On Iron Metabolism and Its Regulation

Iron is a critical metal for several vital biological processes. Most of the body’s iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.     

Insights into the Role of the Discontinuous TM7 Helix of Human Ferroportin through the Prism of the Asp325 Residue

The negatively charged Asp325 residue has proved to be essential for iron export by human (HsFPN1) and primate Philippine tarsier (TsFpn) ferroportin, but its exact role during the iron transport cycle is still to be elucidated. It has been posited as being functionally equivalent to the metal ion-coordinating residue His261 in the C-lobe of the bacterial homolog BbFpn, but the two residues arise in different sequence motifs of the discontinuous TM7 transmembrane helix. Furthermore, BbFpn is not subject to extracellular regulation, contrary to its mammalian orthologues which are downregulated by hepcidin. To get further insight into the molecular mechanisms related to iron export in mammals in which Asp325 is involved, we investigated the behavior of the Asp325Ala, Asp325His, and Asp325Asn mutants in transiently transfected HEK293T cells, and performed a comparative structural analysis. Our biochemical studies clearly distinguished between the Asp325Ala and Asp325His mutants, which result in a dramatic decrease in plasma membrane expression of FPN1, and the Asp325Asn mutant, which alters iron egress without affecting protein localization. Analysis of the 3D structures of HsFPN1 and TsFpn in the outward-facing (OF) state indicated that Asp325 does not interact directly with metal ions but is involved in the modulation of Cys326 metal-binding capacity. Moreover, models of the architecture of mammalian proteins in the inward-facing (IF) state suggested that Asp325 may form an inter-lobe salt-bridge with Arg40 (TM1) when not interacting with Cys326. These findings allow to suggest that Asp325 may be important for fine-tuning iron recognition in the C-lobe, as well as for local structural changes during the IF-to-OF transition at the extracellular gate level. Inability to form a salt-bridge between TM1 and TM7b during iron translocation could lead to protein instability, as shown by the Asp325Ala and Asp325His mutants.     

Comparative Evaluation of Sucrosomial Iron and Iron Oxide Nanoparticles as Oral Supplements in Iron Deficiency Anemia in Piglets

Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.     

Heart Ferroportin Protein Content Is Regulated by Heart Iron Concentration and Systemic Hepcidin Expression

The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, to approximately 200% of control values. This increase in heart ferroportin protein is very probably caused by a decrease in systemic hepcidin expression, in accordance with the classical regulation of ferroportin by hepcidin. However, the control of heart ferroportin protein by systemic hepcidin could apparently be overridden by changes in heart non-heme iron content since injection of ferric carboxymaltose to mice at 300 mg Fe/kg resulted in an increase in liver hepcidin expression, heart non-heme iron content, and also a threefold increase in heart ferroportin protein content. In a separate experiment, feeding an iron-deficient diet to young Wistar rats dramatically decreased liver hepcidin expression, while heart non-heme iron content and heart ferroportin protein content decreased to 50% of controls. It is, therefore, suggested that heart ferroportin protein is regulated primarily by the iron regulatory protein/iron-responsive element system and that the regulation of heart ferroportin by the hepcidin-ferroportin axis plays a secondary role.     

Betaine Alleviates High-Fat Diet-Induced Disruption of Hepatic Lipid and Iron Homeostasis in Mice

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat deposition in the liver, which is often associated with disrupted iron homeostasis. Betaine has been reported to be hepatoprotective, yet whether and how betaine ameliorates high-fat diet-induced disruption of hepatic lipid and iron homeostasis remains elusive. In this study, mice were fed either standard (CON) or high-fat diet (HFD) for 9 weeks to establish a NAFLD model. Mice raised on HF diet were then assigned randomly to HF and HFB groups, HFB group being supplemented with 1% (w/v) of betaine in the drinking water for 13 weeks. Betaine supplementation significantly alleviated excessive hepatic lipid deposition and restored hepatic iron content. Betaine partly yet significantly reversed HFD-induced dysregulation of lipogenic genes such as PRARγ and CD36, as well as the iron-metabolic genes including FPN and HAMP that encodes hepcidin. Similar mitigation effects of betaine were observed for BMP2 and BMP6, the up-stream regulators of hepcidin expression. Betaine significantly rectified disrupted expression of methyl transfer gene, including BHMT, GNMT and DNMT1. Moreover, HFD-modified CpG methylation on the promoter of PRARγ and HAMP genes was significantly reversed by betaine supplementation. These results indicate that betaine alleviates HFD-induced disruption of hepatic lipid and iron metabolism, which is associated with modification of CpG methylation on promoter of lipogenic and iron-metabolic genes.     

Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury

Hemolysis is known to cause acute kidney injury (AKI). The iron regulatory hormone hepcidin, produced by renal distal tubules, is suggested to exert a renoprotective role during this pathology. We aimed to elucidate the molecular mechanisms of renal hepcidin synthesis and its protection against hemoglobin-induced AKI. In contrast to known hepatic hepcidin induction, incubation of mouse cortical collecting duct (mCCD_cl1) cells with IL-6 or LPS did not induce Hamp1 mRNA expression, whereas iron (FeS) and hemin significantly induced hepcidin synthesis (p < 0.05). Moreover, iron/heme-mediated hepcidin induction in mCCD_cl1 cells was caused by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, as indicated by increased nuclear Nrf2 translocation and induced expression of Nrf2 downstream targets GCLM (p < 0.001), NQO1 (p < 0.001), and TXNRD1 (p < 0.005), which could be prevented by the known Nrf2 inhibitor trigonelline. Newly created inducible kidney-specific hepcidin KO mice demonstrated a significant reduction in renal Hamp1 mRNA expression. Phenylhydrazine (PHZ)-induced hemolysis caused renal iron loading and oxidative stress in both wildtype (Wt) and KO mice. PHZ treatment in Wt induced inflammatory markers (IL-6, TNFα) but not Hamp1. However, since PHZ treatment also significantly reduced systemic hepcidin levels in both Wt and KO mice (both p < 0.001), a dissection between the roles of systemic and renal hepcidin could not be made. Combined, the results of our study indicate that there are kidney-specific mechanisms in hepcidin regulation, as indicated by the dominant role of iron and not inflammation as an inducer of renal hepcidin, but also emphasize the complex interplay of various iron regulatory mechanisms during AKI on a local and systemic level.     

Modeling CVD synthesis of carbon nanotubes: Nanoparticle formation from ferrocene

Catalyst nanoparticles play an important role in the synthesis of carbon nanotubes. In this paper, we present a two-equation model that can predict the formation process of iron nanoparticles from ferrocene fed into a CVD reactor. The model, combined with an axisymmetric two-dimensional computational fluid dynamics (CFD) simulation, includes the mechanism of nucleation and surface growth of an iron particle and bi-particle collision. The model predicts that the diameter of a particle will increase with an increase in the reaction temperature or the radial distance from the center of the reactor. Iron particles may deposit on the reactor wall; our model predicts that the thickness of the layer consisting of deposited iron particles will decrease with an increase in the axial distance from the entrance. The first prediction was validated by experimental observations reported by other researchers. In addition to the CFD simulation, a dimensional analysis was conducted to find pi-numbers that govern the process of particle formation; three pi-numbers were identified. Furthermore, one-dimensional governing equations were obtained under the assumptions of constant diffusion coefficient and collision frequency function, and solutions for particle diameter were obtained in qualitative agreement with the earlier CFD simulations.     

Iron Homeostasis in Health and Disease

Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload.     

Hemosiderin Accumulation in Liver Decreases Iron Availability in Tachycardia-Induced Porcine Congestive Heart Failure Model

Despite advances in the management of iron deficiency in heart failure (HF), the mechanisms underlying the effects of treatment remain to be established. Iron distribution and metabolism in HF pathogenesis need to be clarified. We used a porcine tachycardia-induced cardiomyopathy model to find out how HF development influences hepatic and myocardial iron storing, focusing on ferritin, the main iron storage protein. We found that cumulative liver congestion (due to the decrease of heart function) overwhelms its capacity to recycle iron from erythrocytes. As a consequence, iron is trapped in the liver as poorly mobilized hemosiderin. What is more, the ferritin-bound Fe³⁺ (reflecting bioavailable iron stores), and assembled ferritin (reflecting ability to store iron) are decreased in HF progression in the liver. We demonstrate that while HF pigs show iron deficiency indices, erythropoiesis is enhanced. Renin–angiotensin–aldosterone system activation and hepatic hepcidin suppression might indicate stress erythropoiesisinduced in HF. Furthermore, assembled ferritin increases but ferritin-bound Fe³⁺ is reduced in myocardium, indicating that a failing heart increases the iron storage reserve but iron deficiency leads to a drop in myocardial iron stores. Together, HF in pigs leads to down-regulated iron bioavailability and reduced hepatic iron storage making iron unavailable for systemic/cardiac needs.     

