SiO_(2) Induces Iron Overload and Ferroptosis in Cardiomyocytes in a Silicosis Mouse Model

Objective The aim of this study was to explore the role and mechanism of ferroptosis in SiO_(2)-induced cardiac injury using a mouse model.Methods Male C57BL/6 mice were intratracheally instilled with SiO_(2) to create a silicosis model.Ferrostatin-1(Fer-1)and deferoxamine(DFO)were used to suppress ferroptosis.Serum biomarkers,oxidative stress markers,histopathology,iron content,and the expression of ferroptosis-related proteins were assessed.Results SiO_(2) altered serum cardiac injury biomarkers,oxidative stress,iron accumulation,and ferroptosis markers in myocardial tissue.Fer-1 and DFO reduced lipid peroxidation and iron overload,and alleviated SiO_(2)-induced mitochondrial damage and myocardial injury.SiO_(2) inhibited Nuclear factor erythroid 2-related factor 2(Nrf2)and its downstream antioxidant genes,while Fer-1 more potently reactivated Nrf2 compared to DFO.Conclusion Iron overload-induced ferroptosis contributes to SiO_(2)-induced cardiac injury.Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO_(2) cardiotoxicity,potentially via modulation of the Nrf2 pathway.

Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

Compound of icariin,astragalus,and puerarin mitigates iron overload in the cerebral cortex of Alzheimer＇s disease mice

Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer＇s disease.Icariin,astragalus,and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer＇s disease mice,although the underlying mechanism remains unclear.In the present study,APPswe/PS1ΔE9 transgenic mice were administered icariin,astragalus,and puerarin（120,80,and 80 mg/kg,respectively,once a day,for 3 months）.Iron levels were detected by flame atomic absorption spectroscopy.Interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were measured in the cerebral cortex by enzyme linked immunosorbent assay.Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry.Our results demonstrate that after treatment,iron levels and malondialdehyde content are decreased,while glutathione peroxidase and superoxide dismutase activities are increased.Further,interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were reduced.These results confirm that compounds of icariin,astragalus,and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response.

Molecular pathogenesis and clinical conse-quences of iron overload in liver cirrhosis

BACKGROUND: The liver, as the main iron storage compart-ment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Exces-sive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. DATA SOURCES: PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease pro-gression. We have also included literature on adjuvant thera-peutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. RESULTS: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identiifcation of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause signiifcant improvement of liver functions in patients with iron overload. Phlebotomy can have beneifcial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. CONCLUSION: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and avail-able data suggest that it can be considered as target for adju-vant therapy in this condition.

Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

Iron overload and cofactors with special reference to alcohol,hepatitis C virus infection and steatosis/insulin resistance

There are several cofactors which affect body iron metabolism and accelerate iron overload. Alcohol and hepatic viral infections are the most typical examples for clarifying the role of cofactors in iron overload. In these conditions, iron is deposited in hepatocytes and Kupffer cells and reactive oxygen species （ROS） produced through Fenton reaction have key role to facilitate cellular uptake of transferrin-bound iron. Furthermore, hepcidin, antimicrobial peptide produced mainly in the liver is also responsible for intestinal iron absorption and reticuloendothelial iron release. In patients with ceruloplasmin deficiency, anemia and secondary iron overload in liver and neurodegeneration are reported. Furthermore, there is accumulating evidence that fatty acid accumulation without alcohol and obesity itself modifies iron overload states. Ineffective erythropoiesis is also an important factor to accelerate iron overload, which is associated with diseases such as thalassemia and myelodysplastic syndrome. When this condition persists, the dietary iron absorption is increased due to the increment of bone marrow erythropoiesis and tissue iron overload will thereafter occurs. In porphyria cutanea tarda, iron is secondarily accumulated in the liver.

