Imbalance In Iron Homeostasis Research Articles

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.

Foxo1 is an iron-responsive transcriptional factor regulating systemic iron homeostasis

AbstractThe liver plays a crucial role in maintaining systemic iron homeostasis by secreting hepcidin, which is essential for coordinating iron levels in the body. Imbalances in iron homeostasis are associated with various clinical disorders related to iron deficiency or iron overload. Despite the clinical significance, the mechanisms underlying how hepatocytes sense extracellular iron levels to regulate hepcidin synthesis and iron storage are not fully understood. In this study, we identified Foxo1, a well-known regulator of macronutrient metabolism, which translocates to the nucleus of hepatocytes in response to high-iron feeding, holo-transferrin, and bone morphogenetic protein 6 (BMP6) treatment. Furthermore, Foxo1 plays a crucial role in mediating hepcidin induction in response to both iron and BMP signals by directly interacting with evolutionally conserved Foxo binding sites within the hepcidin promoter region. These binding sites were found to colocalize with Smad-binding sites. To investigate the physiological relevance of Foxo1 in iron metabolism, we generated mice with hepatocyte-specific deletion of Foxo1. These mice exhibited reduced hepatic hepcidin expression and serum hepcidin levels, accompanied by elevated serum iron and liver nonheme iron concentrations. Moreover, high-iron diet further exacerbated these abnormalities in iron metabolism in mice lacking hepatic Foxo1. Conversely, hepatocyte-specific Foxo1 overexpression increased hepatic hepcidin expression and serum hepcidin levels, thereby ameliorating iron overload in a murine model of hereditary hemochromatosis (Hfe−/− mice). In summary, our study identifies Foxo1 as a critical regulator of hepcidin and systemic iron homeostasis. Targeting Foxo1 may offer therapeutic opportunities for managing conditions associated with aberrant iron metabolism.

Protective effect of methylene blue in iron-induced neurotoxicity

Iron deposits have been identified as an intriguing pathological finding in the brain. Although generally considered benign, and, to a certain degree, necessary for various biochemical processes and functions, recent research suggests that abnormal iron deposits may exert harmful effects on brain tissue. Excessive iron accumulation in the brain, due to an imbalance in iron homeostasis and exacerbated by endogenous hydrogen peroxide (H2O2), can contribute to neurodegenerative diseases like Alzheimer's and Parkinson's diseases. This occurs through the Fenton reaction, where iron and H2O2 produce highly reactive hydroxyl radicals (•OH), causing oxidative stress and damaging cellular components. This oxidative damage leads to neuronal dysfunction and death, promoting aggregation of misfolded proteins and the progression of neurodegenerative diseases.Methylene blue, a versatile medication used in methemoglobinemia treatment and diagnostics, shows promise in the prevention of possible brain damage from iron deposits. It may act by inhibiting the Fenton reaction, and reducing hydroxyl radical production. By reducing oxidative stress, methylene blue can mitigate iron-induced neurotoxicity in neurodegenerative diseases.We propose early treatment with methylene blue in patients with initial signs of neurodegenerative diseases and excessive iron deposits in the brain detected with Magnetic Resonance Imaging.

NRF/CNC Proteins Mediate Ferroptosis in Diseases

Ferroptosis is a novel form of cell death characterized by an imbalance of iron homeostasis and lipid peroxidation. It has been found to play a key role in guiding the fate of cells, and is closely related to the occurrence and development of a variety of diseases. One of the most important characteristics of ferroptosis is that it is unique not only in terms of morphology and biochemistry but also has a complex and diverse regulatory pathway network. NRF/CNC proteins, which act as important transcriptional activators, have recently been found to have a pivotal regulatory effect on ferroptosis through inhibition. Therefore, further research on the regulatory pathway of ferroptosis through NRF proteins could help to understand the development of various diseases and contemplate new ideas for corresponding treatments. This paper aims to summarize the regulatory roles played by NRF proteins, mainly NRF1 and NRF2, in the onset and development of ferroptosis and to describe the regulatory relationships and research prospects of ferroptosis in diseases

Multifunctional Sr/Se co-doped ZIF-8 nanozyme for chemo/chemodynamic synergistic tumor therapy via apoptosis and ferroptosis.