Regulation of Ferroptosis by Non-Coding RNAs in Head and Neck Cancers

Ferroptosis is a newly identified mode of programmed cell death characterized by iron-associated accumulation of lipid peroxides. Emerging research on ferroptosis has suggested its implication in tumorigenesis and stemness of cancer. On the other hand, non-coding RNAs have been shown to play a pivotal role in the modulation of various genes that affect the progression of cancer cells and ferroptosis. In this review, we summarize recent advances in the theoretical modeling of ferroptosis and its relationship between non-coding RNAs and head and neck cancers. Aside from the significance of ferroptosis-related non-coding RNAs in prognostic relevance, we also review how these non-coding RNAs participate in the regulation of iron, lipid metabolism, and reactive oxygen species accumulation. We aim to provide a thorough grounding in the function of ferroptosis-related non-coding RNAs based on current knowledge in an effort to develop effective therapeutic strategies for head and neck cancers.     

基于开尔文探针技术的磷酸铁锂表面势研究

依托新颖的表面表征技术开尔文探针力显微镜（KPFM）获悉磷酸铁锂表面势的情况,以期深入研究锂离子在磷酸铁锂表面的动力学行为。研究结果表明,磷酸铁锂薄膜在常温下的功函数为5.38 eV,并且其功函数随着外界温度的上升而呈现出逐渐下降的趋势,在80℃时的功函数为4.69 eV。此现象意味着高温状况下的磷酸铁锂具有较好的电子迁移能力。此外,非原位的开尔文探针检测发现不同电压平衡状态下的磷酸铁锂具有不同的表面功函数。充电至4.3 V时,磷酸铁锂功函数为4.91 eV,放电至2.5 V时,功函数稳定在5.01 e V。显然,磷酸铁锂的功函数非常敏感于表面的锂离子脱出量。研究从功函数的新角度探究磷酸铁锂表面的锂离子动力学行为,期望能够为其他储能材料的脱锂过程研究提供参考。     

Heme alkylation by artesunic acid and trioxaquine DU1301, two antimalarial trioxanes

The sesquiterpene Artemisinin, an antimalarial drug that is effective against multidrug-resistant Plasmodium falciparum strains, contains a 1,2,4-trioxane, and the endoperoxide function plays a key role in its biological activity. However, its poor solubility means that hemisynthetic derivatives, such as artesunic acid, are preferred for drugs.The reductive activation of the peroxide function of artemisinin by iron(II)-heme produces heme derivatives that are alkylated at meso positions by a C-centered radical derived from artemisinin. We checked if the alkylating ability of trioxane-based drugs toward heme, which might be related to its parasiticidal activity, is a general feature by comparing the chemical reactivity toward heme of the clinically relevant derivative artesunic acid and DU1301, a drug of the trioxaquine family, that is active against P. falciparum. Both artesunic acid and trioxaquine DU1301 efficiently alkylated the heme macrocycle after activation of their peroxide function by the iron(II) of heme itself and thus gave rise to covalently coupled heme-drug products. This heme-drug adduct formation might be related to the high antimalarial activity of DU1301.     

The Oral Ferroportin Inhibitor VIT-2763 Improves Erythropoiesis without Interfering with Iron Chelation Therapy in a Mouse Model of β-Thalassemia

In β-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbb^th3/+ mouse model of β-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbb^th3/+ mouse model of β-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbb^th3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in β-thalassemia.     

Scavenging Bacterial Siderophores with Engineered Lipocalin Proteins as an Alternative Antimicrobial Strategy

Iron acquisition mediated by siderophores, high-affinity chelators for which bacteria have evolved specific synthesis and uptake mechanisms, plays a crucial role in microbiology and in host–pathogen interactions. In the ongoing fight against bacterial infections, this area has attracted biomedical interest. Beyond several approaches to interfere with siderophore-mediated iron uptake from medicinal and immunochemistry, the development of high-affinity protein scavengers that tightly complex the siderophores produced by pathogenic bacteria has appeared as a novel strategy. Such binding proteins have been engineered based on siderocalin—also known as lipocalin 2—an endogenous human scavenger of enterobactin and bacillibactin that controls the systemic spreading of commensal bacteria such as Escherichia coli. By using combinatorial protein design, siderocalin was reshaped to bind several siderophores from Pseudomonas aeruginosa and, in particular, petrobactin from Bacillus anthracis, none of which is recognized by the natural protein. Such engineered versions of siderocalin effectively suppress the growth of corresponding pathogenic bacteria by depriving them of their iron supply and offer the potential to complement antibiotic therapy in situations of acute or persistent infection.     

