Iron Storage Diseases Research Articles

Whole-body R2∗ mapping to quantify tissue iron in iron storage organs: reference values and a genotype

To define reference values for the transverse relaxation rate (R2∗) in iron storage organs and to investigate the role of human haemochromatosis protein (HFE) genotype on iron storage. Whole-body magnetic resonance imaging (MRI) including a five-echo gradient-echo sequence was performed in 483 volunteers (269 men, mean age 59.3±12.2 years) without clinical evidence of an iron storage disease at 1.5 T. R2∗ values were assessed for liver, spleen, pancreas, heart, bones, and brain parenchyma. The HFE genotype was determined regarding the single nucleotide polymorphisms (SNPs) rs74315324, rs1799945, rs41303501, rs1800562, rs1800730. R2∗ values were compared among participants without and with at least one mutation. R2∗ reference values were defined using volunteers without any mutation. Three hundred and one participants had no mutations in any HFE SNP, 182 had at least one mutation. HFE gene mutations were distributed as (heterozygous/homozygous) rs1799945:132/9, rs1800562:33/1, and rs1800730:11/0. Mean R2∗ values±SD (per second) in the group without mutation were: liver: 33.4±12.7, spleen: 24.1±13.8, pancreas: 27.2±6.6, heart: 32.7±11.8, bone: 69.3±21.0, brain parenchyma: 13.9±1.2. No significant difference in R2∗ values were found between participants with and without the HFE gene mutation for any examined iron storage organ (pliver=0.09, pspleen=0.36, ppancreas=0.08, pheart=0.36, pbone=0.98, pbrain=0.74). Reference values of R2∗ in iron storage organs are feasible to support the diagnosis of iron storage diseases. Non-specific mutations in HFE SNPs appear not to affect the phenotype of tissue iron accumulation.

Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease.

Background & AimsFerroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin‐encoding gene SLC40A1. Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidin‐induced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant.MethodsThe ferroportin disease variants R178Q andA77D and the HH4‐variant C326Y were overexpressed in HEK‐293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin‐ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases.ResultsIn the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D‐variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD.ConclusionsThese results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin‐mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.

Nanoscopic X-ray imaging and quantification of the iron cellular architecture within single fibroblasts of Friedreich's ataxia patients.

Friedreich's ataxia (FRDA) is a neurodegenerative disease characterized by an increase in intracytoplasmic iron concentration. Here the nanoscale iron distribution within single fibroblasts from FRDA patients was investigated using synchrotron-radiation-based nanoscopic X-ray fluorescence and X-ray in-line holography at the ID16A nano-imaging beamline of the ESRF. This unique probe was deployed to uncover the iron cellular two-dimensional architecture of freeze-dried FRDA fibroblasts. An unsurpassed absolute detection capability of 180 iron atoms within a 30 nm × 50 nm nanoscopic X-ray beam footprint was obtained using state-of-the-art X-ray focusing optics and a large-solid-angle detection system. Various micrometre-sized iron-rich organelles could be revealed for the first time, tentatively identified as endoplasmic reticulum, mitochondria and lysosomes. Also a multitude of nanoscopic iron hot-spots were observed in the cytosol, interpreted as chaperoned iron within the fibroblast's labile iron pool. These observations enable new hypotheses on the storage and trafficking of iron in the cell and ultimately to a better understanding of iron-storage diseases such as Friedreich's ataxia.

Cardiac T2 * mapping: Techniques and clinical applications.

Cardiac T2* mapping is a noninvasive MRI method that is used to identify myocardial iron accumulation in several iron storage diseases such as hereditary hemochromatosis, sickle cell disease, and β‐thalassemia major. The method has improved over the years in terms of MR acquisition, focus on relative artifact‐free myocardium regions, and T2* quantification. Several improvement factors involved include blood pool signal suppression, the reproducibility of T2* measurement as affected by scanner hardware, and acquisition software. Regarding the T2* quantification, improvement factors include the applied curve‐fitting method with or without truncation of the signals acquired at longer echo times and whether or not T2* measurement focuses on multiple segmental regions or the midventricular septum only. Although already widely applied in clinical practice, data processing still differs between centers, contributing to measurement outcome variations. State of the art T2* measurement involves pixelwise quantification providing better spatial iron loading information than region of interest‐based quantification. Improvements have been proposed, such as on MR acquisition for free‐breathing mapping, the generation of fast mapping, noise reduction, automatic myocardial contour delineation, and different T2* quantification methods. This review deals with the pro and cons of different methods used to quantify T2* and generate T2* maps. The purpose is to recommend a combination of MR acquisition and T2* mapping quantification techniques for reliable outcomes in measuring and follow‐up of myocardial iron overload. The clinical application of cardiac T2* mapping for iron overload's early detection, monitoring, and treatment is addressed. The prospects of T2* mapping combined with different MR acquisition methods, such as cardiac T1 mapping, are also described. Level of Evidence: 4 Technical Efficacy Stage: 5J. Magn. Reson. Imaging 2019.

