that food deprivation can increase hepcidin production in mice. We have examined this effect in more detail to determine whether the pathway(s) that are responsible might provide novel targets for pharmaceutical intervention in disorders of iron homeostasis. C57BL/6 mice were deprived of food for 5, 10, 16, or 24 h before euthanasia, then blood and tissue samples were collected for analysis. The effect of food deprivation was also examined in Hfe-/- mice, a model of hereditary hemochromatosis, as well as mice that were maintained on an iron-deficient diet or injected with erythropoietin. Food deprivation increased the hepatic expression of the gene that encodes hepcidin, hepcidin antimicrobial peptide 1 ( Hamp1), with maximal expression observed after 16 h, and was able to overcome the reduction in Hamp1 expression associated with Hfe deficiency. Food deprivation also increased Hamp1 expression in response to stimuli that more strongly suppress the gene, such as iron deficiency and erythropoietin treatment, but the effects were not significant. These results indicate that Hamp1 induction by food deprivation is independent of HFE and suggest that targeting the pathway regulated by food deprivation could have clinical benefit in iron-loading conditions.-Mirciov, C. S. G., Wilkins, S. J., Anderson, G. J., Frazer, D. M. Food deprivation increases hepatic hepcidin expression and can overcome the effect of Hfe deletion in male mice.
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Inadequate iron levels during early life can have adverse consequences for the developing infant. Iron deficiency during this critical period of growth can affect brain development and cognitive function, problems that can be lifelong despite subsequent correction of the iron deficit. Therefore, it is critical that the suckling infant has sufficient iron for their developmental needs. Much of the iron used in the immediate post-natal period is stored iron that was acquired from the mother in the final trimester of pregnancy, however, despite having low iron levels, breast milk can also make a significant contribution to infant iron needs. This reflects the ability of the suckling infant to absorb dietary iron far more efficiently than is possible after weaning. The mechanisms underlying this enhanced iron absorption are poorly understood. The iron export protein ferroportin is essential for this process, as it is in adults, however, the role of other molecules normally involved in iron absorption following weaning is less clear. The composition and distribution of iron in breast milk may be important, as could the contribution of more distal parts of the gastrointestinal tract. This review discusses the potential role of each of the above components in intestinal iron absorption during suckling and highlights the need for further research into this important process.
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Animales Lactantes/metabolismo , Absorción Intestinal , Hierro de la Dieta/metabolismo , Animales , Humanos , Hierro/metabolismo , Deficiencias de HierroRESUMEN
Chelators are commonly used to remove excess iron in iron-loading disorders. Deferoxamine (DFO) is an effective and safe iron chelator but an onerous parenteral administration regimen limits its routine use. To develop more effective methods for delivering iron chelators, we examined whether amphiphilic copolymer nanoparticles (NPs) could deliver DFO more efficiently. Physical characterization showed a uniform and stable preparation of DFO nanoparticles (DFO-NPs) with an average diameter of 105.3 nm. In macrophage (RAW264.7) and hepatoma (HepG2) cell lines, DFO-NPs proved more effective at depleting iron than free DFO. In wild-type mice previously loaded with iron dextran, as well as Hbb th3 /+ and Hfe -/- mice, which are predisposed to iron loading, DFO-NPs (40 mg/kg DFO; alternate days; 4 weeks) reduced hepatic iron levels by 71, 46, and 37%, respectively, whereas the equivalent values for free DFO were 53, 7, and 15%. Staining for tissue iron and urinary iron excretion confirmed these findings. Pharmacokinetic analysis showed that NP-encapsulated DFO had a much longer elimination half-life than free DFO (48.63 ± 28.80 vs 1.46 ± 0.59 h), and that DFO-NPs could be readily taken up by tissues and in particular by hepatic Kupffer cells. In vitro, DFO-NPs were less toxic to several cell lines than free DFO, and in vivo they did not elicit any specific inflammatory responses or histological changes. Our results suggest that using a nanoformulation of DFO is a valuable strategy for improving its efficiency as an iron chelator and that this could broaden its clinical use for the treatment of human iron overload disorders.