Rationale: Cancer continues to be a significant public health issue. Traditional treatments such as surgery, radiotherapy, and chemotherapy often fall short because of intrinsic issues such as lack of specificity and poor drug delivery, leading to insufficient drug concentration at the tumor site and/or potential side effects. Consequently, improving the delivery of conventional chemotherapy drugs like doxorubicin (DOX) is crucial for their therapeutic efficacy. Successful cancer treatment is achieved when regulated cell death (RCD) of cancer cells, which includes apoptotic and non-apoptotic processes such as ferroptosis, is fundamental to successful cancer treatment. The developing field of nanozymes holds considerable promise for innovative cancer treatment approaches. Methods: A dual-metallic nanozyme system encapsulated with DOX was created, derived from metal-organic frameworks (MOFs), designed to combat tumors by depleting glutathione (GSH) and concurrently liberating DOX. The initial phase of the study examined the GSH oxidase-mimicking function of the dimetallic nanozyme (ZIF-8/SrSe) through enzyme kinetic assays and Density Functional Theory (DFT) simulations. Following this, we probed the ability of ZIF-8/SrSe@DOX to release DOX in response to the tumor microenvironment in vitro, alongside examining its anticancer capabilities and mechanisms prompting apoptosis or ferroptosis in cancer cells. Moreover, we established tumor-bearing animal models to corroborate the anti-tumor effectiveness of our nanozyme complex and to identify the involved apoptotic and ferroptotic pathways implicated. Results: Enzyme kinetic analyses demonstrated that the ZIF-8/SrSe nanozyme exhibits substantial GSH oxidase-like activity, effectively oxidizing reduced GSH to glutathione disulfide (GSSG), while also inhibiting glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). This inhibition led to an imbalance in iron homeostasis, pronounced caspase activation, and subsequent induction of apoptosis and ferroptosis in tumor cells. Additionally, the ZIF-8/SrSe@DOX nanoparticles efficiently delivered DOX, causing DNA damage and further promoting apoptotic and ferroptotic pathways. Conclusions: This research outlines the design of a novel platform that combines chemotherapeutic agents with a Fenton reaction catalyst, offering a promising strategy for cancer therapy that leverages the synergistic effects of apoptosis and ferroptosis.

Ferroptosis in the Pathogenesis of Alzheimer’s Disease: The New Evidence for Validation of FAB Model

Alzheimer’s disease is an age-associated progressive disorder, characterized by neurodegeneration and following cognitive decline. Several pathological alterations are implicated in its pathogenesis, hence etiology is still poorly understood. Ferroptosis is an alternative form of cell death, driven by intracellular accumulation of iron with subsequent reactive oxygen species formation, which damages membranes, proteins, and DNA, causing cell death. The imbalance in iron homeostasis is rapidly gaining weight as a neurodegeneration cause, increasing the need to develop in vivo and in vitro models to understand the role of ferroptosis in Alzheimer’s disease pathogenesis. This review focuses on the mechanisms of ferroptosis in the pathogenesis of AD, giving a detailed overview of the available in vivo and in vitro methods and their applications, as well as describing in detail the ferrous amyloid buthionine (FAB) model.

Iron and β-Cell Function: Implications for Diabetes Pathophysiology

Background: The intricate relationship between iron metabolism and diabetes mellitus has become a subject of increasing interest, with a growing body of evidence suggesting that iron plays a significant role in the pathophysiology of diabetes. Spe-cifically, the impact of iron on β-cell function has emerged as a critical area of study. Β cells, located in the pancreatic islets of Langerhans, are responsible for insulin synthesis and secretion. Purpose: Understanding how iron influences these vital cells is crucial for unraveling the complexities of diabetes development and progression. Methods: This review synthesizes current literature on the interaction between iron and β-cell function, exploring the molecular and cellular mechanisms underlying this relationship. We conducted a systematic search of databases, including PubMed and Scopus, to identify relevant studies published up to the present date. Articles were selected based on their focus on iron homeostasis, β-cell function, and their implica-tions for diabetes pathophysiology. Results: Iron is an essential micronutrient that participates in various cellular pro-cesses, including energy metabolism and reactive oxygen species (ROS) regulation. In β cells, iron is intricately involved in insulin synthesis, folding, and maturation. However, an imbalance in iron homeostasis can lead to oxidative stress, mitochon-drial dysfunction, and impaired insulin secretion. The reviewed literature provides compelling evidence that alterations in iron levels can adversely affect β-cell func-tion, contributing to the development and progression of diabetes. Excess iron has been associated with increased oxidative stress within β cells, leading to damage and dysfunction. Furthermore, iron-induced ROS may activate inflammatory pathways, promoting β-cell apoptosis and insulin resistance in peripheral tissues. Conversely, iron deficiency may also impact β-cell health. Insufficient iron availability can com-promise the efficiency of insulin synthesis and secretion, potentially contributing to glucose dysregulation. Iron-deficient conditions may lead to alterations in cellular energy metabolism, further exacerbating the vulnerability of β cells to stressors. Conclusions: Understanding the nuanced interplay between iron and β-cell function has implications for diabetes management. Therapeutic strategies aimed at modulating iron levels, such as iron chelation or dietary interventions, hold promise for preserving β-cell health and improving glycemic control. This review underscores the intricate relationship between iron and β-cell function, providing valuable insights into the pathophysiology of diabetes. Whether through excess or deficiency, iron significantly influences the health and function of β cells, shaping the landscape of diabetes development. Further research is warranted to delineate the precise mecha-nisms involved and to explore targeted interventions that may harness the therapeutic potential of modulating iron levels in diabetes management.

