Decreased Serum Iron Levels Research Articles

Tripanossomose em equinos na região sul do Brasil

Background : : : : Trypanosoma evansi ( T. evansi ) is a protozoan which causes trypanosomosis in livestock in many countries of Southeast Asia, Africa and South America. Patterns of disease vary from acute epidemics with high case-fatality rates to subclinical and/or chronic disease in endemic animal populations. It is a problem of great economic importance due to the death of sick animals and high cost of treatment. This article aims to review the outbreaks of the infection by T. evansi in horses that occurred in southern Brazil. Review : These outbreaks were discussed in terms of epidemiology, clinical signs, laboratory tests, pathological findings, diagnosis and treatment by addressing the differences between the cases occurred in the state of Rio Grande do Sul and in other Brazilian states. The outbreaks due to T. evansi in livestock animals are endemic in warm-climate areas. At the Rio Grande do Sul state, most of the equine trypanosomosis occurs in the summer. This can be easily explained by the high number of bloodsucking insects, which are responsible for the mechanical transmission of the flagellate among the animals. Clinical signs such as progressive weight loss, lethargy, incoordination, instability, atrophy and paralysis of the hind limbs, difficulty in standing and walking, subcutaneous edema and abortion are often reported in T. evansi- infected equines. Anemia is the clinical alteration most observed in these infections, although its pathogenicity still remains unclear. In the present study anemia was associated with lipid peroxidation and decrease in serum iron levels and in acetylcholinesterase activity. Necropsy alterations found in the outbreaks reported in the Rio Grande do Sul state are commonly described in infections by T. evansi , except by the neurological alterations as necrotizing encephalitis of the white matter associated with edema, demyelinization and perivascular lymphoplasmocytic infiltrate. The diagnosis of the equine trypanosomosis was based on morphology and biometry of the trypomastigote forms in peripheral blood smears stained with Quick Panoptic or Giemsa methods, immunohistochemic, xenodiagnostic, and PCR T. evansi- specific. A new therapeutic protocol using diminazene aceturate at a dose of 7 mg kg -1 was tested in one of the outbreaks. This approach cured all the infected animals. Conclusion : Although T. evansi was diagnosed for the first time in Rio Grande do Sul state in 2002, veterinary clinicians have reported clinical signs such as paralysis of the pelvic members, fever and weight loss since the 80’s and 90’s. Therefore, the lack of knowledge of the disease might have been responsible for the unpublished data. Another hypothesis is the suspect of babesiosis, since both illnesses have marked anemia and hyperthermia. Moreover, as the diminazene aceturate has trypanocidal and babesicidal action, animals may have been misdiagnosed with babesiosis and may have recovered from the T. evansi infection. Only few researches on trypanosomosis are found in the southern region of Brazil. Prevalence studies with more sensible techniques are necessary in order to clarify the spread of the disease and the economic losses that it causes to farmers.

Correlations between abnormal iron metabolism and non-motor symptoms in Parkinson's disease.

Despite a growing body of evidence suggests that abnormal iron metabolism plays an important role in the pathogenesis of Parkinson's disease (PD), few studies explored its role in non-motor symptoms (NMS) of PD. The present study aimed to investigate the relationship between abnormal iron metabolism and NMS of PD. Seventy PD patients and 64 healthy controls were consecutively recruited to compare serum iron, ceruloplasmin, ferritin, and transferrin levels. We evaluated five classic NMS, including depression, anxiety, pain, sleep disorder, and autonomic dysfunction in PD patients using the Hamilton Depression Scale (HAMD), the Hamilton Anxiety Scale (HAMA), the short form of the McGill Pain Questionnaire, the Pittsburgh Sleep Quality Index and the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms, respectively. Hierarchical multiple regression analysis was used to investigate the correlations between abnormal iron metabolism and NMS. No differences in serum ceruloplasmin and ferritin levels were examined between PD patients and healthy controls, but we observed significantly decreased serum iron levels and increased serum transferrin levels in PD patients in comparison with healthy controls. After eliminating confounding factors, HAMD scores and HAMA scores were both negatively correlated with serum iron levels and positively correlated with serum transferrin levels. In summary, abnormal iron metabolism might play a crucial role in the pathogenesis of depression and anxiety in PD. Serums levels of iron and transferrin could be peripheral markers for depression and anxiety in PD.

Anemia and dysregulation of iron metabolism in multiple sclerosis

Anemia is one of the common diseases comorbid with multiple sclerosis (MS). This article reviews the prevalence and types of anemia in MS patients. It has been shown that anemia is often accompanied by a decrease in serum iron level. The authors present the data on iron metabolism in patients with MS and MRI findings concerning deposits of iron in the gray matter of the brain. The causal relationship between abnormalities in iron metabolism and MS remains unclear; this study allows to approach the understanding of the MS pathogenesis and to increase the efficacy of therapy for this disease.