Effect of iron overload on electrophysiology of slow reaction autorhythmic cells of left ventricular outflow tract in guinea pigs

Objective: To investigate the electrophysiology effects and mechanism of iron overload on the slow response autorhythmic cells in the left ventricular outflow tract of guinea pigs.Methods: Standard microelectrode cell recording techniques were adopted to observe the electrophysiological effects of different concentrations of Fe^(2+)(100 μmol/L, 200 μmol/L) on the left ventricular outflow tract autorhythmic cells.Heart tissues were perfused with FeSO_4(200 μmol/L) combing with CaCl_2(4.2 mmol/L), Verapamil,(1 μmol/L), and nickel chloride(200μmol/L) respectively to observe the influences of these contents on electrophysiology of FeSO_4(200μmol/L) on the left ventricular outflow tract autorhythmic cells.Results: Fe^(2+)at both 100 μmol/L and 200 μmol/L could change the electrophysiological parameters of the slow response autorhythmic cells of the left ventricular outflow tract in a concentrationdependent manner resulting into decrease in Vmax, APA and MDP, slower RPF and VDD, and prolonged APD_(50) and APD_(90)(P all <0.05).Besides, perfusion of increased Ca^(2+) concentration could partially offset the electrophysiological effects of Fe^(2+)(200 μmol/L).The L-type calcium channel(LTCC) blocker Verapamil(1 μmol/L) could block the electrophysiological effects of Fe^(2+)(200 μmol/L).But the T-type calcium channel(TTCC) blocker nickel chloride(NiCl_2, 200 μmol/L) could not block the electrophysiological effects of Fe^(2+)(200 μmol/L).Conclusions: Fe^(2+) can directly change the electrophysiological characteristics of the slow response autorhythmic cells of the left ventricular outflow tract probably through the L-type calcium channel.

Iron overload and immunity

Progress in the characterization of genes involved in the control of iron homeostasis in humans and in mice has improved the definition of iron overload and of the cells affected by it. The cell involved in iron overload with the greatest effect on immunity is the macrophage. Intriguing evidence has emerged, however, in the last 12 years indicating that parenchymal iron overload is linked to genes classically associated with the immune system. This review offers an update of the genes and proteins relevant to iron metabolism expressed in cells of the innate immune system, and addresses the question of how this system is affected in clinical situations of iron overload. The relationship between iron and the major cells of adaptive immunity, the T lymphocytes, will also be reviewed. Most studies addressing this last question in humans were performed in the clinical model of Hereditary Hemochromatosis. Data will also be reviewed demonstrating howthe disruption of molecules essentially involved in adaptive immune responses result in the spontaneous development of iron overload and how they act as modifiers of iron overload.

Iron overload and HFE gene mutations in Polish patients with liver cirrhosis

BACKGROUND:Increased liver iron stores may contribute to the progression of liver injury and fibrosis,and are associated with a higher risk of hepatocellular carcinoma development.Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients.HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins.This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis.METHODS:Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases.Liver function tests and serum iron markers were assessed in both groups.All patients were screened for HFE mutations (C282Y,H63D,S65C).Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes.RESULTS:The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis.There were no differences in the prevalence of all HFE mutations in both groups.In patients with a diagnosis of hepatocellular carcinoma,no significant associations with iron disorders and HFE gene mutations were found.CONCLUSIONS:Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations.Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis.As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease,there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.

Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C

BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.

HFE gene in primary and secondary hepatic iron overload

Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe （HFE） gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non- alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.

Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia

Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver d isease and severeiron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis.Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis.An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.

Neurotoxic effects of iron overload under high glucose concentration

Iron overload can lead to cytotoxicity, and it is a risk factor for diabetic peripheral neuropathy. However, the underlying mechanism remains unclear. We conjectured that iron overload-induced neurotoxicity might be associated with oxidative stress and the NF-E2-related factor 2 （Nrf2）/ARE signaling pathway. As an in vitro cellular model of diabetic peripheral neuropathy, PC12 cells ex- posed to high glucose concentration were used in this study. PC12 cells were cultured with ferric ammonium citrate at different concentrations to create iron overload. PC12 cells cultured in ferric ammonium citrate under high glucose concentration had significantly low cell viability, a high rate of apoptosis, and elevated reactive oxygen species and malondialdehyde levels. These changes were dependent on ferric ammonium citrate concentration. Nrf2 mRNA and protein expression in the ferric ammonium citrate groups were inhibited markedly in a dose-dependent manner. All changes could be inhibited by addition of deferoxamine. These results indicate that iron overload aggravates oxidative stress injury in neural cells under high glucose concentration and that the Nrf2/ARE sigfnaling pathway might play an important role in this process.

Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome

AIM： To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical, biochemical and histopathological findings. METHODS： We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes. The metabolic syndrome （MS） was defined according to ATPⅢ criteria. Iron overload was assessed by liver biopsy. Liver histology was evaluated by Ishak＇s score and iron accumulation by Deugnier＇s score; steatosis was diagnosed when present in ≥ 5% of hepatooltes. RESULTS： According to transferrin saturation levels, we observed significant differences in the amount of hepatic iron overload and iron distribution, as well as the number of metabolic abnormalities. Using Receiving Operating Curve analysis, we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload （P 〈 0.0001）. Patients with ≥2 metabolic alterations and steatosis had lower amount of hepatic iron, lower transferrin saturation and higher sinusoidal iron than patients with 〈 2 MS components and absence of steatosis. CONCLUSION： In our patients, the presence of ≥ 2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome. By contrast, patients with transferrin saturation ≥ 60% had more severe iron overload, few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload.

Natural Iron Chelators: An Orthomolecular Approach to Treat Iron Overload and Its Related Diseases

Despite its various vital roles in the different body’s metabolisms,iron may have a hazardous impact on health when it exceeds its normal values.Iron overload is triggered by many genetic and behavioral factors.Furthermore,excessive iron levels have also been observed in many pathologies such as Alzheimer’s,Parkinson’s,cardiovascular and some cancerous diseases.This paper describes a set of natural iron chelators as an effective and a safe orthomolecular approach in chelating iron.Orthomolecular medicine is based on providing patients with nutritional supplementation at high doses to treat and prevent diseases.This paper describes the properties of a set of flavonoids and phenolic acids such as curcumin and ferulic acid that can be administered as supplements to patients suffering from iron overload since they are classified as strong chelators.Those natural iron chelators’supplements are mainly extracted from fruits,vegetables,and plants.As chelators,they are able to bind effectively to iron,inhibit the production of reactive oxygen species,and reduce the levels of oxidative stress.They can also play an effective therapeutic role in the treatment of neurodegenerative,cardiovascular,diabetic,and cancerous diseases thanks to their iron chelation,antioxidant,and anti-inflammatory properties.

High Incidence of Pulmonary Tuberculosis in ART Naive Remunerated Blood Donors with Human Immunodeficiency Virus Type-1 Infection: Possible Role of Iron Overload

Iron overload is reported to be associated with immune alterations and increased susceptibility to infections. HIV infection is characterized by progressive immunodeficiency leading to invasion by opportunistic pathogens. It was of interest to find out if disease course in HIV type-1 infection could have any relation with alteration in body iron status among individuals with history of oral iron intake. A follow-up study of immunologic and virologic markers in relation to disease progression was undertaken on asymptomatic HIV-1 positive blood donors with history of oral iron intake (subgroup I) compared to those without such history (subgroup II). High serum iron was associated with elevated levels of Th2 category of cytokines, heightened immune activation, faster decline in CD4 + T lymphocyte count and higher viral set point. Pulmonary tuberculosis (PT) was the most common AIDS related illness (ARI) (>70%) recorded among subgroup I compared to non-PT category of ARI. Median ARI free duration (months) was shorter among those who developed PT compared to those developing non-PT category of ARI i.e. 30 (95% CI as 26,32) versus 67(95% CI as 60,71) in subgroup I and 47 (95% CI as 42,49) versus 80 (95% CI as 72,87) in subgroup II (P P < 0.001 for PT versus non-PT in both subgroups). The present study indicates that body iron overload resulting from excess intake of iron may be associated with qualitative defects in cell mediated immunity at early stage of HIV-1 infection that may facilitate subsequent acquisition of pulmonary tuberculosis, shorter ARI free duration and reduced survival.

Iron Depletion Improves Glycemic Control in Poorly Controlled Type 2 Diabetic Patients with Iron Overload and Negative Main HFE-Gene Mutations