The Effects of Medicago Sativa and Allium Porrum on Iron Overload in Rats.

Purpose:Iron overload may occur due to regular blood transfusions and high intestinal iron absorption. Currently, there is no effective drug without side effects for the treatment of iron excess in thalassemia and other iron storage diseases, except chelation therapy, which is the only safe method for iron excretion. Thus, scientists are more focused on medicinal plants rich in phytochemical compounds for the removal of iron in thalassemia. Therefore this study was managed to discover the therapeutic potential of hydro- alcoholic extract of Allium porrum and Medicago sativa for iron chelating potential.Methods:Aerial parts of Allium porrum and Medicago sativa werecollected in Yasuj Iran. Rats were divided into seven groups each containing six. Extracts were administrated in four groups (two groups for each extract) by single doses of each plant with 200 and 400 mg / kg body weight by (i.p.) route every other day for28 days. Group 1 as negative control received saline (0.5 ml/kg) by (i.p.) route. Positive control received iron dextran 200 mg/kg body weight. Experimental groups 1 and 2 for each plant extract were fed with 200 and 400 mg/kg, hydro-alcoholic extract respectively via (i.p.) route, 1 h after the injection of iron dextran. Standard group was treated with deferoxamine (DF) 50 mg/kg by (i.p.) route1 h after the injection of iron dextran. Serum iron (SI) and serum total iron binding capacity (TIBC) were determined. The serum ferritin was then measured using enzyme immunoassay ELISA kit for rat. For Analysis of data ANOVA test was used.Results:Hydro-alcoholic extract of Medicago sativa and Allium porrum at 400 mg/kg showed significant (p<0.05) iron chelating activity compared to control. The plant extracts with dose 200 mg/kg also reduced the iron and ferritin content but the effect was lower level compared to higher doses. The plant extract effects were similar to that of standard drug deferoxamine. Iron and ferritin levels were significantly reduced in experimental groups when compared to positive group especially in Medicago sativap<0.05. There was no difference between standard drugs and last concentration of plant extracts.Conclusion:protective effect of M. sativa and A. Porrum against iron overload in rat model was reported. Significant decrease in serum ferritin and iron concentration was reported in iron overload rats which induced by iron dextran.

Abstract A32: Studying circadian disruption as a novel risk factor of hepatocellular carcinoma using mouse models