Investigation of Iron Metabolism for Regulating Megakaryopoiesis and Platelet Count According to the Mechanisms of Anemia

Iron deficiency anemia (IDA) is characterized by depletion of total body iron stores or a poor supply of plasma iron. By contrast, chronic inflammation makes iron unavailable for hematopoiesis through a cytokinemediated cascade and leads to a condition known as anemia of chronic disease (AOC). However, the laboratory data regarding the regulatory role of iron metabolism on platelet count has not been fully discussed yet. In this study, we investigated the relationship between iron status and platelet production according to different anemic mechanisms representing different iron metabolisms. The study included a total of 759 specimens. Blood samples were obtained through venipuncture. The complete blood count was measured using an Advia 2120 (Siemens Healthcare Diagnostics Inc., USA). Biochemical indices including iron level were estimated using a Toshiba chemical analyzer (Toshiba, Japan). In the AOC group, we found a significant relationship between platelet count and serum iron level (p < 0.27), whereas there was no correlation in the IDA group. Moreover, when the AOC patient group was subdivided by serum iron level, a remarkable difference was observed as follows. The platelet count was significantly correlated with serum iron level only in the AOC group with decreased serum iron levels (serum iron < 50 µg/dL) (p < 0.0001), while there was no correlation in the AOC group with normal serum iron levels (serum iron 50 - 100 µg/dL). Iron deficiency in AOC involves upregulated hepcidin production induced by elevated inflammatory cytokines. This can cause increased iron sequestration in macrophages and decreased iron absorption for bone marrow. The condition of decreased megakaryocytic iron supply makes megakaryocytes with higher ploidy which can release more platelets than lower ploidy. Moreover, reactive thrombocytosis in inflammatory states occurs by cytokine cascades involving interleukin 6 and thrombopoietin in AOC. These two features may enhance thrombocytosis in patients of AOC with decreased iron level. In the future, further study should be performed to elucidate regulating mechanism of iron metabolism for megakaryopoiesis in AOC patients, and guide proper supplemental therapy of iron to decrease thrombotic risk due to reactive thrombocytosis in various kinds of anemia.

Influence of exhaustive aerobic exercise on some cytokines and serum iron parameters in canine experimental model

The aim of the experiment was to study the effect of exhaustive exercise on some cytokines and iron status parameters. We used 12 male, mongrel dogs divided into two groups – animals from experimental group were submitted to exercise at moderate intensity with exhaustion as the end-point; animals from control group did no exercise. Serum levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), hepcidin prohormone, serum iron (SI), total iron binding capacity (TIBC) and transferrin saturation (TS) were measured before exercise (BE), right after exercise (0 hour) and on 2, 4, 24, 48 and 72 hours after exercise. SI, TIBC and TS were measured also on day 7 and 14 after exercise. Serum levels of TNF-α increased after the exhaustive exercise. Serum levels of IL-6 demonstrated an increase at 0 hour, but increase was not statistically significant compared to BE level. Serum levels of hepcidin prohormone marked a slight increase 48 hours after the exercise, but change was insignificant. Levels of SI decreased on hour 72 (P&lt;0.01) and on day 7 (P&lt;0.01) and 14 (P&lt;0.05) after the exercise, as compared to BE level. Similar were changes in TS. TIBC decreased on 4, 24 and 72 hours (P&lt;0.05) after exercise, but only compared to control group. In conclusion, exhaustive exercise causes inflammatory response and a significant decrease in SI levels.

Serum Iron and Haemoglobin Estimation in Oral Submucous Fibrosis and Iron Deficiency Anaemia: A Diagnostic Approach.

