Redox active plasma iron in C282Y/C282Y hemochromatosis

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4527-4531 ◽  
Author(s):  
Caroline Le Lan ◽  
Olivier Loréal ◽  
Tally Cohen ◽  
Martine Ropert ◽  
Hava Glickstein ◽  
...  
Keyword(s):  
Iron Overload ◽  
Oxygen Radicals ◽  
Active Component ◽  
Transferrin Saturation ◽  
Alcoholic Cirrhosis ◽  
Healthy Controls ◽  
Plasma Iron ◽  
Redox Active ◽  
Genetic Hemochromatosis

Abstract Labile plasma iron (LPI) represents the redox active component of non–transferrin-bound iron (NTBI). Its presence in thalassemic patients has been recently reported. The aim of the present study was to quantify LPI in HFE genetic hemochromatosis (GH) and to characterize the mechanisms accounting for its appearance. We studied 159 subjects subdivided into the following groups: (1) 23 with iron overloaded GH; (2) 14 with iron-depleted GH; (3) 26 with dysmetabolic hepatosiderosis; (4) 33 with alcoholic cirrhosis; (5) 63 healthy controls. Both NTBI and LPI were substantially higher in patients with iron-overloaded GH than in those with iron-depleted GH or in healthy controls. LPI was significantly correlated with serum transaminase increase in this group. LPI was elevated in the alcoholic cirrhosis subgroup of severely affected patients. LPI was found essentially when transferrin saturation exceeded 75%, regardless of the etiologic condition. Transferrin saturation above 75% was related to iron overload in GH and to liver failure in alcoholic cirrhosis. LPI is present in C282Y/C282Y hemochromatosis and may be a marker of toxicity due to its potential for catalyzing the generation of reactive oxygen radicals in vivo.

scholarly journals Labile plasma iron in iron overload: redox activity and susceptibility to chelation

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2670-2677 ◽  
Author(s):  
Breno P. Esposito ◽  
William Breuer ◽  
Pornpan Sirankapracha ◽  
Pensri Pootrakul ◽  
Chaim Hershko ◽  
...  
Keyword(s):  
Iron Overload ◽  
Oral Treatment ◽  
Oxidation Products ◽  
Redox Activity ◽  
Iron Chelators ◽  
Plasma Iron ◽  
Redox Active ◽  
Reactive Radicals

Abstract Plasma non-transferrin-bound-iron (NTBI) is believed to be responsible for catalyzing the formation of reactive radicals in the circulation of iron overloaded subjects, resulting in accumulation of oxidation products. We assessed the redox active component of NTBI in the plasma of healthy and β-thalassemic patients. The labile plasma iron (LPI) was determined with the fluorogenic dihydrorhodamine 123 by monitoring the generation of reactive radicals prompted by ascorbate but blocked by iron chelators. The assay was LPI specific since it was generated by physiologic concentrations of ascorbate, involved no sample manipulation, and was blocked by iron chelators that bind iron selectively. LPI, essentially absent from sera of healthy individuals, was present in those of β-thalassemia patients at levels (1-16 μM) that correlated significantly with those of NTBI measured as mobilizer-dependent chelatable iron or desferrioxamine chelatable iron. Oral treatment of patients with deferiprone (L1) raised plasma NTBI due to iron mobilization but did not lead to LPI appearance, indicating that L1-chelated iron in plasma was not redox active. Moreover, oral L1 treatment eliminated LPI in patients. The approach enabled the assessment of LPI susceptibility to in vivo or in vitro chelation and the potential of LPI to cause tissue damage, as found in iron overload conditions. (Blood. 2003;102:2670-2677)

Molecular Diagnosis of the First Ferroportin Mutation (C326Y) in the Far East Causing a Dominant Form of Inherited Iron Overload.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3204-3204 ◽  
Author(s):  
Vip Viprakasit ◽  
Alison T. Merryweather-Clarke ◽  
Yingyong Chinthammitr ◽  
Lisa Schimanski ◽  
Hal Drakesmith ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Far East ◽  
Rflp Analysis ◽  
Causative Mutation ◽  
The Far East ◽  
Hfe Mutations ◽  
Genetic Hemochromatosis

