Abnormal Iron Metabolism Research Articles

Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review).

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and can lead to liver cirrhosis or liver cancer in severe cases. In recent years, the incidence of NAFLD has increased substantially. The trend has continued to increase and has become a key point of concern for health systems. NAFLD is often associated with metabolic abnormalities caused by increased visceral obesity, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, atherosclerosis and systemic microinflammation. Therefore, the pathophysiological mechanisms of NAFLD must be clarified to develop new drug treatment strategies. Recently, researchers have conducted numerous studies on the pathogenesis of NAFLD and have identified various important regulatory factors and potential molecular mechanisms, providing new targets and a theoretical basis for the treatment of NAFLD. However, the pathogenesis of NAFLD is extremely complex and involves the interrelationship and influence of multiple organs and systems. Therefore, the condition must be explored further. In the present review, the abnormal metabolic process, including glucose, lipid, amino acid, bile acid and iron metabolism are reviewed. It was concluded that NAFLD is associated with an imbalanced metabolic network that involves glucose, lipids, amino acids, bile acids and iron, and lipid metabolism is the core metabolic process. The current study aimed to provide evidence and hypotheses for research and clinical treatment of NAFLD.

Liver Sinusoidal Endothelial Cells at the Crossroad of Iron Overload and Liver Fibrosis.

Significance: Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent Advances: Multiple mechanisms underlying the profibrogenic role of iron have been proposed. The pivotal role of liver sinusoidal endothelial cells (LSECs) in iron-level regulation, as well as their morphological and molecular dedifferentiation occurring in liver fibrosis, has encouraged research on LSECs as prime regulators of very early fibrotic events. Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of hepatic stellate cells, while LSECs capillarization precedes the onset of liver fibrosis. Critical Issues: In the present review, the morphological and molecular alterations occurring in LSECs after liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron dysregulation and LSEC dedifferentiation synergize to exacerbate and promote the progression of liver fibrosis. Future Directions: LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression. Antioxid. Redox Signal. 35, 474-486.

Application of modern neuroimaging technology in the diagnosis and study of Alzheimer's disease.

Neurological abnormalities identified via neuroimaging are common in patients with Alzheimer’s disease. However, it is not yet possible to easily detect these abnormalities using head computed tomography in the early stages of the disease. In this review, we evaluated the ways in which modern imaging techniques such as positron emission computed tomography, single photon emission tomography, magnetic resonance spectrum imaging, structural magnetic resonance imaging, magnetic resonance diffusion tensor imaging, magnetic resonance perfusion weighted imaging, magnetic resonance sensitive weighted imaging, and functional magnetic resonance imaging have revealed specific changes not only in brain structure, but also in brain function in Alzheimer’s disease patients. The reviewed literature indicated that decreased fluorodeoxyglucose metabolism in the temporal and parietal lobes of Alzheimer’s disease patients is frequently observed via positron emission computed tomography. Furthermore, patients with Alzheimer’s disease often show a decreased N-acetylaspartic acid/creatine ratio and an increased myoinositol/creatine ratio revealed via magnetic resonance imaging. Atrophy of the entorhinal cortex, hippocampus, and posterior cingulate gyrus can be detected early using structural magnetic resonance imaging. Magnetic resonance sensitive weighted imaging can show small bleeds and abnormal iron metabolism. Task-related functional magnetic resonance imaging can display brain function activity through cerebral blood oxygenation. Resting functional magnetic resonance imaging can display the functional connection between brain neural networks. These are helpful for the differential diagnosis and experimental study of Alzheimer’s disease, and are valuable for exploring the pathogenesis of Alzheimer’s disease.