Oral Submucous Fibrosis (OSMF) is a premalignant condition with potential malignant behaviour characterized by juxta-epithelial fibrosis of the oral cavity. In the process of collagen synthesis, iron gets utilized, by the hydroxylation of proline and lysine, leading to decreased serum iron levels. The trace element like iron is receiving much attention in the detection of oral cancer and precancerous condition like OSMF as it was found to be significantly altered in these conditions. The aim of this study was to compare the haemoglobin and serum iron values of OSMF subjects with that of iron deficiency anaemia subjects. Total of 120 subjects were included, 40 subjects with the OSMF, 40 with the iron deficiency anemia without tobacco chewing habit, 40 healthy control subjects without OSMF and iron deficiency anaemia. A total of 5ml of venous blood was withdrawn from all the subjects and serum iron and haemoglobin levels were estimated for all the subjects. Estimation of iron was done using Ferrozine method and haemoglobin by Sahli's method. The statistical method applied were Kruskal Wallis, Mann Whitney and Pearson correlation coefficient test. There was a statistically significant difference in serum iron and haemoglobin level in all three groups (p<0.05). The serum iron level was lowest in OSMF group and haemoglobin was lowest in iron deficiency anaemia group. A progressive decrease in serum iron and haemoglobin levels from Stage I of OSMF to the Stage IV of OSMF was also observed. The iron deficiency anaemia group was not found to be suffering from OSMF in the absence of areca-nut or tobacco chewing habits, but OSMF patients with chewing habits were found to be suffering from iron deficiency anaemia. There is a progressive decrease in serum iron and haemoglobin levels from Stage I of OSMF to the Stage IV of OSMF so it can be used as an auxillary test in assessment of prognosis of the disease.

Iron Storage Rather Than Serum Iron Levels Is an Important Contributor to Iron-Induced Oxidative Stress Levels in Mice

Introduction:Iron, an essential element for various biological processes, can induce oxidative stress. In iron overload diseases, cardiovascular events are associated with increased oxidative stress accompanied by elevated iron storage and serum iron. However, it has not been investigated whether it is iron storage or serum iron that is the most important contributor to oxidative stress levels, and the relationship between iron metabolism and oxidative stress is not clear. Moreover, no biomarker that can sensitively detect iron-induced oxidative stress has yet been reported. Therefore, we first investigated the sensitivities of several biomarkers to detect oxidative stress induced in mice by altering the amount of total body iron; then using the most sensitive marker, we investigated mechanisms underlying iron metabolism and oxidative stress by exploring the contributions of iron storage and serum iron levels to oxidative stress levels by modulating body iron status in mice.Methods:This study used 8-week-old male BALB/c mice. In the first part of the study, we investigated several oxidative stress markers in iron-loaded mice. Mice were intravenously administered iron-dextran (to load iron) or vehicle for 5 days. Nine days after the first injection, we measured serum oxidative stress markers (derivatives of reactive oxygen metabolites [d-ROMs] analyzed by measuring the total amount of hydroperoxides via the Fenton reaction, malondialdehyde [MDA], and hydroxynonenal [HNE]), serum hepcidin level, and hepatic iron content.In the second part of the study, iron dynamics was modulated by 2 interventions: (1) Mice were intravenously administered 10 μg/kg of epoetin beta pegol (C.E.R.A.), a long-acting erythropoiesis-stimulating agent, or vehicle. Five days later, we determined hemoglobin, serum hepcidin level, serum iron level, hepatic iron content, and d-ROMs. (2) Mice were fed a ferric citrate diet containing 5000 ppm iron or a control diet containing 100 ppm iron for 28 days; we then evaluated serum iron level, hepatic iron content, and d-ROMs.In the third part of the study, we also evaluated oxidative stress marker d-ROMs by modulating serum iron levels and iron storage independently by 3 interventions: (1) Mice intraperitoneally administered 200 μg/head of anti-erythropoietin antibody or control IgG every other day were analyzed 96 hours later. (2) Mice injected with 100 μg/head of synthetic hepcidin or vehicle were analyzed 4 hours later. (3) Mice intravenously administered iron-dextran (48 mg/kg) or vehicle once a day for 5 days were analyzed.Results:In the first part of the study, compared with the control group, iron-loaded mice exhibited dose-dependent increases in serum hepcidin level, hepatic iron content, and serum d-ROMs, whereas no change was observed in MDA or HNE.In the second part of the study, hemoglobin level was significantly higher in C.E.R.A.-treated mice than in vehicle-treated mice. Serum hepcidin level, serum iron level, hepatic iron content, and d-ROMs were all significantly lower in C.E.R.A.-treated mice than in vehicle-treated mice. In mice fed the ferric citrate diet, serum iron level, hepatic iron content, and d-ROMs were all higher than in mice fed the control diet.In the third part of the study, in mice given anti-erythropoietin antibody, serum iron level was elevated, but hepatic iron content was not changed resulted from iron overflow with inhibition of erythropoiesis, and d-ROMs was not changed. Mice given synthetic hepcidin showed decreased serum iron level, but no significant changes were detected in hepatic iron content or d-ROMs. In mice given iron-dextran, no significant change in serum iron level was observed; however, hepatic iron content and d-ROMs levels increased compared to control mice.Conclusions:We demonstrated that d-ROMs was a sensitive marker of iron-induced oxidative stress. Modulating body iron status by several interventions, we demonstrated that iron storage, rather than serum iron levels, contributed to the level of oxidative stress marker. The results of our C.E.R.A. treatment study suggest a new rationale for treatment with C.E.R.A.: that enhancement of iron metabolism by C.E.R.A., leading to a decrease in oxidative stress by reducing iron storage, contributes to tissue protective properties. C.E.R.A. may have beneficial implications for improving prognosis by correcting oxidative stress-related disorders. DisclosuresNoguchi-Sasaki:Chugai Pharmaceutical Co., Ltd.: Employment. Sasaki:Chugai Pharmaceutical Co., Ltd.: Employment. Matsuo-Tezuka:Chugai Pharmaceutical Co., Ltd.: Employment. Kurasawa:Chugai Pharmaceutical Co., Ltd.: Employment. Yorozu:Chugai Pharmaceutical Co., Ltd.: Employment. Shimonaka:Chugai Pharmaceutical Co., Ltd.: Employment.