Abstract Hepatocellular carcinoma (HCC) is previously considered a rare type of cancer in the Western world, but shows an annual increase of 3.5% since 1992 and is currently ranked second only to pancreatic cancer for cancer-related deaths in the United States due to its lack of early detection markers and poor prognosis. HCC is particularly difficult to treat because its development impairs liver normal drug metabolic function leading to chemoresistant. Although chronic infections with hepatitis B or C virus are the major risk factors for HCC worldwide, liver metabolic diseases associated with obesity such as non-alcoholic fatty liver diseases, diabetes mellitus and iron-storage diseases, account for the majority of HCC cases in the U.S. The rapid increase in obesity and obesity-associated metabolic disease in recent years suggests that the incidence of metabolic dysfunction-induced HCC is likely continually to increase in the States in the future. However, most existing HCC animal models develop tumors either following the treatment of carcinogens or ablation of a key liver tumor suppression pathway, which do not follow the same pathophysiological mechanisms of tumor initiation and progression as metabolic disorder-induced HCC in humans. Hence, there is a critical need to establish animal models that develop spontaneous HCC in response to chronic metabolic stress to study the mechanism of metabolic dysfunction-induced HCC, identify early detection markers associated with these types of HCC, and investigate the role of liver metabolic disruption in anticancer treatment. Most physiological processes including nutrient intake, storage and metabolism follows a circadian rhythm in mammals since our homeostatic systems are shaped by the evolutionary adaptation to daily light/dark changes in the environment. Disruption of circadian homeostasis leads to a coupled increase in the risk of obesity, liver metabolic syndromes and cancers in both night-shift human workers and animal models. We have previously reported that circadian gene-mutant mouse models show a significant increased risk to cancer. Our recent studies have revealed that disrupting circadian rhythm in wild-type mice by chronic jet-lag following a schedule that mimics the night-shift working schedules in humans leads to a progressive deregulation of multiple plasma and hepatic metabolic parameters in the serum and induction of multiple liver metabolic syndromes including hepatosteatosis as well as liver inflammation and uncontrolled hepatocytes and bile duct proliferation prior to HCC onset. Genome-wide array analyses have led to identify a time-dependent deregulation of all known key pathways controlling metabolism, energy storage, redox levels, cell proliferation, inflammatory response and tumor suppression in the liver of mice lacking circadian homeostasis. Our studies have established an excellent mouse model to study the role of metabolic dysfunction in spontaneous HCC induction. Further studies will lead to elucidate the mechanism of HCC induction by chronic metabolic disruption and identify novel serum and hepatic biomarkers for HCC early detection and treatment. Citation Format: Nicole M. Kettner, David D. Moore, Loning Fu. Studying circadian disruption as a novel risk factor of hepatocellular carcinoma using mouse models. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A32.

Thirty year retrospective evaluation of pneumonia in a bottlenose dolphin Tursiops truncatus population

Pneumonia is one of the most common causes of morbidity in bottlenose dolphins Tursiops truncatus. To better understand associations of pneumonia with demographics, microbiology, pathology, and histopathology, a retrospective study on 42 dolphins from the US Navy Marine Mammal Program dolphin population was conducted (1980 to 2010). A total of 21 (50%) of the dolphins evaluated had pneumonia confirmed by histopathology. Bacterial and fungal pneumonia was present in 42.9 and 28.6% of cases (9 and 6 cases), respectively, with Staphylococcus aureus as the most common confirmed pathogen (4 cases, 19%). Other pathogens identified as the cause of pneumonia were Cryptococcus neoformans, Erysipelothrix rhusiopathiae, Histoplasma capsulatum, parainfluenza virus, Proteus species, Pseudomonas aeruginosa, and Streptococcus zooepidemicus. Neither sex nor age was a predictor of pneumonia. While many of the infections involved disseminated disease, lungs were consistently the most severely affected organs. The present study demonstrates the high susceptibility of dolphins to respiratory infections. Areas that warrant further investigation include eosinophilic pneumonia, chronic infections, co-infections, and metabolic or iron-storage diseases. There is a continuing need to improve the early diagnosis and effective treatment of pneumonia in dolphins.

Iron Storage Disease in Red Deer ( Cervus elaphus elaphus) is not associated with Mutations in the HFE Gene

Iron storage diseases are rare conditions of dysregulated iron metabolism in man and animals. A genetic basis has been confirmed only for human haemochromatosis. Iron storage disease was diagnosed in six related, 2-year-old male red deer of the same herd. These animals presented with weight loss and rough hair coats. Haematological examination was unremarkable. At necropsy examination, gross lesions were restricted to cachexia. Microscopical examination revealed severe, diffuse hepatocellular necrosis and iron accumulation in hepatocytes, Kupffer cells, cardiac myocytes and renal tubular cells in all affected animals. Four animals also had moderate bridging fibrosis in the liver. Hepatic iron concentrations were increased (1108-2275 mg/kg wet weight; reference range 100-200 mg/kg). Drinking water in rusty iron tubs in the deer park contained eight times more iron than the accepted level for human drinking water. To test for a possible genetic basis of increased iron uptake and storage in red deer, the cervid haemochromatosis gene (HFE) was identified. Sequence comparisons between the six diseased animals and three healthy free-ranging unrelated animals failed to identify differences in the HFE sequences. Furthermore, the disease was not associated with common amino acid substitutions reported in human patients with haemochromatosis, including C282Y and H63D. Polymorphisms in other non-HFE genes involved in iron metabolism may have led to a higher sensitivity to iron and this, together with the high iron content of the drinking water, may have been the cause of the observed iron storage in these red deer.

