Prevent Iron Accumulation Research Articles

The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain.

Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux. The absence of this protein in humans and rodents produces progressive neurodegeneration with brain iron accumulation. Astrocytes express high levels of Cp and iron efflux from these cells has been shown to be central for oligodendrocyte maturation and myelination. To explore the role of astrocytic Cp in brain development and aging we generated a specific conditional KO mouse for Cp in astrocytes (Cp cKO). Deletion of Cp in astrocytes during the first postnatal week induced hypomyelination and a significant delay in oligodendrocyte maturation. This abnormal myelin synthesis was exacerbated throughout the first two postnatal months and accompanied by a reduction in oligodendrocyte iron content, as well as an increase in brain oxidative stress. In contrast to young animals, deletion of astrocytic Cp at 8 months of age engendered iron accumulation in several brain areas and neurodegeneration in cortical regions. Aged Cp cKO mice also showed myelin loss and oxidative stress in oligodendrocytes and neurons, and at 18 months of age, developed abnormal behavioral profiles, including deficits in locomotion and short-term memory. In summary, our results demonstrate that iron efflux-mediated by astrocytic Cp-is essential for both early oligodendrocyte maturation and myelin integrity in the mature brain. Additionally, our data suggest that astrocytic Cp activity is central to prevent iron accumulation and iron-induced oxidative stress in the aging CNS.

органогеРациональные комбинации в фармакотерапии железодефицита

Iron deficiency remains one of the most common deficiencies worldwide. An inadequate and unbalanced diet may cause a lack of other nutrients necessary for hematopoiesis, which increases the risk of iron deficiency and makes it difficult to treat. Various pharmacotherapeutic approaches are being studied and applied, including combination medications, which in addition to iron consist of folic acid, copper/manganese gluconate, ascorbic acid, multivitamins, serine, and cyanocobalamin. Folate is a component that affects both the efficacy and safety of pharmacotherapy for iron deficiency. Preclinical animal studies comparing the dynamics of hematological indices confirmed a more rapid achievement of target values with the simultaneous use of iron and folic acid. Clinical studies in a group of pregnant women with iron-deficiency anemia (IDA) demonstrated that folic acid in combination with iron was more effective than iron as monotherapy. The combination of iron and folic acid is also rational in terms of increasing safety: folic acid prevents iron accumulation in the liver and the associated development of fibrosis. Ironinduced liver injury is related to oxidative stress catalyzed by iron overload. Folic acid regulates the transcription of genes involved in oxidative stress in the liver and the activity of 5'-AMP-activated protein kinase. Key words: iron deficiency, folic acid, hematopoiesis, rational pharmacotherapy

Lutein Decreases Inflammation and Oxidative Stress and Prevents Iron Accumulation and Lipid Peroxidation at Glutamate-Induced Neurotoxicity.

The xanthophyll carotenoid lutein has been widely used as supplementation due to its protective effects in light-induced oxidative stress. Its antioxidant and anti-inflammatory features suggest that it has a neuroprotective role as well. Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), which plays a key role in regulating brain function. Excess accumulation of intracellular glutamate accelerates an increase in the concentration of reactive oxygen species (ROS) in neurons leading to glutamate neurotoxicity. In this study, we focused on the effects of glutamate on SH-SY5Y neuroblastoma cells to identify the possible alterations in oxidative stress, inflammation, and iron metabolism that affect the neurological function itself and in the presence of antioxidant lutein. First, ROS measurements were performed, and then catalase (CAT) and Superoxide Dismutase (SOD) enzyme activity were determined by enzyme activity assay kits. The ELISA technique was used to detect proinflammatory TNFα, IL-6, and IL-8 cytokine secretions. Alterations in iron uptake, storage, and release were followed by gene expression measurements and Western blotting. Total iron level detections were performed by a ferrozine-based iron detection method, and a heme assay kit was used for heme measurements. The gene expression toward lipid-peroxidation was determined by RT-PCR. Our results show glutamate changes ROS, inflammation, and antioxidant enzyme activity, modulate iron accumulation, and may initiate lipid peroxidation in SH-SY5Y cells. Meanwhile, lutein attenuates the glutamate-induced effects on ROS, inflammation, iron metabolism, and lipid peroxidation. According to our findings, lutein could be a beneficial, supportive treatment in neurodegenerative disorders.