Cadmium induces iron deficiency anemia through the suppression of iron transport in the duodenum

Cadmium (Cd) is an environmental contaminant that triggers toxic effects in various tissues such as the kidney, liver, and lung. Cd can also cause abnormal iron metabolism, leading to anemia. Iron homeostasis is regulated by intestinal absorption. However, whether Cd affects the iron absorption pathway is unclear. We aimed to elucidate the relationship between the intestinal iron transporter system and Cd-induced iron deficiency anemia. C57BL/6J female and male mice, 129/Sv female mice, and DBA/2 female mice were given a single oral dose of CdCl2 by gavage. After 3 or 24 h, Cd decreased serum iron concentrations and inhibited the expression of iron transport-related genes in the duodenum. In particular, Cd decreased the levels of divalent metal transporter 1 and ferroportin 1 in the duodenum. In addition, human colon carcinoma Caco-2 cells were treated with CdCl2. After 72 h, Cd decreased the expression of iron transport-related factors in Caco-2 cells with a pattern similar to that seen in the murine duodenum. These findings suggest that Cd inhibits iron absorption through direct suppression of iron transport in duodenal enterocytes and contributes to abnormal iron metabolism.

Core-Shell-Satellite Nanomaces as Remotely Controlled Self-Fueling Fenton Reagents for Imaging-Guided Triple-Negative Breast Cancer-Specific Therapy.

Triple-negative breast cancer (TNBC) is highly aggressive and insensitive to conventional targeted therapies, resulting in poor therapeutic outcomes. Recent studies have shown that abnormal iron metabolism is observed in TNBC, suggesting an opportunity for TNBC treatment via the iron-dependent Fenton reaction. Nevertheless, the efficiency of current Fenton reagents is largely restricted by the lack of specificity and low intracellular H2 O2 level of cancer cells. Herein, core-shell-satellite nanomaces (Au @ MSN@IONP) are fabricated, as near-infrared (NIR) light-triggered self-fueling Fenton reagents for the amplified Fenton reaction inside TNBC cells. Specifically, the Au nanorod core can convert NIR light energy into heat to induce massive production of intracellular H2 O2 , thereby the surface-decorated iron oxide nanoparticles (IONP) are being fueled for robust Fenton reaction. By exploiting the vulnerability of iron efflux in TNBC cells, such a self-fueling Fenton reaction leads to highly specific anti-TNBC efficacy with minimal cytotoxicity to normal cells. The PI3K/Akt/FoxO axis, intimately involved in the redox regulation and survival of TNBC, is demonstrated to be inhibited after the treatment. Consequently, precise in vivo orthotopic TNBC ablation is achieved under the guidance of IONP-enhanced magnetic resonance imaging. The results demonstrate the proof-of-concept of NIR-light-triggered self-fueling Fenton reagents against TNBC with low ferroportin levels.