Abstract Genetic hemochromatosis (HH) is a common inherited disorder in populations of European origin in which different types of genetic hemochromatosis (type 1–4) have been characterized. Most hemochromatosis-type 1 patients are homozygotes or compound heterozygotes for two HFE mutations C282Y and H63D. Studies of several non-HFE iron overload families led to identification of mutations in hemojuvelin and hepcidin (juvenile form-HFE2A and B), transferrin receptor 2 (HFE3) and ferroportin (HFE4) as a cause of different forms of hemochromatosis. In the Far East, inherited hemochromatosis has rarely been reported and may have been misdiagnosed due to the high prevalence of secondary iron loading from hemoglobin disorders. This report describes, for the first time, non-HFE iron overload in patients from Southeast Asia. The affected Thai family presented with a distinctive clinical phenotype including macrocytosis and elevated transferrin saturation (>95%), increased non-transferrin bound iron (NTBI) as well as raised serum ferritin and marked hepatic hemochromatosis. Our patients tolerated therapeutic phlebotomy well. DNAs from peripheral blood leukocytes were firstly analyzed for three common HFE mutations (C282Y, H63D and IVS5+1 G→A). Subsequently, we screened all coding sequences, promoters and exon/intron boundaries of the HFE, HAMP, TfR2, HJV and SLC40A1 genes using denaturing high performance liquid chromatography (DHPLC). The entire coding region and splice sites of these genes were amplified and directly sequenced. We identified a novel mutation (C326Y) in ferroportin (SLC40A1, IREG-1, MTP-1), a membrane iron transport protein due to a G→A substitution at nucleotide 1281 in exon 7. This mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis using Sfa NI. Six hundred Thai and two hundred Vietnamese chromosomes were analyzed for the C326Y mutation by RFLP analysis and it was not detected in any of the healthy controls studied. This result suggested that the G→A substitution is not a common polymorphism and is likely to be the causative mutation for the phenotype in this family. Previous reported mutations of ferroportin, including A77D and V162del, which lead to type IV hemochromatosis, were characterized by increased serum ferritin despite normal transferrin saturation, in contrast to our patients’ phenotype. These autosomal dominant mutants are postulated to lead to disease due to loss of iron exporting function. Preliminary in vivo assay using transient transfection of wild-type and ferroportin mutants in HeLa or 293T cells revealed, as expected, a loss of function and diminished surface membrane localisation in A77D and V162del mutants. Surprisingly, the C326Y mutant was indistinguishable from wt ferroportin in both iron status of the cell and protein localization suggesting different pathophysiology leading to iron overload in our patients.

Clinical, Pathological, and Molecular Correlates in Ferroportin Disease. A Study of Two Novel Mutations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 706-706
Author(s):  
Domenico Girelli ◽  
Ivana De Domenico ◽  
Claudia Bozzini ◽  
Ilaria Tenuti ◽  
Nadia Soriani ◽  
...  
Keyword(s):  
Iron Overload ◽  
Cellular Localization ◽  
Transferrin Saturation ◽  
Cell Types ◽  
Mouse Bone Marrow ◽  
Pathological Features ◽  
Functional Studies ◽  
Type Iv