Intestinal Dmt1 is Required for Iron Loading in Mice Modeling β‐Thalassemia Intermedia

β‐thalassemia intermedia (βTI) is characterized by chronic anemia, ineffective erythropoiesis, and excessive intestinal iron absorption leading to systemic iron overload. Divalent metal‐ion transporter 1 (DMT1), the main intestinal iron transporter, may mediate excessive iron absorption in Th3/+ mice, which model βTI.ObjectiveTo determine if intestinal DMT1 is required for iron‐loading in beta‐thalassemia, and if so, to utilize a ginger nanoparticle‐derived lipid vector (GDLVs) siRNA delivery system to normalize iron absorption in Th3/+ mice.HypothesisDMT1 mediates excessive iron absorption in βTI mice and decreasing DMT1 expression by GDLVs‐siRNA will prevent iron accumulation in these mice.MethodsTh3/+ mice were crossed with mice lacking intestinal DMT1 generating double KOs. Also, weanling mice were gavaged daily for 16 days with GDLVs carrying functional DMT1 siRNA, and iron absorption and iron loading were assessed.ResultsLiver, spleen, kidney, heart, and duodenum non‐heme iron levels were decreased in Th3/+ mice lacking intestinal DMT1. Serum non‐heme iron content, serum ferritin levels, and transferrin saturation also decreased in Th3/+ mice lacking intestinal DMT1. Splenomegaly was alleviated in the double KO mice. Oral gavage of GDLVs carrying DMT1 siRNA blunted intestinal DMT1 expression and mitigated hepatic and splenic iron loading. Serum non‐heme iron levels, serum ferritin, and transferrin saturation also decreased in Th3/+ mice receiving GDLVs with DMT1 siRNA.ConclusionIntestinal DMT1 is required for iron‐loading in Th3/+ mice, and in vivo DMT1 knock down is an effective approach to blunt iron loading in mice modeling βTI.

The [2Fe-2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes.

Considered a key aging gene, CISD2, encoding CDGSH iron-sulfur domain-containing protein 2, plays a central role in regulating calcium homeostasis, preventing mitochondrial dysfunction, and the activation of autophagy and apoptosis in different cells. Here, we show that cardiomyocytes from CISD2-null mice accumulate high levels of iron and contain high levels of transferrin receptor and ferritin. Using proteomics and transmission electron microscopy, we further show that the lack of CISD2 induces several features of the aging process in young mice, but other features are not induced. Taken together, our findings suggest that CISD2 protects cardiomyocytes from overaccumulation of iron, which is common in aging hearts and can contribute to the pathogenesis of heart failure.

ASSESSMENT OF THE AUTONOMIC AND PERIPHERAL NERVE FUNCTION IN PATIENTS WITH THALASSAEMIC SYNDROME IN A TERTIARY CARE HOSPITAL - A CROSS SECTIONAL STUDY

INTRODUCTION: β-thalassaemia is an inherited disorder of haemoglobin characterized by an absence or reduced synthesis of the β-globin chain. The net result is an excess of α-chains, which precipitate and destroy the red cell precursors, leading to anaemia, skeletal changes, splenomegaly and numerous other complications. Treatment is by regular blood transfusion coupled with iron chelation therapy to prevent iron accumulation and organ damage. AIM: To assess the autonomic and peripheral nerve function in patients with thalassaemic syndrome. MATERIALAND METHODS: Patients attending the Thalassaemia Clinic of Medical College Hospital, Kolkata. Indoor patients from Medicine st th ward and Institute of Haematology and Transfusion Medicine wards of Medical College Hospital, Kolkata from 1 May 2008 to 30 April 2009. After inclusion patients were divided into following groups: Group1 (THAL1): Patients requiring regular blood transfusion and are either receiving inadequate iron chelation or no iron chelation at all. Group2 (THAL2): Patients who require regular blood transfusion and are receiving adequate iron chelation. Group3 (THAL3): Patients who do not require regular blood transfusion RESULT: The median value of distal latency of right common peroneal nerve is slightly increased in all 3 groups. The normal value should be < 4.55ms, thus increase in distal latency is seen in all 3 groups. The median values of distal latency of left common peroneal nerve as well as distal latency of common peroneal nerve as a whole is within normal limits. Distal latency of common peroneal nerve (p value=0.012). Proximal latency of left common peroneal nerve(p value=0.013). Proximal latency of common peroneal (p value=0.001) CONCLUSION: There is demyelinating type of neuropathy of right common peroneal nerve of all the groups. This indicates presence of motor peripheral neuropathy in patients of thalassaemia. All other latencies and amplitudes of both motor and sensory nerves are within normal limits. There were statistically increased motor latencies in patients receiving iron chelation therapy with adequate chelation when compared to the other groups, although the overall latency was within acceptable limits of the laboratory standards. This may be due to subclinical affection of the motor nerves in the form of demyelination. Therefore, the role of toxic effects of iron chelator on peripheral nerves needs to be studied further.