Influence of inflammatory and lipidic parameters on red blood cell distribution width in a healthy population.

Red blood cell distribution width (RDW) is a routine red blood cell count parameter which has been shown to be associated with inflammatory parameters. Recently, some authors proposed that RDW seems to be a marker of an adverse lipidic profile. In order to clarify whether RDW is related to inflammation, plasma lipids, or both, we determined anthropometric, hematimetric, inflammatory and lipidic parameters in 1111 healthy subjects. RDW correlated directly with age, body mass index (BMI), inflammatory parameters (plasma viscosity, erythrocyte sedimentation rate (ESR), fibrinogen, leukocyte and neutrophil count), and inversely with iron and hematimetric parameters (P < 0.05). When subjects were divided according to gender, RDW correlated inversely with triglycerides only in women (P < 0.05). When subjects were classified into RDW-quartiles, increased RDW values were accompanied by decreased serum iron levels and hematimetric indices (P < 0.01), whereas age and inflammatory markers increased according to RDW-quartiles (P < 0.001 and P < 0.05, respectively). However, plasma lipids did not change with increasing RDW-quartiles (P > 0.05). In the linear regression analysis, age, hemoglobin, MCV (beta coefficient: 0.202, -0.234, -0.316, P < 0.001) and fibrinogen (beta coefficient: 0.059, P = 0.048) were the only independent predictors of RDW. The present study indicates that RDW is associated with inflammatory markers and hematimetric indices, but not with plasma lipid levels in a healthy population.

Blood withdrawal affects iron store dynamics in primates with consequences on monoaminergic system function

Iron homeostasis is essential for the integrity of brain monoaminergic functions and its deregulation might be involved in neurological movement disorders such as the restless legs syndrome (RLS). Although iron metabolism breakdown concomitantly appears with monoaminergic system dysfunction in iron-deficient rodents and in RLS patients, the direct consequences of peripheral iron deficiency in the central nervous system (CNS) of non-human primates have received little attention. Here, we evaluated the peripheral iron-depletion impact on brain monoamine levels in macaque monkeys. After documenting circadian variations of iron and iron-related proteins (hemoglobin, ferritin and transferrin) in both serum and cerebrospinal fluid (CSF) of normal macaques, repeated blood withdrawals (RBW) were used to reduce peripheral iron-related parameter levels. Decreased serum iron levels were paradoxically associated with increased CSF iron concentrations. Despite limited consequences on tissue monoamine contents (dopamine – DA, 3, 4-dihydroxyphenylacetic acid – DOPAC, homovanillic acid, L-3, 4-dihydroxyphenylalanine – L-DOPA, 5–8 hydroxytryptamine – 5-HT, 5-hydroxyindoleacetic acid – 5-HIAA and noradrenaline) measured with post-mortem chromatography, we found distinct and region-dependent relationships of these tissue concentrations with CSF iron and/or serum iron and/or blood hemoglobin. Additionally, striatal extracellular DA, DOPAC and 5-HIAA levels evaluated by in vivo microdialysis showed a substantial increase, suggesting an overall increase in both DA and 5-HT tones. Finally, a trending increase in general locomotor activity, measured by actimetry, was observed in the most serum iron-depleted macaques. Taken together, our data are compatible with an increase in nigrostriatal DAergic function in the event of iron deficiency and point to a specific alteration of the 5-HT/DA interaction in the CNS that is possibly involved in the etiology of RLS.