Abstract Background: Mutations in the iron exporter Ferroportin (Fpn) lead to type IV hemochromatosis (Ferroportin Disease, FD), a dominantly inherited disorder with heterogeneous clinical and biochemical patterns. Some patients present with predominant macrophage iron overload (M), marked elevation of serum ferritin, normal-to-low transferrin saturation (TS), and, possibly, iron restricted erythropoiesis. Others present with a phenotype resembling classical HFE-related hemochromatosis, i.e. characterized by high TS and predominant hepatocyte iron overload (H). These differences are thought to reflect heterogeneity in the functional behaviour of Fpn mutant proteins. Methods: Two unrelated probands referring to the Centre for Iron Overload Disorders in Verona because of non-HFE hemochromatosis were screened for Fpn mutations by DHPLC (Cremonesi L, Br J Haematol 2005). The functional behaviour of mutants Fpn was studied by generating Fpn-GFP constructs transfected into different cell types (HEK293T, Cos7, and mouse bone marrow macrophages), and analyzing their cellular localization, as well as their capabilities to bind hepcidin and export iron (De Domenico I, PNAS 2005). The two mutations were also expressed in zebrafish, to evaluate their impact on iron-dependent erythropoiesis. Results: Patient 1, a 59 year old male, had clinical, biochemical (TS 74.8%, ferritin 9,000 μg/l), and pathological features (marked iron overload in either macrophages and hepatocytes, absence of overt cirrhosis) somewhat ambiguous, possibly suggesting a type M Fpn variant with late secondary hepatocyte overload. He was found to be heterozygous for the new L233P mutation. Functional studies revealed that Fpn L233P does not appropriately traffic to the cell surface, resulting in inappropriate inhibition by hepcidin. Fpn L233P expression in vivo in zebrafish resulted in iron limited erythropoiesis, consistent with a type M mutation leading to macrophage iron retention. Patient 2, a 59 year old female, had features more clearly suggesting a type M Fpn variant (TS 22.7%, ferritin 1,771 μg/l, macrophage iron load), but tolerated very well phlebotomies without developing signs of anemia. She was found to be heterozygous for the new I152F mutation. Functional studies revealed a unique pattern (never observed until now), since Fpn I152F localized appropriately on cell membrane, bound near normally to hepcidin, but showed a “primary” deficit of iron export capability. I152F expression in zebrafish resulted in a trend towards iron limited erythropoiesis, though quantitatively less clear than L223P. Conclusions: FD is a heterogeneous disease caused by generally “private” mutations in Fpn. The clinical, biochemical, and pathological features vary depending on the different behaviour of mutant Fpn. In vitro and in vivo molecular expression studies are very useful to clarify the pathophysiogical spectrum of this disease.

scholarly journals Implications of Low Zinc and Copper Levels As Well As Altered Iron Trafficking Proteins on Oxidant Stress in Patients with Transfusion Dependant Thalassemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1289-1289
Author(s):  
Patrick B Walter ◽  
Michael Minkley ◽  
Caitlin Curtis ◽  
Hodge Maeve ◽  
Razavi Morty ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Transferrin Receptor ◽  
Oxidative Stress Markers ◽  
Soluble Transferrin Receptor ◽  
Secondary Complications ◽  
Plasma Iron ◽  
Stress Markers ◽  
Iron Trafficking ◽  
Redox Active

