Role of vitamin C as an adjuvant therapy to different iron chelators in young β-thalassemia major patients: efficacy and safety in relation to tissue iron overload.

PubMed

Elalfy, Mohsen S; Saber, Maha M; Adly, Amira Abdel Moneam; Ismail, Eman A; Tarif, Mohamed; Ibrahim, Fatma; Elalfy, Omar M

2016-03-01

Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload. This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Anemia management in haemodialysis. EuCliD database in Spain].

PubMed

Avilés, B; Coronel, F; Pérez-García, R; Marcelli, D; Orlandini, G; Ayala, J A; Rentero, R

2002-01-01

We present the results on Anaemia Management in Fresenius Medical Care Spain dialysis centres as reported by EuCliD (European Clinical Database), evaluating a population of 4,426 patients treated in Spain during the year 2001. To analyse the erythropoietin dose and the haemoglobin levels we divided the population in two groups according to the time with dialysis treatment: patients treated less than six months and patients between six months, and four years on therapy. We compared our results with the evidence based recommendations Guidelines: the European Best Practice Guidelines (EBPG) and the US National Kidney Foundation (NKF-K/DOQI). We also compared our results with those presented by the ESAM2 on 2,618 patients on dialysis in Spain carried out in the second half of the year 2000. We observed that 70% of the population reaches an haemoglobin value higher that 11 g/dl, with a mean erythropoietin (rHu-EPO) dose of 111.9 Ul/kg weight/week (n = 3,700; SD 74.9). However, for those patients on treatment for less than six months, the mean Haemoglobin only reaches 10.65 g/dl (n = 222; SD 1.4). The rHu-EPO was administrated subcutaneously in 70.2% of the patients. About the iron therapy, 86% of the patients received iron treatment and the administration route was intravenous in 93% of the population. The ferritin levels were below 100 micrograms/dl in 10% of the patients and 26.4% showed a transferrin saturation index (TSAT) below 20%. The erythropoieting resistance index (ERI), as rHu-EPO/haemoglobin, has been used to evaluate the response to rHu-Epo, according to different variables. It was observed that the following factors lead to a higher rHu-EPO resistance: intravenous rHu-EPO as administration route, the presence of hypoalbuminemia, increase of protein C reactive, Transferrin saturation below 20% and starting dialysis during the last six months.

Biological variability of transferrin saturation and unsaturated iron binding capacity

PubMed Central

Adams, PC; Reboussin, DM; Press, RD; Barton, JC; Acton, RT; Moses, GC; Leiendecker-Foster, C; McLaren, GD; Dawkins, FW; Gordeuk, VR; Lovato, L; Eckfeldt, JH

2007-01-01

Background Transferrin saturation is widely considered the preferred screening test for hemochromatosis. Unsaturated iron binding capacity has similar performance at lower cost. However, the within-person biological variability of both these tests may limit their ability at commonly used cut points to detect HFE C282Y homozygous patients. Methods The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 primary care participants for iron overload using tansferrin saturation, unsaturated iron binding capacity, ferritin and HFE C282Y and H63D genotyping. Transferrin saturation and unsaturated iron binding capacity were performed at initial screening and again when selected participants and controls returned for a clinical examination several months later. A missed case was defined as a C282Y homozygote who had transferrin saturation below cut point (45 % women, 50 % men) or unsaturated iron binding capacity above cut point (150 μmol/L women, 125 μmol/L men) at either the initial screening or clinical examination, or both, regardless of serum ferritin. Results There were 209 C282Y previously undiagnosed homozygotes with transferrin saturation and unsaturated iron binding capacity testing done at initial screening and clinical examination. Sixty-eight C282Y homozygotes (33%) would have been missed at these transferrin saturation cut points (19 men, 49 women, median SF 170 μg/L, first and third quartiles 50 and 474 μg/L), and 58 homozygotes (28 %) would have been missed at the unsaturated iron binding capacity cut points (20 men, 38 women, median SF 168 μg/L, quartiles 38 and 454 μg/L). There was no advantage to using fasting samples. Conclusions The within-person biological variability of transferrin saturation and unsaturated iron binding capacity limit their usefulness as an initial screening test for expressing C282Y homozygotes. PMID:17976429

Potential effects of omega-3 fatty acids on anemia and inflammatory markers in maintenance hemodialysis patients.