OP0006 ABNORMAL IRON METABOLISM AND MITOCHONDRIAL DYSFUNCTION: INVESTIGATING A NOVEL PATHOLOGICAL MECHANISM IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Iron is vital for numerous essential physiological processes including erythropoiesis and energy metabolism (as iron is found in the mitochondrial electron transport chain, the central site of ATP production). Iron homeostasis is tightly controlled by a number of regulators including; 1. Hepcidin, which prevents iron release from stores (under the influence of IL6 and IL1β); 2. Ferritin, an iron storage protein; 3. Lipocalin-2 (LCN2), which is released upon innate immune activation that induces iron sequestration; 4. Transferrin, which binds circulating iron and enables its transport to effector cell targets; 5. Haptoglobin, which binds free haemoglobin and assisting iron recycling; 6. Erythropoietin (EPO), which stimulates erythropoiesis as a result of hypoxia.Chronic inflammation may result in dysregulation of iron metabolism and in turn impair mitochondrial function yet little is known regarding how these processes change in systemic lupus erythematosus (SLE).Objectives:In this study, we investigated how dysregulation of iron metabolism may occur in SLE and subsequently sought to identify how a lack of iron may ultimately induce abnormal mitochondrial function.Methods:1. Investigating abnormal iron metabolism in SLE.Serum samples from patients with SLE (n=39) and healthy controls (HC, n=17) were assessed hepcidin, IL-1ß, IL-6, ferritin, LCN2, EPO, haptoglobin and transferrin levels by ELISA. Hierarchical cluster analysis of normalised data (converted to Z-scores) was performed using MeV software in order to characterise patient groups based upon iron metabolism profile. Anti-dsDNA antibody titres, complement C3 levels and SLEDAI-2K were excluded to limit the influence of these variables on cluster analysis. Results were presented as a heatmap.2. Studying mitochondrial function in iron deficiency and SLE. Peripheral blood mononuclear cells (PBMCs) from HCs and patients with SLE were analysed using Seahorse Respirometry, which measures mitochondrial oxygen consumption rate (a measure of energy metabolism dependent upon oxidative phosphorylation). To assess differences between health, iron deficiency and SLE 3 groups were assessed; 1. PBMCs derived from HCs; 2. PBMCs from patients with SLE; 3. Healthy PBMCs cultured in iron deficient condition, in which cells were treated with the potent iron chelator, Deferiprone.Results:Figure 1a demonstrates that four groups were identified following cluster analysis. In spite of excluding markers of disease activity, these groups showed significant differences in SLEDAI-2K (shown in Figure 1b). In summary, patients with more active disease (Groups C and D) showed higher levels of hepcidin (which prevents the release of iron from stores, under the influence of IL-1ß and IL-6) and reduced transferrin thus suggesting that iron is inefficiently transported when compared with those with less active disease (in Groups A and B).Figure 2a demonstrates that basal mitochondrial respiration is significantly reduced in PBMCs derived from healthy controls when grown in iron deficiency conditions (following treatment with Deferiprone and is lower still in those with SLE. Figure 2b shows that PBMCs from patients with SLE have reduced maximal mitochondrial respiration capacity that is comparable to the levels seen in iron deficient healthy PBMCs.Conclusion:Patients with SLE demonstrate abnormalities in iron metabolism that results in cellular iron deficiency as iron is not released from stores, nor adequately transported at the rate required to meet physiological demands. Furthermore, PBMCs derived from patients with SLE who impaired basal and maximal respiration that is comparable with healthy PBMCs treated potent iron chelation. This suggests that abnormal iron metabolism may in turn limit mitochondrial energy metabolism in SLE and represents a potential future therapeutic target.

Mendeteksi Tepi Citra Penyakit Hemokromatosis Dengan Menggunakan Metode Log (Laplacian Of Gaussian)

Hemochromatosis is a genetic or hereditary disease. Abnormalities of iron metabolism characterized by excessive deposition of iron in the tissues. Derivative conditions that cause the body to absorb too much iron from the food eaten. Excess iron is stored in organs such as the liver, heart and pancreas. Excess iron can cause toxicity to these organs, and is life threatening because it can cause diseases such as cancer, cardiac arrhythmias, and cirrhosis. LOG method (Laplacian of Gaussian) is a second-order edge detection operator or has a derivative filter whose function can detect areas that have rapid changes (rapit change) such as edges (edges) in the image. But this laplacian is very sensitive or low to the presence of noise. For that, the image will be smoothed first by using Gaussian. Thus a new derivative function is known, namely LoG or Laplacian of Gaussian. Many methods are used in solving edge detection problems, including Prewitt Operators, Sobel Operators, Canny Operators, but among all these methods, the Laplacian of Gaussian method is the method most often used in detecting edges. For this reason, it is hoped that the LoG (Laplacian of Gaussian) method can help to detect hemochromatosis. Can help how severe the disease has developed, and what symptoms can later be caused, so that it can help in the healing process.