Autolysis Affects the Iron Cargo of Ferritins in Neurons and Glial Cells at Different Rates in the Human Brain

Iron is known to accumulate in neurological disorders, so a careful balance of the iron concentration is essential for healthy brain functioning. An imbalance in iron homeostasis could arise due to the dysfunction of proteins involved in iron homeostasis. Here, we focus on ferritin—the primary iron storage protein of the brain. In this study, we aimed to improve a method to measure ferritin-bound iron in the human post-mortem brain, and to discern its distribution in particular cell types and brain regions. Though it is known that glial cells and neurons differ in their ferritin concentration, the change in the number and distribution of iron-filled ferritin cores between different cell types during autolysis has not been revealed yet. Here, we show the cellular and region-wide distribution of ferritin in the human brain using state-of-the-art analytical electron microscopy. We validated the concentration of iron-filled ferritin cores to the absolute iron concentration measured by quantitative MRI and inductively coupled plasma mass spectrometry. We show that ferritins lose iron from their cores with the progression of autolysis whereas the overall iron concentrations were unaffected. Although the highest concentration of ferritin was found in glial cells, as the total ferritin concentration increased in a patient, ferritin accumulated more in neurons than in glial cells. Summed up, our findings point out the unique behaviour of neurons in storing iron during autolysis and explain the differences between the absolute iron concentrations and iron-filled ferritin in a cell-type-dependent manner in the human brain.Graphical The rate of loss of the iron-filled ferritin cores during autolysis is higher in neurons than in glial cells.

Broadening horizons: the multifaceted functions of ferroptosis in kidney diseases.

Ferroptosis is an iron-dependent programmed cell death pattern that is characterized by iron overload, reactive oxygen species (ROS) accumulation and lipid peroxidation. Growing viewpoints support that the imbalance of iron homeostasis and the disturbance of lipid metabolism contribute to tissue or organ injury in various kidney diseases by triggering ferroptosis. At present, the key regulators and complicated network mechanisms associated with ferroptosis have been deeply studied; however, its role in the initiation and progression of kidney diseases has not been fully revealed. Herein, we aim to discuss the features, key regulators and complicated network mechanisms associated with ferroptosis, explore the emerging roles of organelles in ferroptosis, gather its pharmacological progress, and systematically summarize the most recent discoveries about the crosstalk between ferroptosis and kidney diseases, including renal cell carcinoma (RCC), acute kidney injury (AKI), diabetic kidney disease (DKD), autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, lupus nephritis (LN) and IgA nephropathy. We further conclude the potential therapeutic strategies by targeting ferroptosis for the prevention and treatment of kidney diseases and hope that this work will provide insight for the further study of ferroptosis in the pathogenesis of kidney-related diseases.

Loss of PPR protein Ppr2 induces ferroptosis-like cell death in Schizosaccharomyces pombe.

Ferroptosis is a form of iron- and lipid peroxidation-mediated programmed cell death that occurs widely in mammalian cells. However, this phenomenon is rarely reported in unicellular eukaryotes. Here, we address whether ferroptosis occurs in the model unicellular eukaryote Schizosaccharomyces pombe (S. pombe). Deletion of the pentatricopeptide repeat (PPR) gene ppr2 encoding as a general mitochondrial translation factor required for mitochondrial translation disrupts iron homeostasis and induces oxidative stress, resulting in loss of cell viability. The small-molecular ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1) partially rescued the ppr2 deletion-induced cell death. The amount of malondialdehyde, a lipid peroxidation marker, in Δppr2 cells was higher than that in wild type. Using C11-BODIPY 581/591, an oxidation-sensitive fluorescent lipid peroxidation probe, we showed that Δppr2 cells have a large amount of lipid peroxidation compared to wild-type cells. Deletion of ferric reductase transmembrane component 1 (frp1) encoding S. pombe ferric reductase, which is required for ferric iron uptake, partially rescued the cell death of Δppr2 cells. Our results suggest that ppr2 deletion causes an imbalance in iron homeostasis and redox, leading to ferroptosis-like cell death in S. pombe.