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The stimulation of erythrocyte formation increases the demand for iron by the bone marrow and this in turn may affect the levels of circulating diferric transferrin. As this molecule influences the production of the iron regulatory hormone hepcidin, we hypothesized that erythropoiesis-driven changes in diferric transferrin levels could contribute to the decrease in hepcidin observed following the administration of erythropoietin. To examine this, we treated mice with erythropoietin and examined diferric transferrin at various time points up to 18 hours. We also investigated the effect of altering diferric transferrin levels on erythropoietin-induced inhibition of Hamp1, the gene encoding hepcidin. We detected a decrease in diferric transferrin levels 5 hours after erythropoietin injection and prior to any inhibition of the hepatic Hamp1 message. Diferric transferrin returned to control levels 12 hours after erythropoietin injection and had increased beyond control levels by 18 hours. Increasing diferric transferrin levels via intravenous iron injection prevented the inhibition of Hamp1 expression by erythropoietin without altering hepatic iron concentration or the expression of Erfe, the gene encoding erythroferrone. These results suggest that diferric transferrin likely contributes to the inhibition of hepcidin production in the period shortly after injection of erythropoietin and that, under the conditions examined, increasing diferric transferrin levels can overcome the inhibitory effect of erythroferrone on hepcidin production. They also imply that the decrease in Hamp1 expression in response to an erythropoietic stimulus is likely to be mediated by multiple signals.
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Eritropoyesis/efectos de los fármacos , Eritropoyetina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hepcidinas/sangre , Transferrina/farmacología , Animales , Masculino , Ratones , Factores de TiempoRESUMEN
Fe is an essential nutrient for many bacteria, and Fe supplementation has been reported to affect the composition of the gut microbiota in both Fe-deficient and Fe-replete individuals outside pregnancy. This study examined whether the dose of Fe in pregnancy multivitamin supplements affects the overall composition of the gut microbiota in overweight and obese pregnant women in early pregnancy. Women participating in the SPRING study with a faecal sample obtained at 16 weeks' gestation were included in this substudy. For each subject, the brand of multivitamin used was recorded. Faecal microbiome composition was assessed by 16S rRNA sequencing and analysed with the QIIME software suite. Dietary intake of Fe was assessed using a FFQ at 16 weeks' gestation. Women were grouped as receiving low (<60 mg/d, n 94) or high (≥60 mg/d; n 65) Fe supplementation. The median supplementary Fe intake in the low group was 10 (interquartile range (IQR) 5-10) v. 60 (IQR 60-60) mg/d in the high group (P<0·001). Dietary Fe intake did not differ between the groups (10·0 (IQR 7·4-13·3) v. 9·8 (IQR 8·2-13·2) mg/d). Fe supplementation did not significantly affect the composition of the faecal microbiome at any taxonomic level. Network analysis showed that the gut microbiota in the low Fe supplementation group had a higher predominance of SCFA producers. Pregnancy multivitamin Fe content has a minor effect on the overall composition of the gut microbiota of overweight and obese pregnant women at 16 weeks' gestation.