Inverse correlation between serum interleukin-6 and iron levels among Japanese adults: a cross-sectional study

BackgroundInterleukin-6 (IL-6) is a multifunctional cytokine that is produced by many different cell types, and plays an important role in the regulation of inflammation, immune responses, the acute-phase response, and hematopoiesis. Previous laboratory and clinical studies have shown that IL-6 causes a significant decrease in serum iron levels. Therefore, we conducted an epidemiological study to examine the association between serum IL-6 and iron levels.MethodsIn total, 280 Japanese individuals aged 20–78 years were enrolled when they visited a clinic located in an urban area for Helicobacter pylori (H. pylori) infection tests and subsequent eradication; 65.3% were infected with H. pylori. Subjects with gastric cancer, idiopathic thrombocytopenia, or IL-6 > 10 pg/mL were excluded from the study. Serum iron and IL-6 levels were measured using the 2-nitroso-5-(N-propyl-3-sulfopropylamino) phenol method and chemiluminescence enzyme immunoassay, respectively.ResultsGeometric mean iron and IL-6 levels were 111.5 μg/dL and 1.77 pg/mL, respectively, for men, and 89.4 μg/dL and 1.55 pg/mL, respectively, for women. The logarithm of serum iron levels was negatively correlated with the logarithm of IL-6 levels in men (r = −0.19, p = 0.047), but not in women (r = −0.035, p = 0.65). Regression analysis, adjusted for sex, age, and H. pylori infection status, showed that the logarithm of serum iron levels was significantly associated with a decreased logarithm of IL-6 levels (β = −0.053, p = 0.041). The odds ratio for low serum iron levels adjusted for sex, age, and H. pylori infection status was 7.88 (95% CI 1.29–48.06) in those with an IL-6 level > 4 pg/mL.ConclusionLower serum iron levels are significantly associated with higher serum IL-6 levels among Japanese adults.

Hepcidin is Linked to Hypoferremia in Patients With Rheumatic Valve Disease

Hepcidin has been shown to be an acute phase reactant, induced by infection and inflammation. Ongoing inflammation was shown in rheumatic valve disease (RVD). In this study we want to investigate whether there is a relationship between inflammation and impaired iron metabolism and the role of hepcidin on serum iron levels. Fourty-six patients with RVD and 34 healthy individuals were included in the study. Serum hepcidin, high-sensitive C-reactive protein (hs-CRP), hemoglobin, hematocrit, iron, iron-binding capacity, ferritin levels were measured. Serum hepcidin levels were significantly increased in patients with RVD than in control group (316 ± 121 ng/mL vs 435 ± 126 ng/mL; P < .001). Serum hs-CRP levels were no significantly higher in the patient group in than in the control group (3.9 ± 3.6 mg/L vs 3.5 ± 3.7 mg/L; P = .521). Hepcidin levels are decreased independently from hs-CRP levels as a compensatory mechanism to increase the iron absorption in response to decreased serum iron levels in patients with RVD.

Haptoglobin 2–2 phenotype is associated with decreased serum iron levels in endstage renal disease patients resistant to rhEPO therapy

(2014). Haptoglobin 2–2 phenotype is associated with decreased serum iron levels in endstage renal disease patients resistant to rhEPO therapy. British Journal of Biomedical Science: Vol. 71, No. 2, pp. 79-81.

Initial Change Of Iron Metabolic Flux Prior To Differentiation Of Erythroid Progenitors After Epoetin Beta Pegol (C.E.R.A.) Treatment

IntroductionErythropoiesis and iron metabolism are inextricably linked. Developing immature erythroblasts have an extremely high iron requirement, especially during hemoglobin synthesis. Hepcidin, which inhibits iron efflux by binding to iron exporter ferroportin, is suppressed to promote the supply of required iron. Suppression of hepcidin after erythropoiesis-stimulating agent (ESA) treatment is mainly in an indirect manner, especially via erythropoietic activity, but the nature of suppressive mechanism of hepcidin is still unknown. Epoetin beta pegol (C.E.R.A.) is a novel long-acting ESA, which potentially has intensive and continuous effects on reduction of hepcidin. In the present study, we investigated change of iron metabolic flux associated with enhanced erythropoiesis by C.E.R.A. to analyze the mechanism underlying suppression of hepcidin. MethodsInitial change of iron metabolism was analyzed in C57BL/6N mice intravenously treated with 10 μg/kg of C.E.R.A. or vehicle. Hematological indices such as reticulocyte counts and iron indices including serum hepcidin and iron levels were measured. Reticulocyte hemoglobin equivalent (Ret-He) which reflects the iron status of reticulocyte was also determined. Ter119 and transferrin receptor (CD71) expression on bone marrow cells was evaluated by flow cytometry for analysis of the maturation status of bone marrow erythroblasts. ResultsC.E.R.A. suppressed serum hepcidin levels after 9 hours, while serum iron levels were significantly decreased at 9 hours followed by recovery to the control levels at 24 hours. Ter119(+)CD71(high) immature erythroblasts were decreased and CD71 expression levels on the same cells were increased at 9 hours after C.E.R.A. treatment. C.E.R.A. elevated reticulocyte counts and Ret-He levels at 48 hours. Discussion and ConclusionTransient decrease in serum iron levels and continuous suppression of serum hepcidin levels were observed in early phase after C.E.R.A. treatment, prior to increase in erythroblasts through proliferation and differentiation of erythroid progenitors. Furthermore, considering decrease in immature erythroblasts followed by increase in hemoglobin-rich reticulocytes, it is possible that initial change of iron metabolic flux occurred by the accelerated iron incorporation into immature erythroblasts through CD71 recycling after C.E.R.A. treatment. These results suggest that sensing initial change of iron metabolic flux leads to suppression of hepcidin after C.E.R.A. treatment, but further analysis is needed for the mechanism of increase in iron absorption into immature erythroblasts immediately after C.E.R.A. treatment independent of differentiation of erythroid progenitors. Disclosures:No relevant conflicts of interest to declare.