Nuciferine protects against folic acid-induced acute kidney injury by inhibiting ferroptosis.

Acute kidney injury is a common clinical problem with no definitive or specific treatment. Therefore, the molecular mechanisms of acute kidney injury must be fully understood to develop novel treatments. Nuciferine, a major bioactive compound isolated from the lotus leaf, possesses extensive pharmacological activities. Its effect on folic acid-induced acute kidney injury, however, remains unknown. Here, we aimed to clarify the pharmacological effects of nuciferine and its mechanisms of action in acute kidney injury. The effects of nuciferine on folic acid-induced acute kidney injury in mice were investigated. HK-2 human proximal tubular epithelial cells and HEK293T HEK cells were used to evaluate the protective effect of nuciferine on RSL3-induced ferroptosis. Nuciferine treatment mitigated the pathological alterations, ameliorated inflammatory cell infiltration and improved kidney dysfunction in mice with folic acid-induced acute kidney injury. In HK-2 and HEK293T cells, nuciferine significantly prevented RSL3-induced ferroptotic cell death. Mechanistically, nuciferine significantly inhibited ferroptosis by preventing iron accumulation and lipid peroxidation in vitro and in vivo. Moreover, knockdown of glutathione (GSH) peroxidase 4 (GPX4) abolished the protective effect of nuciferine against ferroptosis. Nuciferine ameliorated renal injury in mice with acute kidney injury, perhaps by inhibiting the ferroptosis. Nuciferine may represent a novel treatment that improves recovery from acute kidney injury by targeting ferroptosis.

Myricetin reduces cytotoxicity by suppressing hepcidin expression in MES23.5 cells.

Multiple studies implicate iron accumulation in the substantia nigra in the degeneration of dopaminergic neurons in Parkinson's disease. Indeed, slowing of iron accumulation in cells has been identified as the key point for delaying and treating Parkinson's disease. Myricetin reportedly plays an important role in anti-oxidation, anti-apoptosis, anti-inflammation, and iron chelation. However, the mechanism underlying its neuroprotection remains unclear. In the present study, MES23.5 cells were treated with 1 × 10-6 M myricetin for 1 hour, followed by co-treatment with 400 nM rotenone for 24 hours to establish an in vitro cell model of Parkinson's disease. Our results revealed that myricetin alleviated rotenone-induced decreases in cell viability, suppressed the production of intracellular reactive oxygen species, and restored mitochondrial transmembrane potential. In addition, myricetin significantly suppressed rotenone-induced hepcidin gene transcription and partly relieved rotenone-induced inhibition of ferroportin 1 mRNA and protein levels. Furthermore, myricetin inhibited rotenone-induced phosphorylation of STAT3 and SMAD1 in MES23.5 cells. These findings suggest that myricetin protected rotenone-treated MES23.5 cells by potently inhibiting hepcidin expression to prevent iron accumulation, and this effect was mediated by alteration of STAT3 and SMAD1 signaling pathways.

A Multicenter, Italian Trial of Early Iron Chelation Therapy with Low Dose Deferasirox (Exjade®) in Patients with Low/Intermediate-1 Risk MDS at the Beginning of Transfusional Story

A Multicenter, Italian Trial of Early Iron Chelation Therapy with Low Dose Deferasirox (Exjade®) in Patients with Low/Intermediate-1 Risk MDS at the Beginning of Transfusional Story

PS1296 ERYTROCYTAPHERESIS IN ACERULOPLASMINEMIA PREVENTS PROGRESSION OF CEREBRAL IRON ACCUMULATION AFTER CHELATOR‐INDUCED NORMALIZATION OF IRON STORES