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications.

The global diabetes epidemic and its complications are increasing, thereby posing a major threat to public health. A comprehensive understanding of diabetes mellitus (DM) and its complications is necessary for the development of effective treatments. Ferroptosis is a newly identified form of programmed cell death caused by the production of reactive oxygen species and an imbalance in iron homeostasis. Increasing evidence suggests that ferroptosis plays a pivotal role in the pathogenesis of diabetes and diabetes-related complications. In this review, we summarize the potential impact and regulatory mechanisms of ferroptosis on diabetes and its complications, as well as inhibitors of ferroptosis in diabetes and diabetic complications. Therefore, understanding the regulatory mechanisms of ferroptosis and developing drugs or agents that target ferroptosis may provide new treatment strategies for patients with diabetes.

The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Myelodysplasticsyndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs. Here, we provide an overview of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML.

Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis.

Sideroflexins (SLC56 family) are highly conserved multi-spanning transmembrane proteins inserted in the inner mitochondrial membrane in eukaryotes. Few data are available on their molecular function, but since their first description, they were thought to be metabolite transporters probably required for iron utilization inside the mitochondrion. Such as numerous mitochondrial transporters, sideroflexins remain poorly characterized. The prototypic member SFXN1 has been recently identified as the previously unknown mitochondrial transporter of serine. Nevertheless, pending questions on the molecular function of sideroflexins remain unsolved, especially their link with iron metabolism. Here, we review the current knowledge on sideroflexins, their presumed mitochondrial functions and the sparse—but growing—evidence linking sideroflexins to iron homeostasis and iron-sulfur cluster biogenesis. Since an imbalance in iron homeostasis can be detrimental at the cellular and organismal levels, we also investigate the relationship between sideroflexins, iron and physiological disorders. Investigating Sideroflexins’ functions constitutes an emerging research field of great interest and will certainly lead to the main discoveries of mitochondrial physio-pathology.

Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus

Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca2+, ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5−/− mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca2+/calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5−/− mice than WT mice. Furthermore, treatment with N-acetyl-cysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5−/− mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding iron-mediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis.

The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.

Iron concentrations in neurons and glial cells with estimates on ferritin concentrations

BackgroundBrain iron is an essential as well as a toxic redox active element. Physiological levels are not uniform among the different cell types. Besides the availability of quantitative methods, the knowledge about the brain iron lags behind. Thereby, disclosing the mechanisms of brain iron homeostasis helps to understand pathological iron-accumulations in diseased and aged brains. With our study we want to contribute closing the gap by providing quantitative data on the concentration and distribution of iron in neurons and glial cells in situ. Using a nuclear microprobe and scanning proton induced X-ray emission spectrometry we performed quantitative elemental imaging on rat brain sections to analyze the iron concentrations of neurons and glial cells.ResultsNeurons were analyzed in the neocortex, subiculum, substantia nigra and deep cerebellar nuclei revealing an iron level between (0.53pm 2) and (0.68pm 2),upmu hbox {M}. The iron concentration of neocortical oligodendrocytes is fivefold higher, of microglia threefold higher and of astrocytes twofold higher compared to neurons. We also analyzed the distribution of subcellular iron concentrations in the cytoplasm, nucleus and nucleolus of neurons. The cytoplasm contains on average 73% of the total iron, the nucleolus—although a hot spot for iron—due to its small volume only 6% of total iron. Additionally, the iron level in subcellular fractions were measured revealing that the microsome fraction, which usually contains holo-ferritin, has the highest iron content. We also present an estimate of the cellular ferritin concentration calculating 133pm 25 ferritin molecules per upmu hbox {m} in rat neurons.ConclusionGlial cells are the most iron-rich cells in the brain. Imbalances in iron homeostasis that lead to neurodegeneration may not only be originate from neurons but also from glial cells. It is feasible to estimate the ferritin concentration based on measured iron concentrations and a reasonable assumptions on iron load in the brain.

Iron and Alzheimer's Disease: From Pathogenesis to Therapeutic Implications.

As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death. There is an imbalance in iron homeostasis in Alzheimer’s disease (AD). Excessive iron contributes to the deposition of β-amyloid and the formation of neurofibrillary tangles, which in turn, promotes the development of AD. Therefore, iron-targeted therapeutic strategies have become a new direction. Iron chelators, such as desferoxamine, deferiprone, deferasirox, and clioquinol, have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Given the limitations and side effects of the long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin, as self-synthesized naturally small molecules, have shown very intriguing biological activities in blocking Aβ-aggregation, tauopathy and neuronal damage. Despite a lack of evidence for any clinical benefits, the conjecture that therapeutic chelation, with a special focus on iron ions, is a valuable approach for treating AD remains widespread.