Huperzine A, reduces brain iron overload and alleviates cognitive deficit in mice exposed to chronic intermittent hypoxia

Chronic intermittent hypoxia (CIH) is a consequence of obstructive sleep apnea (OSA), which increases reactive oxygen species (ROS) generation, resulting in oxidative damage and neurocognitive impairment. This study was designed to determine whether abnormal iron metabolism occurs in the brain under conditions of CIH and whether Huperzine A (HuA) could improve abnormal iron metabolism and neurological damage. The mouse model of CIH was established by reducing the percentage of inspired O2 (FiO2) from 21% to 9% 20 times/h for 8 h/day, and Huperzine A (HuA, 0.1 mg/kg, i.p.) was administered during CIH exposure for 21 days. HuA significantly improved cognitive impairment and neuronal damage in the hippocampus of CIH mice via increasing the ratio of Bcl-2/Bax and inhibiting caspase-3 cleavage. HuA considerably decreased ROS levels by downregulating the high levels of NADPH oxidase (NOX 2, NOX 4) mediated by CIH. There was an overload of iron, which was characterized by high levels of ferritin (FTL and FTH) and transferrin receptor 1 (TfR1) and low levels of ferroportin 1 (FPN1) in the hippocampus of CIH mice. Decreased levels of TfR1 and FTL proteins observed in HuA treated CIH group, could reduce iron overload in hippocampus. HuA increased PSD 95 protein expression, CREB activation and BDNF protein expression to protect against synaptic plasticity impairment induced by CIH. HuA acts as an effective iron chelator to attenuate apoptosis, oxidative stress and synaptic plasticity mediated by CIH.

Abdominal magnetic resonance imaging examination of Tibetan patients with abnormal iron metabolism and a preliminary study of correlations with blood cell analysis.

ObjectiveThe objective was to investigate factors influencing the high incidence of abnormal iron metabolism in a Tibetan population.MethodsThis was a retrospective observational study. Magnetic resonance imaging and blood analysis of 363 Tibetan patients were performed and patients divided into normal and abnormal groups based on the clinical diagnostic standard. The upper limit of normal liver iron content was 50 μmol/g. We analyzed the association between abnormal iron metabolism and blood cell indicators using the Spearman rank correlation test.ResultsIn male patients, differences in mean corpuscular hemoglobin (MCH) and MCH concentration in blood between the normal and abnormal groups were significant. Abnormal iron metabolism in male patients was positively correlated with MCH and MCH concentration. In female patients, differences in erythrocytes, hemoglobin, and hematocrit levels between the two groups were significant. Erythrocyte counts and hemoglobin and hematocrit levels of female patients were positively correlated.ConclusionIron overload in male patients was correlated with an increase in MCH and MCH concentration, and that in female patients was correlated with levels of erythrocytes, hemoglobin, and hematocrit. The incidence rate of iron overload was higher in males than in females and was correlated with age in this Tibetan population.

Disease correction by intraparenchymal or cisternal delivery of a modified AAV8 capsid expressing codon optimized NAGLU for mucopolysaccharidosis type IIIB mice

The ferroportin Q248H mutation is relatively common in sub-Saharan Africa. No previous study examined its relationship with atypical diabetes mellitus (DM) in this area.To determine the potential interactions between ferroportin Q248H mutation, hyperferritinemia and DM in South Kivu (RDC).Presence of ferroportin Q248H mutation and iron status were investigated in diabetic patients (n = 179, age (mean) 57.7 years, CRP (median) 0.16 mg/L) and non-diabetic subjects (n = 86, age 44.5 years, CRP 0.07 mg/L) living in the city of Bukavu. Hyperferritinemia was considered for values greater than 200 and 300 μg/L in women and in men, respectively.The prevalence of ferroportin Q248H mutation [12.1%] was non-significantly higher in diabetics than non-diabetics [14.0% vs. 8.1%, p = 0.17]. Similarly, hyperferritinemia frequency was higher in diabetic patients with Q248H mutation [44.0% vs. 14.3%, p = 0.16] and in mutation carriers [37.0% vs 16.5%, p = 0.001] than in the control groups, respectively. The association between Q248H mutation and DM was nevertheless not significant [adjusted OR 1.70 (95% CI: 0.52–5.58), p = 0.37], whereas hyperferritinemia [OR 2.72 (1.24–5.98), p = 0.01] showed an independent effect after adjustment for age and metabolic syndrome.The present work suggests a potential association between abnormal iron metabolism, ferroportin Q248H mutation and atypical DM in Africans, which may be modulated by environmental factors.