Background:Hereditary aceruloplasminemia (HA) is a rare autosomal recessive disorder. It comprises mutations in the ceruloplasmin genes leading to the absence of ceruloplasmin, a protein required for iron oxidaztion that enables incorporation into transferrin. Due to diminished iron export from storage cells and a usually mild anemic state due to ineffective iron incorporation, iron absorption is increased resulting in the accumulating of iron in parenchymal cells like hepaocytes, insulin producing pancreatic cells and neurons in the brain that may resultin diabetes, anaemia, retinal degradation and neurological disorders (symptomatic penetrance is high but not 100%)..Several case reports illustrate that iron chelating theray (ICT), when appropriately dosed, may result in normaliztaion of live iron content and iron storage, but a decrease in cerebral iron content has not been observed. The follow‐up of most studies is also short (1 year or less). Only two case reports describe that the iron content in the brain remainded stable for 4 and 13 year during treatment with ICT without any neurological symptoms.Aims:We hypothesized that progressive accumulation of iron in the brain may also be prevented by applying erythrocytapheresis (EA) after normalization of physiological iron stores by ICT. In this way, a continuous increased demand for maximal erythropoiesis by erythrocytapheresis (EA) is induced that may result in the immediately utilization of every absorbed iron atom by the bone marrow and preventingparenchymal accumuation.Methods:A HA patient with a low normal haemoglobin, insulin‐dependent diabetes and no neurological symptoms, is treated with EA for six years now, after normalizing ferritin levels and liver iron with ICT; cerebral iron depostits were not depleted by ICT.Results:This controlled removal of erythrocytes created an enduring asymptomatic low haemoglobin level (around 10 g/dl,), ferritin level within the normal range (mean ferritin of 199 ± 60.9 μg/L before every EA). The liver iron content measured by MRI remained at the same normal level as reached after ICT, and the cerebral iron content, which was not diminished after iron chelation, remained stable. No neurological symptoms have appeared so far.Summary/Conclusion:EA appears to be an elegant therapy to prevent iron accumulation in the brain after inducing normal iron stores by ICT. The advantage of this approach is that prolonged exposure to ICT and its possible occurring medical and definite financial side effects can be avoided. The application of EA allows for controlled haemoglobin reduction preventing symptoms from anaemia. It remains unsure if this strategy prevented the development of neurological or cognitive symptoms, because the prevalence of these is not 100%. On the other hand does this therapy not harm the patient and may be effective. It may be worthwhile to attemnpt this approach in similar cases and even in those that already developed neurological and/or cognitive sequalae.

UPR Induction Prevents Iron Accumulation and Oligodendrocyte Loss in ex vivo Cultured Hippocampal Slices.

The accumulation of iron within the brain occurs in many chronic disorders including Alzheimer’s and Parkinson’s disease and multiple sclerosis. Outside the CNS, a link between levels of iron and the unfolded protein response has already been established. To determine if such a relationship operates in within the brain, we used our ex vivo hippocampal slice-based model of iron accumulation. Ferrocene addition caused accumulation of iron within slices and loss of oligodendrocytes, an effect that was partially inhibited when ferrocene and ER stressor tunicamycin (Tm) were added together. An upward trend (not found to be statistically significant) in the expression of UPR transcripts in response to ferrocene was demonstrated using real-time PCR, while a significant upregulation of mRNA for B cell immunoglobulin-binding protein (BiP) and C/EBP homologous binding protein (CHOP) occurred following exposure to Tm. In silico analysis revealed consensus DNA-binding sequences for UPR-associated transcription factors within the promoter regions of eight iron-regulatory genes. In addition, dual-staining for CHOP and oligodendrocyte transcription factor 2 (OLIG2) or Ionized calcium binding adaptor molecule 1 (Iba1) showed nuclear expression of CHOP in some oligodendrocyte-lineage cells in response to Tm or Tm+ferrocene, but CHOP was rarely found in microglia. Co-expression of UPR-associated activated transcription factor 6 (ATF6) was detected in the nuclei of some oligodendrocyte-lineage cells exposed to Tm alone, or to Tm and ferrocene, but rarely in microglia. These data highlight the therapeutic potential of targeting UPR-associated proteins when developing novel treatments for chronic brain disorders that are affected by dysregulated iron.