CD163-Mediated Hemoglobin-Heme Uptake Activates Macrophage HO-1, Providing an Antiinflammatory Function

See related article, pages 943–950 A study by Schaer et al,1 which appears in this issue of Circulation Research , provides evidence suggesting that CD163 acts as a hemoglobin (Hb) transporter and, via activation of macrophages, heme oxygenase-1 (HO-1) provides antiinflammatory activity, presumably by an increase in ferritin. Induction of HO-1 was observed to occur when the cultured macrophages, endothelial cells or tubular cells were exposed to heme or hemoglobin (for a review see Abraham and Kappas2). Heme and denatured hemoglobin toxicity play an important role in a broad spectrum of pathological circumstances such as myocardial ischemia, hypertension, cardiomyopathy, reperfusion, organ transplantation, pulmonary disorders, and inflammation among others.3 In the cell free system, hemoglobin is bound to haptoglobin before clearance by the macrophage hemoglobin scavenger receptor CD163. Schaer et al1 demonstrated that CD163-hemoglobin transport is regarded as a critical step in the hemoglobin clearance pathway in the macrophage, especially under conditions of extreme hemoglobin release resulting from hemolysis. Binding hemoglobin-haptoglobin to CD163 cells also elicits IL-10 secretion, which contributes to the induction of HO-1.4 Thus, CD163 has a functional role as an antioxidant by enhancing HO-1, the major cytoprotective response. This links heme transport directly to a known receptor with well characterized endocytic properties and signaling functions.5 Heme-hemopexin is also taken up by LRP/CD91 and, as such, may inhibit inflammatory functions in phagocytic and antiinflammatory macrophages; however, a link to functional HO-1 was not described. Schaer et al1 demonstrated that induction of HO-1 by Hb is functionally linked to CD163 and, using gene array analysis, were able to show that Hb elicits a noninflammatory transcriptional response in macrophages, presumably by the coordinated increase in ferritin synthesis following the activation of HO-1. This response was mediated by CD163 and did not involve the …

Role of Magnetic Resonance Imaging in Myocardial Iron Assessment

Myocardial iron overload is a common finding in iron storage diseases like β-thalassemia. It is due to frequent transfusions and occurs despite chelation therapy. Cardiac complications (heart failure and arrythmias) lead to early death. MRI can offer a noninvasive index for heart iron deposition, before overt clinical and echocardiographic picture of heart failure takes place. Tissue iron is detected indirectly by the effects on relaxation times of ferritin and hemosiderin iron, interacting with hydrogen nuclei. Paramagnetic ferritin and hemosiderin iron shorten proton relaxation times, particularly T2 and T2*. Conventional MRI measurements are affected by iron excess, the instrumentation used, the applied field strength, the repetition time used in the imaging sequence, and other technical aspects. Myocardial T2* seems to be the most sensitive and easily reproducible index of myocardial iron deposition. However multicenter trials are needed for further evaluation of this technique. Keywords: mri, myocardial iron, thalassemia

The cell's cookbook for iron--sulfur clusters: recipes for fool's gold?

The right ingredients: Novel biosynthetic pathways for iron–sulfur clusters (see figure) are being unraveled rapidly in the model organism Saccharomyces cerevisiae. This hot research field provides new insights into the assembly of iron–sulfur proteins as well as into the origin of life, mitochondrial evolution, and iron-storage diseases.

AtNAP7 is a plastidic SufC-like ATP-binding cassette/ATPase essential for Arabidopsis embryogenesis

In bacteria, yeast, and mammals, iron-sulfur (Fe-S) cluster-containing proteins are involved in numerous processes including electron transfer, metabolic reactions, sensing, signaling, and regulation of gene expression. In humans, iron-storage diseases such as X-linked sideroblastic anemia and ataxia are caused by defects in Fe-S cluster availability. The biogenesis of Fe-S clusters involves several pathways, and in bacteria, the SufABCDSE operon has been shown to play a vital role in Fe-S biogenesis and repair during oxidative stress. Although Fe-S proteins play vital roles in plants, Fe-S cluster biogenesis and maintenance and physiological consequences of dysfunctional Fe-S cluster assembly remains obscure. Here we report that Arabidopsis plants deficient for the SufC homolog AtNAP7 show lethality at the globular stage of embryogenesis. AtNAP7 is expressed in developing embryos and in apical, root, and floral meristems and encodes an ATP-binding cassette/ATPase that can partially rescue growth defects in an Escherichia coli SufC mutant during oxidative stress. AtNAP7 is plastid-localized, and mutant embryos contain abnormal developing plastids with disorganized thylakoid structures. We found that AtNAP7 can interact with AtNAP6, a plastidic Arabidopsis SufD homolog, and because Arabidopsis plastids also harbor SufA, SufB, SufS, and SufE homologs, plastids probably contain a complete SUF system. Our results imply that AtNAP7 represents a conserved SufC protein involved in the biogenesis and/or repair of oxidatively damaged Fe-S clusters and suggest an important role for plastidic Fe-S cluster maintenance and repair during Arabidopsis embryogenesis.