Abstract Introduction:Patients with transfusion dependent thalassemia (TDT) have a genetic anemia that causes incomplete erythropoiesis and iron overload. Plasma zinc deficiency is also seen in roughly 25% of patients with TDT. Iron overload is thought to be related to a number of secondary complications in TDT including cardiomyopathy and diabetes. However, in TDT the effects of altered Zn status are not as well characterized and the effects of low copper (Cu) are even less well known. One possible cause of these complications is oxidative damage to tissues. This oxidative stress can be caused by labile plasma iron (LPI), a component of the non-transferrin bound iron pool, which is often seen in individuals suffering from iron overload. LPI is both redox-active and chelatable and is the likely culprit distributing iron to extra-hepatic tissues. Through reactive Fenton chemistry, LPI, can also cause lipid peroxidation releasing malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which are damage-associated molecular patterns and markers of oxidative tissue damage that activate the immune system to induce inflammation. Incomplete erythropoiesis as well as transfusional iron overload are responsible for an increase in the amount of poorly handled, redox active LPI in TDT. Thus, we hypothesized that changes in the levels of key iron trafficking proteins (such as soluble transferrin receptor (sTfR) or hemopexin) would affect oxidative stress levels in TDT. We also hypothesized that metal dyshomeostasis, such as a functional Zn or Cu deficiency would affect oxidative stress. Aims: The purpose of this pilot project is to 1) Determine the state of circulating levels of oxidative stress markers and iron trafficking proteins in TDT patients and 2) Explore the relationship between the markers and proteins measured in (1)and the Zn and Cu status of TDT patients. Methods:39 subjects with informed consent were enrolled (29 patients with TDT and 10 controls). Liver iron concentration (LIC) was measured by a superconducting quantum interference device (SQUID™). LPI was measured using dihydrorhodamine 123. Both MDA and MDA + 4-HNE were measured using N-methyl-2-phenylindole. The iron trafficking proteins sTfR, transferrin, haptoglobin and hemopexin were measured by immunoassay isolation followed by multiplex multiple reaction monitoring mass spectrometry. Zn and Cu were assessed by inductively coupled plasma atomic emission spectroscopy. Fructosamine was measured by quantitative spectrophotometry. Results: Patients with TDT had elevated LIC levels of 2681 ± 2424 ug iron/g wet weight. Plasma levels of the iron trafficking proteins, transferrin, hemopexin and haptoglobin were all decreased in TDT patients (P<0.001) with a corresponding increase in soluble transferrin receptor (StfR) and the LPI (P<0.001). Serum Zn was significantly reduced in TDT patients (p = 0.028) and urinary Zn was significantly elevated (p =0.024). Serum Cu was also significantly reduced in TDT patients (p =0.026). Reduced Zn levels in TDT patients correlated with elevated MDA levels (p = 0.0195, R = -0.382) as were serum Cu levels (p = 0.0158, R = -0.394). Reduced levels of plasma iron trafficking proteins (haptoglobin, hemopexin, and transferrin) were correlated with elevated levels of MDA and LPI (all p-values < 0.05). Plasma MDA was also correlated with fructosamine levels (p < 0.001, R= 0.57). Conclusion: Metal dyshomeostasis involving Zn and Cu may be important contributors to oxidative stress and iron injury in TDT. We confirm previous findings in TDT of elevated levels of LPI as well as the oxidative stress markers MDA and 4-HNE. We expand previous findings of reduced transferrin levels in TDT to show a similar reduction in both haptoglobin and hemopexin. StfR levels were elevated in TDT patients, possibly due to a strong erythropoietic drive. Both reduced haptoglobin and hemopexin as well as decreased Zn and Cu levels and increased Zn excretion appear to be present in TDT. These preliminary findings suggest that low levels of Zn, Cu, haptoglobin and hemopexin may be related to increased oxidative stress and LPI in TDT, which could be important contributors to secondary complications of TDT. Disclosures Walter: Apopharma: Research Funding.

In Vivo Disruption Of The Hepcidin−Ferroportin Regulatory Circuitry Causes Fatal Systemic and Exocrine Pancreatic Iron Overload

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 175-175
Author(s):  
Sandro Altamura ◽  
Hermann Josef Gröne ◽  
Regina Kessler ◽  
Bruno Galy ◽  
Matthias W. Hentze ◽  
...  
Keyword(s):  
Iron Overload ◽  
Molecular Mechanisms ◽  
Histological Analysis ◽  
Conflicts Of Interest ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Accumulation ◽  
Blue Staining ◽  
Hepatic Iron