Iron overload increases the risk of diabetes via mechanisms of abnormal glucose metabolism: insulin deficiency, insulin resistance, and/or hepatic dysfunction. Iron reduction upregulates glucose uptake and improves hepatocytes insulin receptor activity. This study was conducted to examine the effects of iron depletion—via controlled phlebotomy—on the hypoglycemic treatment in poorly controlled type 2 diabetes mellitus (T2DM) patients with non-genetic iron overload. Forty three patients with poorly controlled T2DM and iron overload were divided into 2 groups: iron depletion group and control group. Regular phlebotomy was performed for iron depletion group on monthly basis until serum ferritin reached 20 μg/L or less. Both groups were examined and compared for blood pressure, serum ferritin, lipid profile, HFE-gene, HbA1c, HOMA-IR and number of medicines used for diabetic control. The results had revealed that group differences of HbA1c (-2.64, 95% CI -3.23 to 2.04, p < 0.001) and HOMA-IR (-0.68, 95% CI -0.98 to -0.37, p < 0.001) showed significant decreases in iron depletion group at end of study. Significant decrease in the numbers of hypoglycemic medicines in iron depletion group was shown at end of study (p < 0.001);66.7% of iron depletion group patients were receiving 1 or 2 medicines at end of studyversus none of the control group. Diastolic blood pressure (DBP), triglycerides and LDL-C decreased significantly while HDL-C levels showed significant rise after iron depletion. It can be concluded from the present study that iron depletion therapy is beneficial for improving the efficiency of glycemic control, DBP, and dyslipidemia in poorly controlled type 2 diabetics with iron over load.

Efficacy of deferasirox for the treatment of iron overload in a child affected by Juvenile Hemochromatosis

We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease. Oral iron chelation with low dose deferasirox showed good efficacy and no side effects. The oral iron chelator deferasirox could be a valid option for removing excess iron in early Juvenile Hemochromatosis.

Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising effective iron chelators for the treatment of iron overload in b-thalassemia patients;nonetheless, their side effects have also been reported. 3-Hydroxypyridinone derivatives are being developed as a safer new chelator and in combined chelation therapy. We evaluated the iron-chelating activity of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in iron-loaded C57BL6 mice. The feeding of a ferrocene-supplemented diet (Fe diet) to mice resulted in iron overload, detectable plasma nontransferrin-bound iron (NTBI) and labile plasma iron (LPI), and increases of red cell membrane iron, plasma malondialdehyde (MDA) and excessive tissue iron deposits. Like DFP, the CM1 lowered the levels of the membrane non-heme iron, the NTBI and LPI (p < 0.05) and the MDA after 3 months of treatment. Administration of the Fe diet and the Fe diet along with the chelators did not change the morphology of the liver and heart. Numerous iron accumulations were observed in the liver and spleen tissues of the Fe dietfed mice, whereas the CM1 reduced such iron deposition. Thus, 1-(N-acetyl-6-aminohexyl)-3-hydro- xypyridin-4-one (CM1) can be considered a candidate bidentate oral iron chelator and is effective in the removal of toxic irons in blood compartment and tissues. The effectiveness and toxicity of the CM1 need to be investigated extensively in thalassemia mice and patients with iron overload.

A Revised Classification of Primary Iron Overload Syndromes

Background and Aims:The clinical introduction of hepcidin25(Hep25)has led to a more detailed understanding of its relationship with ferroportin(FP)and divalent metal transporter1 in primary iron overload syndromes(PIOSs).In 2012,we proposed a classification of PIOSs based on the Hep25/FP system,which consists of prehepatic aceruloplasminemia,hepatic hemochromatosis(HC),and posthepatic FP disease(FP-D).However,in consideration of accumulated evidence on PIOSs,we aimed to renew the classification.Methods:We reviewed the 2012 classification and retrospectively renewed it according to new information on PIOSs.Results:Iron-loading anemia was included in PIOSs as a prehepatic form because of the newly discovered erythroferrone-induced suppression of Hep25,and the state of traditional FP-D was remodeled as the BIOIRON proposal.The key molecules responsible for prehepatic PIOSs are low transferrin saturation in aceruloplasminemia and increased erythroferrone production by erythroblasts in iron-loading anemia.Hepatic PIOSs comprise four genotypes of HC,in each of which the synthesis of Hep25 is inappropriately reduced in the liver.Hepatic Hep25 synthesis is adequate in posthepatic PIOSs;however,two mutant FP molecules may resist Hep25 differently,resulting in SLC40A1-HC and FP-D,respectively.PIOS phenotypes are diagnosed using laboratory tests,including circulating Hep25,followed by suitable treatments.Direct sequencing of the candidate genes may be outsourced to gene centers when needed.Laboratory kits for the prevalent mutations,such as C282Y,may be the first choice for a genetic analysis of HC in Caucasians.Conclusions:The revised classification may be useful worldwide.