Ironomycin Induces Diffuse Large B-Cell Lymphoma Cell Death By Targeting Iron Metabolism Addiction

Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy. Although more than half of these patients may achieve long-term remission, the majority of the remaining patients succumb to DLBCL.These patients relapse after conventional Rituximab (R)-based chemotherapy regimen, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) in association with drug resistance. Iron is essential for many fundamental cellular functions, including proliferation and DNA synthesis. Accumulating evidence reveals that abnormal iron metabolism plays an important role in carcinogenesis and in the progression of many tumors. In cancer cells, the demand for iron increases in response to sustained deregulation of cell proliferation and DNA synthesis. Based on these data, we searched to identify if iron metabolism pathway is deregulated in DLBCL and could be exploited to develop novel therapeutic strategies. A list of 63 genes related to iron metabolism in cancer was defined. Using Maxstat R function, we showed that 12 genes out of the 63 investigated have a prognostic value in two independent cohorts of DLBCL patients treated by R-CHOP (Melnick cohort, n=69 and Lenz cohort, n=233). Based on these prognostic genes, we created a gene expression profile (GEP)-based risk score as the sum of the beta coefficients weighted by ±1 according to the patient signal above or below the probe set Maxstat value as previously reported (Herviou L et al. Clinical epigenetics 2018). The iron score was significantly associated with high-risk DLBCL in 3 independent cohorts of patients. GSEA analysis revealed that high-risk DLBCL patients defined by iron score are significantly enriched in genes involved in MYC amplification and MYC targets (p< 0.01). These data demonstrated that high iron score allows to identify DLBCL patients with a poor outcome and that could benefit from targeted therapy. We analyzed the therapeutic interest of Ironomycin, a new promising iron depleting molecule. Ironomycin is known to sequester iron in the lysosome and to induce ferroptosis (Mai TT et al. Nature Chemistry 2017). Ironomycin inhibits DLBCL cell proliferation in a panel of 16 DLBCL cell lines, at nanomolar concentrations (Median IC50: 30nM; range: 7.2 - 91.5 nM) compared to other iron chelators. Ironomycin induces significant cell growth inhibition, apoptosis of DLBCL cells and DNA double strand break accumulation. Furthermore, apoptosis induced by Ironomycin was not reversed by Iron supplementation. Caspase activation and apoptosis induction mediated by Ironomycin could be partially reversed by pan-caspase inhibitor QVD (p<0.001). Ferroptosis inhibitor, Ferrostatin-1, also partially reversed Ironomycin-induced apoptosis (p<0.001). According to ferroptosis induction, Ironomycin induced ROS (CM-H2DCFDA staining), lipid peroxidation (BODIPY-C11 staining) and autophagy (LC3B puncta formation), at 48H, in DLBCL cells. We also identified a delayed progression of replication forks upon Ironomycin treatment in DLBCL cell lines (p<0.0001). Ironomycin induces significant phosphorylation of RPA2 that is a marker of DNA-replication stress and DNA damage response. Interestingly, we identified a significant correlation between basal replication stress monitored by ATR and CHK2 phosphorylation and sensitivity to Ironomycin in DLBCL cell lines. With major importance, we validated the therapeutic interest of Ironomycin in primary DLBCL cells of patients (n=5) without major toxicity for non-tumor cells from the microenvironment. Ironomycin significantly reduces the median number of viable primary DLBCL cells by 69.3% and 77.8%, at respectively 50 and 100nM concentrations (p<0.01 and p<0.001). Furthermore, Ironomycin presented a low toxicity on hematopoietic progenitors (CFU assays, n=5) compared to conventional treatment (p<0.001). We tested the therapeutic interest to combine Ironomycin with conventional chemotherapy used in DLBCL including cyclophosphamide, doxorubicin and etoposide. Interestingly, we identified a significant synergistic effect when Ironomycin is combined with Doxorubicin. Altogether, these data demonstrated that a subgroup of high-risk DLBCL patients could be identified with the iron score and could benefit from Iron metabolism inhibitor treatment. Disclosures Cartron: Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Moreaux:Diag2Tec: Other: Co-founder of Diag2Tec company.