Abstract Systemic iron levels are tightly controlled by the hepatic hormone hepcidin in response to iron availability, inflammation, hypoxia or the iron demand for erythropoiesis. Hepcidin binds to the iron export protein ferroportin (FPN1) to regulate iron release from exporting cells. A mutation of cysteine 326 (C326S) of FPN1 was reported in a patient with non−classical ferroportin disease (Sham et al, 2005) and shown to abrogate hepcidin binding in vitro (Fernandes et al, 2009). To study consequences of the disruption of the hepcidin−ferroportin interaction in vivo, we generated the first knock−in mouse model of C326S non−classical ferroportin disease. Mice with either heterozygous or homozygous C326S FPN alleles are viable and fertile. At 8−weeks of age both heterozygous and homozygous mice show profoundly increased transferrin saturation and serum ferritin levels as well as hepatic iron overload. Histological analysis by Perl’s Prussian blue staining revealed that hepatic iron accumulation is restricted to hepatocytes and that Kupffer cells are spared of iron. In addition, splenic macrophages and duodenal enterocytes are iron−depleted. Macroscopically, C326S homozygous mice show progressive, brown discoloration of the pancreas that correlates with profound iron deposition. Histological analysis reveals that iron localizes exclusively to the exocrine pancreas sparing the islets of Langerhans. Consistently, C326S homozygous mice do not show any signs of diabetes. Pancreatic iron accumulation is closely associated with increased reactive oxygen species (ROS), degeneration of exocrine pancreatic cells, increased plasma lipase and exocrine pancreatic failure. Starting at the age of 33 weeks, pancreatic failure is accompanied by progressive wasting and death. We believe that C326S FPN mice represent the first example of fatal iron overload in an animal model, opening avenues to investigate the underlying molecular mechanisms. Sham R, Phatak PD, West C, et al. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Blood Cells Mol. Dis. 2005; 34:157−61. Fernandes A, Preza GC, Phung Y, et al. The molecular basis of hepcidin−resistant hereditary hemochromatosis. Blood. 2009;114:437−443. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel automated measuring system for evaluating labile plasma iron in serum

2019 ◽  
Vol 56 (6) ◽  
pp. 654-661
Author(s):  
Takeshi Saito ◽  
Katsuya Ikuta ◽  
Mayumi Hatayama ◽  
Kotoe Shibusa ◽  
Kozo Matsui ◽  
...  
Keyword(s):  
Serum Proteins ◽  
Clinical Stage ◽  
Transferrin Saturation ◽  
Automated System ◽  
Measuring System ◽  
Serum Samples ◽  
Oxidative Potential ◽  
Plasma Iron ◽  
Iron Quantification ◽  
Redox Active

BackgroundAs the saturation of transferrin by iron in the serum is approximately 30%, iron loaded to the blood can bind to transferrin not bearing iron. Nevertheless, prolonged iron influx finally results in full transferrin saturation, and iron not bound to transferrin will appear in the serum; this iron is known as non-transferrin-bound iron (NTBI). NTBI damages organs through the production of free radicals. Previously, we established an automated quantification system for NTBI; however, measuring labile plasma iron, which is considered as a highly redox-active component of NTBI, should be a better prognostic factor in iron-overloaded patients.MethodsWe designed and developed a novel system for evaluating labile plasma iron utilizing the Trinder reaction. Automated system was utilized because the previously reported methods for labile plasma iron are intricate and the introduction to the clinical stage has been challenging. Validations such as the contribution of serum proteins and metal ions for this system were evaluated using human serum samples.ResultsWe confirmed that our novel system can evaluate labile plasma iron utilizing Trinder reaction and the oxidative potential of ceruloplasmin in the serum. This system was also confirmed to be clinically practical. Metals other than iron did not influence this system. We observed that samples with high NTBI did not always exhibit high labile plasma iron and vice versa, highlighting the necessity of labile plasma iron quantification in evaluating the toxicity of NTBI.ConclusionsOur novel system should contribute to fundamental and clinical research because it can measure labile plasma iron using the high-throughput automated analyser.

scholarly journals Transmembrane Protease, Serine 6 (TMPRSS6) Antisense Oligonucleotide (IONIS-TMPRSS6-LRX) Reduces Plasma Iron Levels of Healthy Volunteers in a Phase 1 Clinical Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3634-3634
Author(s):  
Michael McCaleb ◽  
Jason Lickliter ◽  
Andrew Dibble ◽  
Eugene Schneider ◽  
Mariam Aghajan ◽  
...  
Keyword(s):  
Clinical Study ◽  
Adverse Events ◽  
Iron Overload ◽  
Antisense Oligonucleotide ◽  
Serum Iron ◽  
Phase 1 ◽  
Transferrin Saturation ◽  
Beta Thalassemia ◽  
Plasma Iron ◽  
Low Levels