Hematologically important mutations: iron storage diseases

Hematologically important mutations: iron storage diseases

Expression of the human ferritin light chain in a frataxin mutant yeast affects ageing and cell death

Ferritin is one of the major eukaryotic proteins involved in regulating iron metabolism and maintaining iron homeostasis. However, Saccaromyces cerevisiae is an exception, possessing no ferritin and using other means to store excess iron. The only potential iron storage protein identified in yeast so far is the homologue of human frataxin (YFH1p). In this study, we found that dysfunction of yeast frataxin shortens mean lifespan by 49% compared to the WT control. Interestingly, the human ferritin L gene can, at least partially, complement the function of yeast frataxin, extending lifespan and protecting cells from death induced by oxidative stress or excess iron. Our findings indicate that ferritin L can perform functions in yeast that are similar to its functions in mammals, and suggest that common mechanisms may exist for preventing iron and oxidative damage in single- and multi-cellular eukaryotic organisms. Clearly, elucidation of the function of human ferritin in yeast would help in gaining a better understanding the molecular basis of iron storage diseases.

Localization of iron transport and regulatory proteins in human cells.

The recent discovery of HFE, the MHC-Class-I-like gene mutated in up to 90% of patients with hereditary haemochromatosis, and the gene encoding the Nramp2/divalent metal transporter-1 (DMT-1) implicated in ferrous iron transport holds promise for a greater understanding of human iron metabolism. Since the HFE protein can be crystallized as a ternary complex with the transferrin receptor and iron-saturated transferrin, and DMT-1 expression is up-regulated in hereditary haemochromatosis, these proteins are likely to interact in a common pathway for human iron homeostasis. To investigate the cellular interactions between the cognate proteins encoded by these genes, we generated a panel of rabbit and avian antisera from human HFE and DMT-1 derived peptides. The antibodies were characterized by ELISA reactions and Western immunoblotting. Immunohistochemical staining showed that DMT-1 protein localized to the brush border of human duodenum where it is predicted to serve as the principal transporter of ferrous iron from the intestinal lumen. In the human cell lines, Caco-2 (small intestinal phenotype upon differentiation) and K562 (erythroleukaemic) HFE, in the presence of iron-saturated transferrin, co-localized with transferrin receptors in an early endosome compartment using confocal immunofluorescence microscopy. This interaction may be critical in small-intestinal crypt cells which express HFE, where it may function to modulate their intrinsic iron status thereby programming iron absorption by DMT-1 in the mature enterocyte. In undifferentiated Caco-2 cells, DMT-1 localized to a discrete late endosome compartment distinct from that occupied by HFE where, in addition to brush-border iron uptake, it may function to regulate the availability of iron delivery to intracellular iron pools. Disruption of the HFE gene as a result of mutations associated with hereditary haemochromatosis may thus impair homeostatic mechanisms controlling iron absorption within the small-intestine epithelium by a direct interaction with transferrin receptors and by subsequent alteration of DMT-1 expression. Identification of the molecular interactions of HFE with DMT-1 and other key components of the iron transport pathway has implications for a mechanistic understanding of the pathophysiology of human iron storage diseases as well as the regulation of normal iron balance.