Repeated Restraint Stress Enhances Hepatic TFR2 Expression and Induces Hepatic Iron Accumulation in Rats.

Abnormal hepatic iron metabolism is detrimental to health. The objective of this study was to detect repeated restraint stress on liver iron metabolism in rats. Twenty-four male rats aged 7 weeks were randomly divided into 2 groups: control group (Con) and repeated restraint stress group (RS). Rats were subjected to 6 h of daily restraint stress for 14 consecutive days in the repeated restraint stress group. The results showed that repeated restraint stress exposure decreased growth performance including impaired final weight (P = 0.07), reducing average daily gain (P = 0.01), and average daily feed intake (P = 0.00) during the 14-day experimental period. Repeated restraint stress exposure did not affect hemoglobin content and plasma iron parameters except downregulated unsaturated iron-binding capacity (P = 0.04). Repeated restraint stress exposure inhibited liver development (P = 0.03) and induced liver iron accumulation (P = 0.05). In addition, repeated restraint stress downregulated the expression of transferrin (TF) and transferrin receptor 2 (TFR2) at the mRNA level (P < 0.01), but upregulated at the protein level (P = 0.03 for TF; P = 0.00 for TFR2). These results indicated that repeated restraint stress induces hepatic iron accumulation, which is closely related to higher expression of hepatic TFR2 protein in rats.

Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.

Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationinvitro, and post-transplantation invivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.

Cases of neuroferritinopathy from Sudan

Neuroferritnopathy is a bag of diseases due to abnormal iron metabolism. It has different underlying genetic and enzymatic abnormalities. On the other hand they share some radiology features. Patients presents with a wide range of cerebral symptoms and signs. Diagnosis depends on the semiology, genetic testing and MRI imaging. No specific treatment is available for these cases and they represent a challenge to the treating neurologist. Here we illustrate 2 interesting cases with their clinical and imaging findings to raise the awareness of such rare diseases and help diagnosing them in a low resource setting.

The Effect of Abnormal Iron Metabolism on Osteoporosis.

Iron is one of the important trace elements in life activities. Abnormal iron metabolism increases the incidence of many skeletal diseases, especially for osteoporosis. Iron metabolism plays a key role in the bone homeostasis. Disturbance of iron metabolism not only promotes osteoclast differentiation and apoptosis of osteoblasts but also inhibits proliferation and differentiation of osteoblasts, which eventually destroys the balance of bone remodeling. The strength and density of bone can be weakened by the disordered iron metabolism, which increases the incidence of osteoporosis. Clinically, compounds or drugs that regulate iron metabolism are used for the treatment of osteoporosis. The goal of this review summarizes the new progress on the effect of iron overload or deficiency on osteoporosis and the mechanism of disordered iron metabolism on osteoporosis. Explaining the relationship of iron metabolism with osteoporosis may provide ideas for clinical treatment and development of new drugs.

1780-P: In High-Fat Diet-Induced Mice Skeletal Muscles, Iron Overload Plays a Critical Role in Leading Insulin Resistance