AB0584 Tocilizumab increases hemoglobin production in patient with juvenile idiopatic arthritis and beta thalassemic trait

BackgroundJuvenile idiopathic arthritis (JIA) is classified as an acquired autoinflammatory disease. The interleukin-1 and interleukin-6 play an pivotal role in pathogenesis of this disease (1). The systemic manifestations as well...

Evaluation of chitosan tripolyphosphate gel beads as bioadsorbents for iron in aqueous solution and in human blood in vitro

AbstractNonimprinted and Fe3+ imprinted chitosan tripolyphosphate gel beads were prepared via physical gel formation. A method based on in situ crosslinking using ethylene glycol diglycidyl ether was developed to imprint the chitosan tripolyphosphate gels with Fe3+ ion without deteriorating the gel beads. The beads were characterized by FTIR, SEM, XRD, and DSC with respect to the chemical structure, surface morphology, crystallinity, and thermal behavior. Swelling kinetics and Fe3+ ion adsorption behavior from aqueous solution were studied. The Fe3+ imprinted and in situ crosslinked beads proved to be durable and effective adsorbents for Fe3+ in solution. The bead prepared by in situ crosslinking and in the presence of 10 mM template ion had an equilibrium iron adsorption capacity of 53.9 mg/g after 3‐hour contact with 5 mM Fe3+ solution. The pros and cons of the beads as biomedical iron adsorbents were tested by evaluating their serum iron removal capacities from human blood. The preliminary tests carried out showed that Fe3+ imprinted beads were more effective in decreasing serum iron in human blood when compared to the nonimprinted beads. The decrease in serum iron level accompanied a parallel decrease in the hemoglobin level. The calcium level was also affected upon contact with the beads. The Fe3+ imprinted beads were less effective than the nonimprinted ones in decreasing the calcium level indicating selectivity towards iron containing species. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Role of hemoglobin and serum iron in oral submucous fibrosis: a clinical study.

Background. Oral submucous fibrosis is a chronic, insidious oral mucosal condition affecting the most parts of the oral cavity with high malignant transformation rate triggered by areca nut chewing, nutritional deficiencies, immunologic processes, and genetic predisposition. OSF causes significant hematological abnormalities resulting in anemia and a decrease in serum iron levels. Aim. The aim of this study was to estimate the hemoglobin and serum iron levels among patients with oral submucous fibrosis and to compare the values with healthy subjects. Materials and Methods. In this hospital-based study 30 diagnosed patients of OSMF and 15 healthy individuals were included, and the values of hemoglobin and serum iron levels were estimated using Sahli's and Ferrene methods. Results. OSMF patients showed significantly lower levels of hemoglobin and serum iron when compared with the healthy subjects. Conclusion. The findings of the study emphasizes on the assessment of hemoglobin and serum iron for patients with oral submucous fibrosis. Also iron therapy should be instituted concomitantly with the initial diagnosis which helps to cease the further progression of the condition. Further extensive studies are indicated to understand the correlation between OSMF and iron deficiency.