Neuropilin-1 Controls Endothelial Homeostasis by Regulating Mitochondrial Function and Iron-Dependent Oxidative Stress

SummaryThe transmembrane protein neuropilin-1 (NRP1) promotes vascular endothelial growth factor (VEGF) and extracellular matrix signaling in endothelial cells (ECs). Although it is established that NRP1 is essential for angiogenesis, little is known about its role in EC homeostasis. Here, we report that NRP1 promotes mitochondrial function in ECs by preventing iron accumulation and iron-induced oxidative stress through a VEGF-independent mechanism in non-angiogenic ECs. Furthermore, NRP1-deficient ECs have reduced growth and show the hallmarks of cellular senescence. We show that a subcellular pool of NRP1 localizes in mitochondria and interacts with the mitochondrial transporter ATP-binding cassette B8 (ABCB8). NRP1 loss reduces ABCB8 levels, resulting in iron accumulation, iron-induced mitochondrial superoxide production, and iron-dependent EC senescence. Treatment of NRP1-deficient ECs with the mitochondria-targeted antioxidant compound mitoTEMPO or with the iron chelator deferoxamine restores mitochondrial activity, inhibits superoxide production, and protects from cellular senescence. This finding identifies an unexpected role of NRP1 in EC homeostasis.

Curcumin Alters Iron Regulation in C2C12 Skeletal Muscle Cells and Prevents Iron Accumulation in a Model of Elevated Oxidative Stress

The Centers for Disease Control and Prevention have stated that as of 2017, 30.3 million people in the United States have diabetes (9.6% of total population), with an additional 84.1 million who have prediabetes (33.9% of total population). Patients with diabetes show signs of iron dysregulation, and recent studies indicate a correlation between iron dysregulation and insulin sensitivity suggesting that iron dysregulation plays a role in diabetes. Unbound cellular iron is highly reactive and can cause increased amounts of free radicals. Curcumin is a naturally occurring compound in the spice, turmeric, and has been shown to be effective in improving insulin sensitivity, although the mechanisms by which it does so are not entirely understood. Curcumin has been shown to bind iron and is very likely to have an effect on iron regulation. The purpose of this study is to understand the effects of curcumin on iron regulation and its ability to prevent iron dysregulation. Differentiated C2C12 mouse skeletal muscle cells were used in normal and high iron conditions, and protein expression and total iron content were analyzed to assess curcumin's effects on iron regulation. Cells were treated with 40 μM curcumin for 12 hours, and then harvested for analysis of protein expression and total iron content. Protein expression of transferrin receptor (TfR) and ferritin heavy chain (FHC) were measured by western blot analysis. Total iron content was measured by using a total iron colorimetric assay. C2C12 cells treated with 40 μM curcumin for 12 hours caused a reduction in TfR protein expression by 19±10% (p=0.02), as well as a reduction in FHC protein expression by 55±16% (p=0.01). The decrease in TfR expression correlated with a reduction in total cellular iron level, although the reduction in total iron was not significant. We then examined the effect of curcumin on iron regulation in high iron conditions to reflect the stress caused by elevated circulating iron levels associated with insulin resistance. In a model of high iron, pre‐treatment of 40 μM curcumin for 12 hours followed by treatment of 10 μM FeCl3 for 24 hours caused a reduction in TfR expression by 23±11% (p=0.008). Curcumin's effects on FHC expression were reversed in this high iron model, as FHC expression increased by 30±17% (p=0.04). Curcumin did not significantly alter total iron levels in this high iron model. Finally, we used a model of elevated oxidative stress to cause iron dysregulation in C2C12 cells, and analyzed curcumin's ability to prevent iron dysregulation. Cells were treated with 10 μM FeCl3 for 24 hours, with 200 μM hydrogen peroxide added during the final 12 hours of treatment. Pre‐treatment with curcumin prevented iron accumulation in cells treated with both iron and hydrogen peroxide (p=0.006). Our results show that curcumin's alteration of iron regulation is dependent upon extracellular iron levels. Results also show that curcumin has the potential to prevent iron dysregulation in an environment of elevated oxidative stress, providing a possible mechanism to its ability to improve insulin sensitivity.Support or Funding InformationThis work was supported by a BYU Mentoring Enhancement Grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Phosphorylation of Akt by SC79 Prevents Iron Accumulation and Ameliorates Early Brain Injury in a Model of Experimental Subarachnoid Hemorrhage.

Previous studies have demonstrated that activation of Akt may alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH). This study is undertaken to determine whether iron metabolism is involved in the beneficial effect of Akt activation after SAH. Therefore, we used a novel molecule, SC79, to activate Akt in an experimental Sprague–Dawley rat model of SAH. Rats were randomly divided into four groups as follows: sham, SAH, SAH + vehicle, SAH + SC79. The results confirmed that SC79 effectively enhanced the defense against oxidative stress and alleviated EBI in the temporal lobe after SAH. Interestingly, we found that phosphorylation of Akt by SC79 reduced cell surface transferrin receptor-mediated iron uptake and promoted ferroportin-mediated iron transport after SAH. As a result, SC79 administration diminished the iron content in the brain tissue. Moreover, the impaired Fe-S cluster biogenesis was recovered and loss of the activities of the Fe-S cluster-containing enzymes were regained, indicating that injured mitochondrial functions are restored to healthy levels. These findings suggest that disrupted iron homeostasis could contribute to EBI and Akt activation may regulate iron metabolism to relieve iron toxicity, further protecting neurons from EBI after SAH.