PubMed

Gharekhani, Afshin; Khatami, Mohammad-Reza; Dashti-Khavidaki, Simin; Razeghi, Effat; Abdollahi, Alireza; Hashemi-Nazari, Seyed-Saeed; Mansournia, Mohammad-Ali

2014-01-07

Anemia is a common complication among hemodialysis (HD) patients. Although intravenous iron and erythropoiesis-stimulating agents revolutionized anemia treatment, about 10% of HD patients show suboptimal response to these agents. Systemic inflammation and increased serum hepcidin level may contribute to this hyporesponsiveness. Considering the anti-inflammatory properties of omega-3 fatty acids, this study aimed to evaluate potential role of these fatty acids in improving anemia and inflammation of chronic HD patients. In this randomized, placebo-controlled trial, 54 adult patients with HD duration of at least 3 months were randomized to ingest 1800 mg of either omega-3 fatty acids or matching placebo per day for 4 months. Anemia parameters including blood hemoglobin, serum iron, transferrin saturation (TSAT), erythropoietin resistance index, and required dose of intravenous iron and erythropoietin, and serum concentrations of inflammatory/anti-inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, C-reactive protein (CRP), hepcidin, ferritin, intact parathyroid hormone (iPTH), and ratios of IL-10 to IL-6 and IL-10 to TNF-α were measured at baseline and after 4 months of the intervention. 45 subjects (25 in the omega-3 and 20 in the placebo group) completed the study. No significant changes were observed in blood hemoglobin, serum iron, TSAT, and required dose of intravenous iron in either within or between group comparisons. Additionally, erythropoietin resistance index as well as required dose of intravenous erythropoietin showed no significant change in the omega-3 group compared to the placebo group. Although a relative alleviation in inflammatory state appeared in the omega-3 group, the mean differences of inflammatory and anti-inflammatory markers between the two groups did not reach statistically significant level except for IL-10-to-IL-6 ratio and serum ferritin level which showed significant changes in favor of omega-3 treatment (P <0.001 and P = 0.003, respectively). Omega-3 fatty acids relatively improved systemic inflammation of chronic HD patients without any prominent benefits on anemia. However, future well-designed studies on larger number of patients may determine utility of omega-3 fatty acids in HD patients with respect to inflammation and anemia.

Aetiology of extrahepatic epithelial iron deposits in siderosis in Bantu

PubMed Central

Buchanan, W. M.

1969-01-01

Twenty-seven specimens of human tissue, obtained by operation, were tested to evaluate the theory that iron uptake by tissues from serum is greater when transferrin is nearly completely saturated than when the degree of saturation is normal. Samples of each tissue were incubated in autologous serum so prepared that in one instance the transferrin was 50% saturated and in the second 90% saturated with iron containing 59Fe. In all samples the uptake of iron was greater from the transferrin which was 90% saturated. The uptake by tissues of epithelial origin was significantly greater than that by non-epithelial tissues. Considerable variation in uptake was noted between samples of the same tissue from different individuals. The role of iron stores in the tissue and folic acid deficiency are discussed. It is concluded that the degree of transferrin saturation is important in determining iron uptake by tissues, especially in those of epithelial origin, and that such uptake may be modified by tissue stores and folic acid deficiency. It is felt that these factors are probably responsible for the extrahepatic parenchymal deposits of iron sometimes found in Bantu subjects with siderosis. PMID:5784982

Low transferrin saturation is associated with impaired fasting glucose and insulin resistance in the South Korean adults: the 2010 Korean National Health and Nutrition Examination Survey.

PubMed

Park, R J; Moon, J D

2015-05-01

The associations of transferrin saturation with diabetes have not been well evaluated and conflicting results have been reported. The purpose of this study is to examine the association of iron indices (serum ferritin and transferrin saturation) with risk of impaired fasting glucose and insulin resistance. We conducted a cross-sectional study in 2413 individuals (1150 men and 1263 women) aged 20-50 years who participated in the 2010 Korean National Health and Nutrition Examination Survey. Participants were free of diabetes, malignancy, liver cirrhosis, chronic renal failure, anaemia, pregnancy and menopause. Fasting plasma glucose, insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured as the outcomes. Impaired fasting glucose was more prevalent in the highest compared with the lowest serum ferritin quartile among men (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.20-3.24) after adjustment for multiple covariates. Following the same adjustment, impaired fasting glucose was less prevalent in the highest compared with the lowest transferrin saturation quartile among men (OR, 0.45; 95% CI, 0.25-0.80) and women (OR, 0.33; 95% CI, 0.14-0.77). Moreover, a higher ferritin level was significantly associated with higher HOMA-IR after adjusting for confounders in men. Lower transferrin saturation was also significantly associated with higher insulin levels and HOMA-IR in both sexes. Lower transferrin saturations were associated with an increased risk of impaired fasting glucose and insulin resistance among general South Korean population. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Computational Modeling and Simulation of Film-Condensation