Iron storage diseases in birds

Parenteral iron is toxic to many species but, because the uptake of iron from the diet is regulated in the intestine, acute intoxication is not seen under natural conditions. Chronic ingestion of large amounts of absorbable iron in the diet can lead to the storage of iron in the liver in many species, including humans. The excess iron is stored within hepatocytes as haemosiderin and can be quantitatively assessed by liver biopsy or at necropsy using special stains such as Perls iron stain and/or biochemical tests. Iron may also be found within the Kupffer cells in the liver and the macrophage cells of the spleen especially where concurrent diseases are present such as haemolytic anaemia, septicaemia, neoplasia and starvation. Iron accumulation in the liver, also known as haemosiderosis, may not always be associated with clinical disease although in severe cases hepatic damage may occur. It is probable that concurrent disease conditions are largely responsible for the degree and nature of the pathological changes described in most cases of haemosiderosis. In some human individuals there may be a genetic predisposition to iron storage disease, haemochromatosis, associated with poor regulation of iron uptake across the intestine. In severe cases iron pigment will be found in the liver, spleen, gut wall, kidney and heart with subsequent development of ascites, heart failure and multisystem pathology. Clinical disease associated with accumulation of iron in the liver, and other tissues, has been reported in many species of bird although it is most commonly reported in Indian hill mynas ( Gracula religiosa ) and toucans ( Ramphastos sp ). It is likely that the tolerance to the build up of tissue iron varies in individual species of bird and that the predominant predisposing factors may differ, even within closely related taxonomic groups.

Iron and Copper Storage Diseases

Iron and Copper Storage Diseases

Quantitative electron spectroscopic imaging in bio‐medicine: evaluation and application

Electron spectroscopic imaging (ESI) with the energy-filtering transmission electron microscope enables the investigation of chemical elements in ultrathin biological sections. An analysis technique has been developed to calculate elemental maps and quantitative distributions from ESI sequences. Extensive experience has been obtained with a practical implementation of this technique. A procedure for more robust element detection has been investigated and optimized. With the use of Fe-loaded Chelex beads, the measurement system has been evaluated with respect to the linearity of the element concentration scale, the reproducibility of the measurements and the visual usage of image results. In liver specimens of a patient with an iron storage disease the detectability of iron was tested and we tried to characterize iron-containing components. The concentration measurement scale is approximately linear up to a relative section thickness of approximately equal to 0.5. Monitoring of this parameter is therefore considered to be important. The reproducibility was measured in an experiment with Fe-Chelex. The iron concentration differed by 6.4% between two serial measurements. Element distributions are in many applications interpreted visually. For this purpose the frequently used net-intensity distributions are regarded as unsuitable. For the quantification and visual interpretation of concentration differences mass thickness correction has to be performed. By contrast, for the detection of elements the signal-to-noise ratio is the appropriate criterion. Application of ESI analysis demonstrated the quantitative chemical capabilities of this technique in the investigation of iron storage diseases. Based on an assumed ferritin iron loading in vivo, different iron components can be discerned in liver parenchymal cells of an iron-overloaded patient.

Effect of reactive oxygen species on the biosynthesis and structure of newly synthesized proteoglycans

The effect of reactive oxygen species (ROS) generated by a xanthine oxidase hypoxanthine system (mainly H 2O 2) on proteoglycan (PG) metabolism and structure was investigated in vitro, using cell monolayers of culturedrabbit articular chondrocytes and purified resident and newly synthesized proteoglycans. It was shown that ROS generated in this system frequently stimulate (at low concentrations), and consistently in hibit (at higher concentrations), the incorporation of 35SO 4 and 3H-glucosamine into PG molecules synthesized by cultured chondrocytes. The inhibition of isotopes' incorporation at higher enzyme concentrations was suppressed completely by heating xanthine oxidase and allopurinol with superoxide dismutase (SOD) and catalase. ROS at high concentration also inhibited 3H-uridine incorporation but had no effect on 35SO 4 and 3H-uridine uptake by the cells. They also alter hyaluronan (HA) and PG monomers by fragmenting the core protein moiety and destroying the hyaluronic acid binding region. Altered PG monomers do not interact with HA to form complexes, but fragmented HA still retain a significant PG monomer-binding capacity. PG-HA complexes are easily and irreversibly destroyed by ROS. These results suggest that ROS may at low fluxes stimulate PG-synthesis under physiological conditions and alter cartilage metabolism and structure in conditions where they are overproduced, such as in rheumatoid arthritis, and in hemochromatosis and other iron storage diseases.

The contribution of liver Ferritin to T 1 and T 2 relaxation in iron storage diseases

The contribution of liver Ferritin to T 1 and T 2 relaxation in iron storage diseases