The crucial impact of iron deficiency definition for the course of precapillary pulmonary hypertension.

Imbalances of iron homeostasis are associated with an adverse clinical outcome of pulmonary hypertension (PH). Herein, we aimed to analyze the impact of iron deficiency (ID) in a real-life PH patient cohort according to different currently used ID definitions. In a retrospective study including 153 precapillary PH patients followed over a mean period of five years, iron deficiency was assessed according to five clinical definitions used in previous trials. The impact of ID on clinical, hematological and hemodynamic parameters was investigated. Depending on the different cutoff levels for serum ferritin and transferrin saturation, currently used ID definitions indicated a prevalence of either true or functional ID in 11 to 75 percent of PH patients. A good diagnostic accuracy was achieved by using the sTFRF/log ferritin (sTFRF) index, which identified 33 to 42 percent of PH patients as being iron deficient. The sTFRF index had the best prediction for the association between ID and clinical outcome. Iron deficient patients with precapillary PH had a significantly higher mortality as compared to non-iron deficiency subjects, which was true for both, PH patients with and without anemia. Although levels of the iron hormone hepcidin were rather affected by ID than by inflammation, they were not associated with the clinical course or mortality of PH subjects. To conclude, ID had a significant impact on the clinical course of precapillary PH patients. The appropriate use of robust biomarkers to define ID is a prerequisite to further evaluate the role of ID and the potential benefit of iron supplementation in precapillary PH patients.

Dietary Iron Modulates Glucose and Lipid Homeostasis in Diabetic Mice.

Imbalance of iron homeostasis has been involved in clinical courses of metabolic diseases such as type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver, through mechanisms not yet fully elucidated. Herein, we evaluated the effect of dietary iron on the development of diabetic syndromes in genetically obese db/db mice. Mice (aged 7weeks) were fed with high-iron (HI) diets (1000mg/kg chow) or low-iron (LI) diets (12mg/kg) for 9weeks. HI diets increased hepatic iron threefold and led to fourfold higher mRNA levels of hepcidin. HI also induced a 60% increase in fasting glucose due to insulin resistance, as confirmed by decreased hepatic glycogen deposition eightfold and a 21% decrease of serum adiponectin level. HI-fed mice had lower visceral adipose tissue mass estimated by epididymal and inguinal fat pad, associated with iron accumulation and smaller size of adipocytes. Gene expression analysis of liver showed that HI diet upregulated gluconeogenesis and downregulated lipogenesis. These results suggested that excess dietary iron leads to reduced mass, increased fasting glucose, decreased adiponectin level, and enhancement of insulin resistance, which indicated a multifactorial role of excess iron in the development of diabetes in the setting of obesity.

Indices of iron homeostasis correlate with airway obstruction in an NHANES III cohort.

Cigarette smoking results in the accumulation of iron both systemically and locally, in the lung thereby causing imbalance in iron homeostasis. This disruption in iron homeostasis can be associated with oxidative stress and consequent tissue injury. Therefore, in this study, we tested the association between iron homeostasis and airway obstruction by examining a large cohort of smokers and non-smokers for relationships between 1) serum ferritin and iron concentrations and transferrin saturation and 2) forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and their ratio (FEV1/FVC). Data from the National Health and Examination Survey III were analyzed. The study population included persons aged 20 years and above with their following data recorded: race, gender, serum ferritin and iron concentrations, and transferrin saturation; the final sample number was 7,251. In the total population, Pearson correlation coefficients between 1) serum ferritin and iron concentrations and transferrin saturation and 2) FVC and FEV1 were significantly positive; whereas those between 1) serum ferritin concentrations and transferrin saturation and 2) FEV1/FVC were significantly negative. With separate analyses, serum ferritin concentrations demonstrated positive associations with FVC and FEV1 but an inverse relationship with FEV1/FVC in smokers and non-smokers. Serum ferritin levels increased with worsening airway obstruction among smokers, and its highest concentrations were found among those with the lowest values of FEV1/FVC ratio (<60%). Comparable to cigarette smokers, serum ferritin concentrations among non-smokers were greatest in those with the lowest FEV1/FVC ratio. Furthermore, elevated levels of serum iron and saturation of transferrin also corresponded with decreased FEV1/FVC ratio among non-smokers. Thus, we conclude that indices of iron homeostasis are associated with airway obstruction in both smokers and non-smokers.