Alk3, a BMP Type I Receptor Is Required for the Induction of Hepatic Hepcidin Gene Expression by Interleukin-6

Abstract 686 Introduction:Anemia of chronic disease (ACD), the second most prevalent form of anemia, is commonly associated with chronic inflammatory, infectious, or neoplastic conditions. ACD is characterized by high hepcidin levels that decrease serum iron levels by inducing degradation of the iron exporter ferroportin. In contrast, a relative deficiency of hepcidin leads to ferroportin overexpression and iron overload. Hepcidin is transcriptionally regulated by interleukin-6 (IL-6) and bone morphogenic protein (BMP) signaling. Binding of BMP ligands to type II and type I BMP receptors induces the type II receptor to phosphorylate and activate one of four type I receptors. We sought to identify the type I BMP receptor that participates in the ability of IL-6 to induce hepatic hepcidin gene expression. Methods:The four type I BMP receptors are Alk1, Alk2, Alk3, and Alk6. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver. In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. Global deficiency of Alk2 or Alk3 is embryonic lethal. To selectively delete Alk2 or Alk3 in hepatocytes, we studied mice homozygous for Alk2 or Alk3 sequences flanked by loxP sites (Alk2fl/fl and Alk3fl/fl, respectively) that also carried a transgene specifying Cre recombinase under the control of the albumin gene promoter (Alb-Cre). Eight- to 12-week-old male mice (Alk2fl/fl, Alk2fl/fl; Alb-Cre, Alk3fl/fl, Alk3fl/fl; Alb-Cre) on a standard, iron-replete diet were injected via the tail vein with an adenovirus specifying IL-6 (Ad.IL-6) or an adenovirus specifying green fluorescent protein (GFP; Ad.GFP), as a control (1010 particles per ml for both). Seventy-two hours later, mice were euthanized, and blood was obtained for measurement of serum iron levels and transferrin saturations. Livers were harvested, and RNA was extracted. Hepatic levels of mRNAs encoding Alk2, Alk3, hepcidin, heme oxygenase-1 (HO-1, a transcriptional target of IL-6), and Id-1 (a BMP gene target) were measured by qRT-PCR. Hepatic STAT3 phosphorylation (a marker of IL-6 receptor activation) was measured using immunoblot techniques. Results:Liver-specific deletion of Alk2 or Alk3 caused mild and severe iron overload, respectively. Injection of Ad.IL-6, but not Ad.GFP, decreased serum iron levels and transferrin saturations in Alk2fl/fl, Alk2fl/fl; Alb-Cre, and Alk3fl/fl mice. In contrast, infection of Alk3fl/fl; Alb-Cre mice with Ad.IL-6 did not alter serum iron levels and only modestly reduced transferrin saturations. Infection with Ad.IL-6 induced of hepatic hepcidin gene expression in Alk2fl/fl, Alk2fl/fl; Alb-Cre, and Alk3fl/fl mice. Hepatic hepcidin mRNA levels were markedly reduced in Ad.GFP-infected Alk3fl/fl; Alb-Cre mice, and infection with Ad.IL-6 failed to increase hepcidin mRNA levels in this genotype. Ad.IL-6 infection induced hepatic Id-1 mRNA levels in Alk2fl/fl, Alk2fl/fl; Alb-Cre, and Alk3fl/fl mice, but not in Alk3fl/fl; Alb-Cre mice. Infection with Ad.IL-6 induced hepatic STAT-3 phosphorylation and HO-1 gene expression in all 4 genotypes of mice. Conclusions:Taken together, these results demonstrate that the response to IL-6, as reflected by STAT-3 phosphorylation and induction of HO-1 gene expression, does not require Alk2 or Alk3. In contrast, BMP signaling, predominantly via Alk3, is essential for the induction of hepcidin gene expression by IL-6. These results suggest that selective inhibition of Alk3 may represent a novel therapeutic approach to the treatment of ACD. Disclosures:Peterson:Massachusetts General Hospital: Patents & Royalties, The Massachusetts General Hospital has filed patents related to the use of small molecule inhibitors of BMP signaling to modulate iron metabolism, and PBY, RTP and KDB may be eligible to receive royalties. Yu:Massachusetts General Hospital: Patents & Royalties, The Massachusetts General Hospital has filed patents related to the use of small molecule inhibitors of BMP signaling to modulate iron metabolism, and PBY, RTP and KDB may be eligible to receive royalties. Bloch:Massachusetts General Hospital: Patents & Royalties, The Massachusetts General Hospital has filed patents related to the use of small molecule inhibitors of BMP signaling to modulate iron metabolism, and PBY, RTP and KDB may be eligible to receive royalties.