Abstract Iron overload is the major cause of morbidity and mortality in beta-thalassemia patients. The low levels of beta-globin and ineffective erythropoiesis in these patients result in the suppression of hepcidin. The inappropriately low levels of hepcidin trigger an increased absorption of dietary iron and increased iron release from storage, causing iron overload. Expression of hepcidin, which is predominately produced in the liver, is negatively regulated by the transmembrane protease, serine 6 (TMPRSS6). Mouse and human genetic data indicated that lowering TMPRSS6 expression could up-regulate hepcidin and ameliorate many of the disease symptoms associated with beta-thalassemia. Previously we identified a highly specific and potent antisense oligonucleotide (ASO) targeting either the murine (Guo et al. J Clin Invest. 2013; 123(4):1531-41) or the human (Aghajan et al, Blood 2016; 128:1013) TMPRSS6 mRNA. Downregulation of TMPRSS6 with ASO treatment resulted in dose-dependent hepcidin upregulation, leading to dramatic reductions in serum iron and transferrin saturation in animal models This in turn ameliorated the anemia and iron overload phenotypes in a mouse model of beta-thalassemia (th3/+ mice), which recapitulates beta-thalassemia intermedia in humans. Herein, we are reporting the initial clinical safety and pharmacodynamics of IONIS-TMPRSS6-LRX. This GalNAc-conjugated, TMPRSS6 ASO was evaluated in a placebo-controlled, double-blind, randomized, single-center Phase 1 clinical study enrolling healthy volunteers. During an 8-week period, placebo or IONIS-TMPRSS6-LRX was administered subcutaneously four times (Weeks 1, 4, 6 and 8) at doses of 20, 40 or 60 mg. At doses of 20 and 40 mg, mean (±SEM) levels of serum iron were reduced 34±10% and 49±7% on week 10 (The 60 mg treatment cohort is ongoing). Consistent with the reduction of plasma iron, the mean (+/-SEM) percent transferrin saturation was reduced from baseline levels of 28±3% and 30±1% to 14±2% and 13±2%, for 20 and 40 mg groups, respectively, at Week 10. Furthermore, plasma hepcidin levels were increased from 2.1±0.6 and 2.5±0.6 nM to 2.7±0.6 and 6.7±0.9 nM, respectively. During this time period, there were small reductions in Hgb (-9±2%), reticulocyte Hgb (-13±2%) at the 40 mg dose. There were no serious adverse events in the study and the treatment-emergent adverse events were generally mild. In summary, IONIS-TMPRSS6-LRX, a novel antisense oligonucleotide targeting TMPRSS6, effectively reduces plasma iron levels and has the potential as a therapeutic for patients with beta-thalassemia and related disorders. The safety profile of IONIS-TMPRSS6-LRX supports further development. Disclosures McCaleb: Ionis Pharmaceuticals, INC: Employment, Equity Ownership. Lickliter:Nucleus Network: Employment. Dibble:Ionis Pharmaceuticals, INC: Employment. Schneider:Ionis Pharmaceuticals, INC: Employment, Other: shareholders. Aghajan:Ionis Pharmaceuticals, Inc: Employment. Guo:Ionis Pharmaceuticals, Inc: Employment. Hughes:Ionis Pharmaceuticals, INC: Employment, Other: shareholders. Geary:Ionis Pharmaceuticals, INC: Employment, Other: shareholders. Monia:Ionis Pharmaceuticals, Inc: Employment, Other: Intellectual property rights.

scholarly journals Duodenal Ferroportin Expression Is Unresponsive to Dietary Iron Excess in Nursing Piglets (FS04-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Peng Ji ◽  
Nicole Doan ◽  
Yining Wang ◽  
Eric Nonnecke ◽  
Bo Lonnerdal
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Protein Expression ◽  
Iron Overload ◽  
Transferrin Saturation ◽  
Pig Model ◽  
Dietary Iron ◽  
Plasma Iron ◽  
High Iron ◽  
Mrna And Protein Expression