Soil Consumed by Chacma Baboons is Low in Bioavailable Iron and High in Clay

Despite widespread consumption of soil among animals, the role of geophagy in health maintenance remains an enigma. It has been hypothesized that animals consume soil for supplementation of minerals and protection against toxins. Most studies determine only the total elemental composition of soil, which may not reflect the amount of minerals available to the consumer. Our aim was to test these hypotheses by evaluating the bioavailability of iron in soil consumed by chacma baboons, using a technique that simulates digestion and adsorption. Our results indicate that, despite variation in absolute iron concentration of soil samples, actual iron bioavailability was low while clay content was quite high. This suggests that iron supplementation is unlikely to be the primary motivation for geophagy in this population, and that detoxification is a plausible explanation. This study demonstrates that more research on bioavailability and clay composition is needed to determine the role geophagy plays in health maintenance.     

The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis

Background  

In observational studies anaemia and iron deficiency are associated with cognitive deficits, suggesting that iron supplementation may improve cognitive function. However, due to the potential for confounding by socio-economic status in observational studies, this needs to be verified in data from randomised controlled trials (RCTs).     

Sleep Disturbance and Metabolic Dysfunction: The Roles of Adipokines

Adipokines are a growing group of peptide or protein hormones that play important roles in whole body metabolism and metabolic diseases. Sleep is an integral component of energy metabolism, and sleep disturbance has been implicated in a wide range of metabolic disorders. Accumulating evidence suggests that adipokines may play a role in mediating the close association between sleep disorders and systemic metabolic derangements. In this review, we briefly summarize a group of selected adipokines and their identified function in metabolism. Moreover, we provide a balanced overview of these adipokines and their roles in sleep physiology and sleep disorders from recent human and animal studies. These studies collectively demonstrate that the functions of adipokine in sleep physiology and disorders could be largely twofold: (1) adipokines have multifaceted roles in sleep physiology and sleep disorders, and (2) sleep disturbance can in turn affect adipokine functions that likely contribute to systemic metabolic derangements.     

Does Coenzyme Q10 Supplementation Improve Human Oocyte Quality?

Acquiring oocyte competence requires optimal mitochondrial function and adequate ATP levels. In this context, CoQ10 supplementation may improve human oocyte quality and subsequent reproductive performance given its role in ATP synthesis and mitochondrial protection from ROS oxidative damage. In infertility treatments, CoQ10 therapy can be orally supplied to promote a more favorable environment for oocyte development in vivo or by its addition to culture media in an attempt to improve its quality in vitro. Human clinical studies evaluating the impact of CoQ10 on reproductive performance are summarized in this review, although the available data do not clearly prove its ability to improve human oocyte quality. The main objective is to provide readers with a complete overview of this topic’s current status as well as the keys for potential future research lines that may help to take this therapy to clinical practice. Indeed, further clinical trials are needed to confirm these results along with molecular studies to evaluate the impact of CoQ10 supplementation on oxidative stress status and mitochondrial function in human gametes.     

The role of iron(iii) and tartrate in the zincate immersion process for plating aluminium

The zincate immersion process is a commercial process used to treat aluminium prior to electroplating. Superior zinc coatings are obtained through modifications to the original process. One such modification involves the addition of ferric chloride, complexed with potassium sodium tartrate, to the plating baths. This paper describes a detailed investigation into the function of these additives. It was found that the addition of tartrate alone did not significantly affect the rate of zinc deposition, the deposit morphology or the position of the aluminium or zinc polarization curves. This suggests that the role of tartrate is solely as a complexing agent to maintain iron (iii) in solution. In contrast to this, the addition of iron(iii)/tartrate had a marked effect on the reaction. It was found that iron(iii) functioned primarily by reducing the size of the zinc crystals as they formed. This produces a thinner and more compact zinc immersion coating.