A High Through-Put Screen Identifies MCP-1 (CCL2) As a Novel Regulator of Iron Homeostasis and a Modifier of Hereditary Hemochromatosis Disease Severity

Abstract 685To identify genes that modify the severity of human iron disorders we pre-selected 74 genes from gene expression profiles of cells and tissues with altered iron levels and assessed whether siRNA-mediated knock-down of these genes affects uptake of transferrin, a key cellular process to acquire iron. This screen identifies the monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, as a critical suppressor of transferrin receptor mRNA expression in human cells. We next analyzed CCL2-deficient mice and demonstrate profound alterations of parameters of systemic iron homeostasis. Specifically, CCL2 knock-out mice show decreased serum iron levels and transferrin saturation, strong iron-overload in the spleen and duodenum as well as mild iron accumulation in the liver. Iron imbalance in CCL2−/− mice is unlikely explained by an impairment of the major control system of systemic iron homeostasis, the hepcidin/ferroportin regulatory system: hepcidin mRNA expression is unaltered and splenic ferroportin protein expression is strongly increased in CCL2−/− mice, as would be expected as a consequence of splenic iron overload. We speculate that increased iron absorption from the plasma, possibly mediated by inappropriately high levels of TfR1 in the spleen, duodenum and liver, may be responsible for tissue iron overload.It is of note that CCL2 levels are strongly decreased in Hfe-deficient mice and patients with Hfe-associated Hereditary Hemochromatosis (HH). We therefore asked whether CCL2 levels could modify disease severity of HH. Analysis of 51 HH patients, all homozygous for the C282Y HFE mutation, confirms significantly lower MCP-1 levels in the serum compared to a group of 23 sex- and age-matched normal controls. Importantly, CCL2 levels in HH patients show a significant negative correlation with liver iron overload at the time point of diagnosis. Furthermore, low CCL2 concentrations are significantly associated with the HLA-A3 genotype and the CD8+ T lymphocyte phenotype, both traits previously shown to correlate with iron overload in HH patients. These patient data and the data from CCL2-deficient mice suggest that appropriate CCL2 expression is required to prevent iron overload.Taken together our data demonstrate the power of siRNA screens to identify novel regulators of iron metabolism in human cells that are critically involved in maintaining systemic iron homeostasis in the mouse and that play a role in modifying hepatic iron overload in the frequent iron overload disorder Hereditary Hemochromatosis. Disclosures:No relevant conflicts of interest to declare.

Effect of epigallocatechin-3-gallate on iron overload in mice with alcoholic liver disease

Iron has long been related to the pathological process of alcoholic liver disease (ALD). Liver iron overload is known to accelerate the development of ALD. In the present study we aimed to examine the effect of epigallocatechin-3-gallate (EGCG) on iron overload of ALD and to explore the potential mechanisms involved in its protection against ALD in mice. Male C57BL/6J mice were given alcohol by intragastric administration for 12 weeks. At the end of 8th week, ALD mice were treated for 4 weeks for 10, 20 and 30 mg kg(-1) EGCG by intraperitoneal injection. Liver injuries were assessed by histopathologic examination and Serum Alanine Aminotransferase (ALT) levels. Serum iron content, hepatic iron concentration and liver malondialdehyde (MDA) contents were examined. In addition, hepcidin mRNA levels and transferrin (Tf) and transferrin receptor 1 (TfR1) protein levels of liver tissue were also evaluated. Compared with model group, treatment of ALD mice with EGCG ameliorated liver injuries, decreased serum iron level, hepatic iron levels and liver MDA contents, increased hepcidin mRNA level and decreased Tf and TfR1 protein expression in the liver. The results of our study explain a new point of view that the protective effect of EGCG on ALD is associated with its iron-chelating property. The possible mechanisms are that EGCG affects hepatic iron uptake and inhibits iron absorption in the small intestinal.

Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone

Erythropoietic activity is known to affect iron homeostasis through regulation of the liver iron regulatory hormone hepcidin. To identify new factors secreted by the erythroblasts that could influence hepcidin synthesis, we set up a coculture model. HuH7 hepatoma cells cocultured with primary human erythroblasts or erythroleukemic UT7 cells presented a 20- to 35-fold increase of hepcidin gene expression. This induction was fully blunted in the presence of a neutralizing oncostatin M antibody, demonstrating that this cytokine, belonging to the IL-6 family of cytokines, was responsible for increased levels of hepcidin expression. We further demonstrated that recombinant oncostatin M induced a dramatic transcriptional increase of hepcidin in HuH7 cells through specific activation of the STAT pathway. Hepcidin induction by oncostatin M was also observed in hepatocytes in primary culture and is believed to be cell specific since no induction was found in isolated bone marrow cells, macrophagic, stromal, and lymphoma-derived cell lines, nor in erythroblasts. Finally, we show that oncostatin M administration in vivo increases hepcidin expression and leads to significantly decreased serum iron levels. This work identifies a new potent inducer of hepcidin expression in the liver and supports a role for modulators of oncostatin M signaling pathway in treating iron disorders.