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Microbioma Gastrointestinal , Hierro/administración & dosificación , Obesidad/complicaciones , Sobrepeso/complicaciones , Embarazo , Adulto , Bacterias , Índice de Masa Corporal , Suplementos Dietéticos , Femenino , Edad Gestacional , Humanos , Edad Materna , Obesidad/microbiología , Sobrepeso/microbiología , Complicaciones del Embarazo , ARN Ribosómico 16S/metabolismo , Análisis de Secuencia de ARN , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Colorectal cancer is the second leading cause of cancer death in the United States. Black Americans suffer even higher incidence and death rates than the general population. Genetics and patient perceptions explain some of this difference, however, modifiable health care system factors such as lack of access to colon cancer screening also contribute. Partnering an academic health center with local community groups, we piloted a colorectal cancer screening program at a Federally Qualified Health Center (FQHC) serving predominately low socioeconomic status Black Americans. The program was designed to identify and remove barriers to screening and improve screening rates. METHOD: At a single center FQHC, we developed an outreach program centered around (1) patient and provider education, (2) immunochemical fecal occult blood test (iFOBT) distribution, and (3) patient navigation. We identified 402 eligible patients, of which 228 (56.7%) completed screening. RESULTS: Our 56.7% screening rate represented a twofold increase above prepilot levels at the clinic. Nine (4%) iFOBT returned positive. Three of these nine patients completed colonoscopy. Screening rates and follow through were higher under a single navigator model. CONCLUSIONS: Our academic-community partnership provided an effective, evidence based, and sustainable model for increasing colorectal cancer screening in a high risk, low resource community.
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Negro o Afroamericano , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/etnología , Detección Precoz del Cáncer/métodos , Educación del Paciente como Asunto/organización & administración , Navegación de Pacientes/organización & administración , Relaciones Comunidad-Institución , Femenino , Humanos , Masculino , Sangre Oculta , Pobreza , Proveedores de Redes de Seguridad/organización & administración , Estados Unidos , Universidades/organización & administraciónRESUMEN
In conditions such as ß-thalassaemia, stimulated erythropoiesis can reduce the expression of the iron regulatory hormone hepcidin, increasing both macrophage iron release and intestinal iron absorption and leading to iron loading. However, in certain conditions, sustained elevation of erythropoiesis can occur without an increase in body iron load. To investigate this in more detail, we made use of a novel mouse strain (RBC14), which exhibits mild ß-thalassaemia intermedia with minimal iron loading. We compared iron homeostasis in RBC14 mice to that of Hbbth3/+ mice, a more severe model of ß-thalassaemia intermedia. Both mouse strains showed a decrease in plasma iron half-life, although the changes were less severe in RBC14 mice. Despite this, intestinal ferroportin and serum hepcidin levels were unaltered in RBC14 mice. In contrast, Hbbth3/+ mice exhibited reduced serum hepcidin and increased intestinal ferroportin. However, splenic ferroportin levels were increased in both mouse strains. These data suggest that in low-grade chronic haemolytic anaemia, such as that seen in RBC14 mice, the increased erythroid iron requirements can be met through enhanced macrophage iron release without the need to increase iron absorption, implying that hepcidin is not the sole regulator of macrophage iron release in vivo.
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Hepcidinas/metabolismo , Hierro/metabolismo , Talasemia beta/metabolismo , Animales , Biomarcadores , Proteínas de Transporte de Catión/metabolismo , Modelos Animales de Enfermedad , Células Precursoras Eritroides/metabolismo , Eritropoyesis , Femenino , Hepcidinas/sangre , Hierro/sangre , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Globinas alfa/metabolismo , Talasemia beta/sangreRESUMEN
PURPOSE OF REVIEW: Iron is essential for normal cellular function and many diseases result from disturbances in iron homeostasis. This review describes some of the recent key advances in iron transport and its regulation, how this relates to iron-related disorders, and emerging therapies for these diseases. RECENT FINDINGS: The iron-regulatory hormone hepcidin and its target, the iron exporter ferroportin (FPN), play central roles in iron homeostasis. Recent studies have expanded our understanding of how hepcidin is regulated in response to stimulated erythropoiesis and have added some new players to the complex network of factors that influences hepcidin expression. Novel structural insights into how FPN transports iron have been an important addition to the field, as has the recognition that some zinc transporters such as ZIP14 can transport iron. Investigations into cardiac iron homeostasis have revealed a key role for FPN, and transferrin receptor 1, which is essential for cellular iron uptake, has been shown to be critical for normal immune function. SUMMARY: The increased understanding of mechanisms of iron homeostasis that has resulted from recent research has greatly improved our ability to diagnose and manage iron-related disorders, and has offered new therapies for this important class of human diseases.