Aim/Hypotheses: Iron plays an important role in many physiological processes, including redox balance, inflammation, and mitochondrial respiratory metabolism. Abnormalities in iron metabolism lead to insulin resistance as well as diabetes. However, the abnormal mechanism of iron metabolism in the muscles of insulin resistance animal models is not precisely well known. Therefore, we investigated the molecular mechanism underlying iron dysregulation in high fat diet-induced C57BL/6J mice skeletal muscles. Methods: We measured intracellular iron content in skeletal muscle tissues and iron metabolism related protein levels, such as transferrin receptor1, heavy chain ferritin, light chain ferritin, DMT1, and ferroportin. To investigate the association between iron content and insulin resistance, we treated iron donor or chelator in an animal model and performed insulin tolerance tests and measurement of insulin signaling. Results: Interestingly, intracellular iron levels were increased in high fat diet-induced mice skeletal muscles. We also observed up-regulation of transferrin receptor 1 (TfR1), ferritin, but did not observe a change of DMT1 and ferroportin. Treatment with iron dextran, an iron donor, in C57BL/6J normal mice induced insulin resistance. However, treatment of desferrioxamine, an iron chelator, in high fat diet-induced insulin resistance mice recovered insulin resistance. Iron overload with iron dextran impaired insulin signaling in skeletal muscles, while iron chelation with desferrioxamine recovered high fat-induced dysregulated insulin signaling. Conclusions/interpretation: Therefore, we consider fine-tuning of skeletal muscle iron levels and highly suggest the use for preventing and/or treating insulin resistance and diabetes. Disclosure S. Choi: None. N. Lee: None. H. Moon: None. H. Kim: None. J. Jeon: None. Y. Kang: None. T. Kim: None. K. Lee: None.

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells

Recently, a new erythroid regulator, erythroferrone (ERFE), which downregulates hepatic hepcidin production, has been identified. However, the relationship between ERFE and abnormal iron metabolism in MDS is unclear. In this study, we examined the level of ERFE mRNA during ex vivo erythroid differentiation using cord blood CD34+ cells and we further analyzed whether ERFE could be produced by MDS cells using a public database (GSE58831). ERFE mRNA was increased during normal erythroid differentiation. An analysis of GSE58831 indicated that ERFE expression in bone marrow (BM) MDS cells was higher than that in healthy volunteer (HV)–derived BM cells. ERFE expression significantly and positively correlated with the expression of erythropoietin (EPO) receptors (EPO-R), ALAS2 (5’-Aminolevulinate Synthase 2), STEAP3 (STEAP family member 3) and the presence of ring sideroblasts or the SF3B1 mutation. These results suggest that EPO-R+ MDS cells with ring sideroblasts or an SF3B1 mutation produce high levels of ERFE that may be associated with a reduction in hepcidin.

Changes of iron metabolism during pregnancy and the establishment of reference intervals for pregnant Chinese women.

Background Abnormalities of iron metabolism in pregnancy pose risks for maternal and fetal health. Robust reference intervals for iron metabolism indices have not been established in a pregnant Chinese population. The purpose of this study was to derive reference intervals for indices of iron metabolism during pregnancy in a Chinese population. Methods A total of 360 healthy pregnant women were recruited and divided into three groups of 120 by gestational age: first trimester (1–13 weeks), second trimester (14–27 weeks) and third trimester (≥28 weeks). An additional 120 healthy non-pregnant women were recruited as the non-pregnant control group. Serum ferritin was measured by electrochemiluminescence immunoassay. Serum iron and total iron-binding capacity were measured by a direct bathophenanthroline method. Transferrin saturation value was calculated with formula TS = SI/TIBC. The reference intervals were established using a non-parametric method. Results In first and second trimesters (combined), the reference intervals for serum ferritin, serum iron, total iron-binding capacity and transferrin saturation are 14.7–184.3 mg/L, 14.50–33.45 µmol/L, 36.53–68.81 µmol/L and 19.04–64.76%, respectively. In the third trimester, the reference intervals for serum ferritin, serum iron, total iron-binding capacity and transferrin saturation are 7.2–122.2 mg/L, 5.83–21.52 µmol/L, 49.40–122.76 µmol/L and 8.22–52.75%, respectively. Conclusion The reference intervals for iron metabolism indices for healthy pregnant Chinese women were established in accordance with CLSI C28-A3 guidelines. This will be a valuable tool for clinical practice and research.