NCOA4 Deficiency Impairs Systemic Iron Homeostasis.

The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2-3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239-614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.

Pre-treatment of rats with ad-hepcidin prevents iron-induced oxidative stress in the brain

Our recent investigation showed that hepcidin can reduce iron in the brain of iron-overloaded rat by down-regulating iron-transport proteins. It has also been demonstrated that iron is a major generator of reactive oxygen species. We therefore hypothesized that hepcidin could prevent iron accumulation and thus reduce iron-mediated oxidative stress in iron-overloaded rats. To test this hypothesis, we investigated the effects of pre-treatment of rats with recombinant-hepcidin-adenovirus (ad-hepcidin) on the contents of iron, dichlorofluorescein and 8-isoprostane in the brain. Hepcidin expression was detected by real-time PCR and immunofluorescence analysis. Iron contents were measured using Perl’s staining as well as graphite furnace atomic absorption spectrophotometry. Dichlorofluorescein and 8-isoprostane were determined using a fluorescence spectrophotometer and an ELISA kit, respectively. We found that hepcidin contents in the cortex, hippocampus, striatum and substantia nigra of rats treated with ad-hepcidin are 3.50, 2.98, 2.93 and 4.07 fold of those of the control rats respectively. Also, we demonstrated that the increased iron as well as dichlorofluorescein and 8-isoprostane levels in all four brain regions, induced by injection of iron dextran, could be effectively prevented by pre-treatment of the rats with ad-hepcidin. We concluded that pre-treatment with ad-hepcidin could increase hepcidin expression and prevent the increase in iron and reduce reactive oxygen species in the brain of iron-overloaded rats.

Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney

We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses.

Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage

Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague–Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH+RR, and SAH+Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron–sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH.

Current approach to iron chelation in children

Transfusion-dependent children, mostly with thalassaemia major, but also and occasionally to a more significant degree, with inherited bone marrow failures, can develop severe iron overload in early life. Moreover, chronic conditions associated with ineffective erythropoiesis, such as non-transfusion-dependent thalassaemia (NTDT), may lead to iron overload through increased gut absorption of iron starting in childhood. Currently, the goal of iron chelation has shifted from treating iron overload to preventing iron accumulation and iron-induced end-organ complications, in order to achieve a normal pattern of complication-free survival and of quality of life. New chelation options increase the likelihood of achieving these goals. Timely initiation, close monitoring and continuous adjustment are the cornerstones of optimal chelation therapy in children, who have a higher transfusional requirements compared to adults in order to reach haemoglobin levels adequate for normal growth and development. Despite increased knowledge, there are still uncertainties about the level of body iron at which iron chelation therapy should be started and about the appropriate degree of iron stores' depletion.

Interplay between Manganese and Iron in Pneumococcal Pathogenesis: Role of the Orphan Response Regulator RitR

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen that is carried asymptomatically in the nasopharynx by up to 70% of the human population. Translocation of the bacteria into internal sites can cause a range of diseases, such as pneumonia, otitis media, meningitis, and bacteremia. This transition from nasopharynx to growth at systemic sites means that the pneumococcus needs to adjust to a variety of environmental conditions, including transition metal ion availability. Although it is an important nutrient, iron potentiates oxidative stress, and it is established that in S. pneumoniae, expression of iron transport systems and proteins that protect against oxidative stress are regulated by an orphan response regulator, RitR. In this study, we investigated the effect of iron and manganese ion availability on the growth of a ritR mutant. Deletion of ritR led to impaired growth of bacteria in high-iron medium, but this phenotype could be suppressed with the addition of manganese. Measurement of metal ion accumulation indicated that manganese prevents iron accumulation. Furthermore, the addition of manganese also led to a reduction in the amount of hydrogen peroxide produced by bacterial cells. Studies of virulence in a murine model of infection indicated that RitR was not essential for pneumococcal survival and suggested that derepression of iron uptake systems may enhance the survival of pneumococci in some niches.