Abstract Objectives In the US, prophylactic iron supplementation without thorough screening for iron deficiency is commonly practiced in both normal weight and low birth weight infants. In a nursing pig model, we previously found that excess dietary iron results in tissue iron overload, suggesting ineffective regulation of intestinal iron absorption. Herein, we aimed to determine if hepcidin-mediated ferroportin (FPN1) degradation is functionally immature in early life. Methods Twelve nursing piglets of normal birth weight (2.1 ± 0.4 kg, PD2) were supplemented with either low (AGAL, 1 mg/d·kg body weight) or high iron (AGAH, 15 mg/d·kg BW)) in form of ferrous sulfate solution. Eight low birth weight (1.2 ± 0.4 kg on PD2) piglets were supplemented with high iron (SGAH, 15 mg/d·kg BW) from PD2 to 21. All piglets were raised by suckling their sows. Blood samples were collected weekly for analysis of hemoglobin, hematocrit, and plasma iron. Duodenal mucosa (DM) and hepatic mRNA and protein expression of iron transporters and regulators were analyzed using RT-qPCR and Western blot. Data were analyzed using PROC MIXED of SAS with CONTRAST statement for planned comparison between AGAL and high iron groups. Results In comparison with AGAL, high iron, regardless of birth weight, significantly (P < 0.05) increased hemoglobin, transferrin saturation (74% vs. 49%), and plasma iron, and resulted in iron overload in DM and liver at PD21. Hepatic mRNA expression of HAMP and FTL in DM increased 275- and 3-fold, respectively, in response to high iron, whereas DMT1 in DM and TFRC in both liver and DM decreased by 7.4-, 3.8- and 5.3-fold, respectively. Consistently, protein expression of DMT1 in DM was lower in SGAH than that in AGAL; However, both mRNA and protein expression of FPN1 in DM and liver remained unaffected by iron provision or birth weight. Conclusions Hepcidin-induced ferroportin degradation is hypo-responsive to iron excess in a nursing pig model. Funding Sources UC Davis, NIFA.

scholarly journals Are Mangiferin and Mangiferin-Containing Plant Extracts Helpful for Iron-Loaded Transfusion-Dependent and Non-Transfusion-Dependent Thalassaemia Patients?

2018 ◽  
Vol 11 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Ari Estuningtyas ◽  
Klaus Zwicker ◽  
Tri Wahyuni ◽  
Purnama Fajri ◽  
Pustika Amalia Wahidiyat ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Complex ◽  
Blood Levels ◽  
Plasma Iron ◽  
Gastric Tubes ◽  
Oral Doses ◽  
Great Burden ◽  
Iron Excretion

Treatment of iron overload in thalassaemia is still a great burden for patients, their families and the health care system in developing countries like Indonesia, because of expensiveness and unwanted side effects of chemical iron-chelating therapeutics. This animal study investigates an extract from the leaves of Mangifera foedica L (EMF) and its major active compound, mangiferin, for chelating and antioxidant treatment of iron overload. Sixty rats were randomly divided into 10 groups: control, iron overload (IO), and IO with mangiferin doses between 50 and 200 mg/g BW or 2390 mg of EMF, applied via gastric tubes. For comparison, deferiprone (DFP) was used. Iron overload was induced by intraperitoneal iron dextran resembling two models, transfusion-dependent (TDT) or nontransfusion-dependent thalassaemia (NTDT). Increasing oral doses of mangiferin and EMF did not result in higher mangiferin plasma levels; however, mangiferin administered for four weeks roughly doubled blood levels compared to two weeks. In the TDT model, mangiferin significantly lowered ferritin levels by 21% and plasma iron levels by 60% (EMF by 50%), almost like DFP (by 70%) and increased iron excretion 6-fold via urine (DFP 15-fold, EMF 2-fold). In the NTDT model mangiferin and EMF decreased ferritin levels significantly by about 30%, without significantly decreasing excess plasma iron. Mangiferin increased iron excretion via urine 4-fold (EMF 2-fold) and tended to diminish Fe accumulation in liver and heart. Iron chelating effects of EMF were weaker than of mangiferin, but its in vivo antioxidant activity was stronger. In vitro, both mangiferin and the mangiferin/FeIII complex are potent superoxide radical scavengers, the iron complex being superior.

Sign in / Sign up

Export Citation Format

Share Document