Role of Tissue Iron in Development of Cardiovascular Delayed Effects of Acute Radiation Exposure

The threat of radiation exposure from terrorist activity, warfare, or accidents creates an urgent need to develop agents to mitigate the acute and chronic effects of high dose rate total body irradiation (TBI). High level short‐term radiation exposure results in rapid organ injury leading to development of the acute radiation syndrome (ARS), which if untreated will result in death within weeks. Survivors of ARS will experience the delayed effects of acute radiation exposure (DEARE), which include development of chronic pathology and dysfunction of multiple organ systems months to years following exposure. However, the factors and mechanisms that regulate the onset and progression of cardiovascular DEARE are unclear. The goal of the current study was to determine the possible role for abnormal iron metabolism in the development of cardiac DEARE, especially vascular pathology. Studies utilized the ARS mouse model with gamma radiation exposure at 853 cGy (LD50) and time points from 1 day to 4 months post‐TBI.Serum iron was elevated at 1 day post‐TBI, peaked at 2 weeks, and returned to non‐irradiated control values by 4 weeks post‐TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number, hematocrit, and hemoglobin concentrations. Perls' Prussian Blue staining was used to detect iron (hemosiderin) deposition in heart paraffin‐embedded tissue sections, and myocardial iron was present as early as 2 weeks post‐TBI. Pretreatment of mice with the iron chelator deferiprone in drinking water decreased myocardial iron deposition (P=0.055), but not serum iron, at 2 weeks. A histological assessment of coronary artery endothelial cell (EC) density showed intimal nuclei per unit area significantly decreased as early as two weeks post‐TBI vs. non‐irradiated controls (P&lt;0.05), and the decrease persisted to 4 months post‐TBI. EC density in deferiprone‐treated mice was significantly increased at 2 and 4 weeks post‐TBI compared to irradiated non‐treated mice (P&lt;0.03). Administration of the ferroptosis inhibitor ferrostatin‐1 via daily i.p. injection for 2 weeks post‐TBI resulted in no change in coronary artery EC density compared to vehicle controls. Taken together, the results suggest the presence of tissue iron contributes to endothelial cell loss occurring early following TBI and is a significant event impacting the development of DEARE. This information may facilitate development of novel medical countermeasures to prevent or mitigate cardiovascular DEARE‐related pathophysiology.Support or Funding InformationNIH 1U01AI107340‐01 (C. Orschell), IUPUI Research Support Funds Grant (S. Miller)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hepcidin as a key iron regulator mediates glucotoxicity-induced pancreatic β-cell dysfunction.

It has been well established that glucotoxicity induces pancreatic β-cells dysfunction; however, the precise mechanism remains unclear. Our previous studies demonstrated that high glucose concentrations are associated with decreased hepcidin expression, which inhibits insulin synthesis. In this study, we focused on the role of low hepcidin level-induced increased iron deposition in β-cells and the relationship between abnormal iron metabolism and β-cell dysfunction. Decreased hepcidin expression increased iron absorption by upregulating transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) expression, resulting in iron accumulation within cells. Prussia blue stain and calcein-AM assays revealed greater iron accumulation in the cytoplasm of pancreatic tissue isolated from db/db mice, cultured islets and Min6 cells in response to high glucose stimulation. Increased cytosolic iron deposition was associated with greater Fe2+ influx into the mitochondria, which depolarized the mitochondria membrane potential, inhibited ATP synthesis, generated excessive ROS and induced oxidative stress. The toxic effect of excessive iron on mitochondrial function eventually resulted in impaired insulin secretion. The restricted iron content in db/db mice via reduced iron intake or accelerated iron clearance improved blood glucose levels with decreased fasting blood glucose (FBG), fasting blood insulin (FIns), HbA1c level, as well as improved intraperitoneal glucose tolerance test (IPGTT) results. Thus, our study may reveal the mechanism involved in the role of hepcidin in the glucotoxcity impaired pancreatic β cell function pathway.