DTIC Science & Technology

2013-01-18

different cases considered in the present work. Table 2: Four different cases corresponding to various thermal boundary conditions ( CWT : constant wall...temperature; UHF: uniform heat flux; and CHT: convection heat transfer) on the channel walls. Cases (a) (b) (c) (d) Top wall BC CWT : Tw2>Tsat UHF: qw...CHT: h & T∞ >Tsat CHT Bottom Wall BC CWT : Tw1<Tsat CWT : Tw1<Tsat CWT : Tw1<Tsat UHF: qw   Page 12 of 18   In the above table, T y

Autoimmune Hepatitis: Diagnostic Dilemma When It Is Disguised as Iron Overload Syndrome.

PubMed

Acharya, Gyanendra K; Liao, Hung-I; Frunza-Stefan, Simona; Patel, Ronakkumar; Khaing, Moe

2017-09-01

Elevated serum ferritin level is a common finding in iron overload syndrome, autoimmune and viral hepatitis, alcoholic and nonalcoholic fatty liver diseases. High transferrin saturation is not a common finding in above diseases except for iron overload syndrome. We encountered a challenging case of 73-year-old female who presented with yellowish discoloration of skin, dark color urine and dull abdominal pain. Initial laboratory tests reported mild anemia; elevated bilirubin, liver enzymes, and transferrin saturation. We came to the final diagnosis of autoimmune hepatitis after extensive workups. Autoimmune hepatitis is a rare disease, and the diagnosis can be further complicated by a similar presentation of iron overload syndrome. Markedly elevated transferrin saturation can simulate iron overload syndrome, but a liver biopsy can guide physicians to navigate the diagnosis.

Inability to detect transferrin receptors on P. falciparum parasitized red cells.

PubMed

Pollack, S; Schnelle, V

1988-01-01

The mechanism by which P. falciparum takes up iron from transferrin has been explored. Binding of 125I labelled transferrin to parasitized red cells at 37 degrees C is two-fold greater than to control cells; at 0 degrees C there is no significant difference. The binding is non-specific as judged from the following: it is not saturable; it is not limited to transferrin as lactoferrin (which has iron binding domains) and bovine serum albumin (which does not) also bind in excess to parasitized red cells. A transferrin receptor complex could not be demonstrated when parasitized red cells, to which 125I transferrin was bound, were solubilized in Triton X100. Previous observation showed that uptake of transferrin iron by parasitized red cells is not accompanied by equimolar uptake of transferrin protein. We therefore suggest that nonspecifically bound transferrin is endocytosed, that the protein is degraded and the iron selectively retained.

Thermal Velocities Arising from Injection in 2-Phase and Superheated Reservoirs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shook, George Michael

2001-01-01

Production from and injection into geothermal reservoirs gives rise to temperature fronts that move through the porous medium. As many as two temperature fronts are observed in 1-D simulations. The first front is related to the saturation temperature of the production pressure. Its velocity can be calculated from the amount of excess heat in the reservoir, defined as the amount of energy above the interface temperature, Ti = Tsat(Pwf). The second temperature front velocity is the same as for single phase liquid conditions.

Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy.

PubMed

Ellervik, C; Tybjaerg-Hansen, A; Appleyard, M; Ibsen, H; Nordestgaard, B G

2010-09-01

We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH). We analysed data from a cross-sectional study of the general population including 8992 individuals from the Copenhagen City Heart Study (CCHS), a follow-up study of 36,480 individuals from the Copenhagen General Population Study (CGPS), and a case-only study of 3815 Scandinavians from the Losartan Intervention For End-point Reduction in Hypertension Genetic Substudy (LIFEGEN) with LVH and hypertension. In the CCHS, individuals with C282Y/C282Y versus wild type/wild type had an odds ratio for antihypertensive medication use of 4.8 (1.8-13; P = 0.003). In the CGPS, the corresponding hazard ratio was 1.7 (1.0-2.3; P = 0.003). Also, hazard ratios for antihypertensive medication use in the CGPS were 1.6 (1.0-2.6; P = 0.05) for transferrin saturation > or =80% vs. <50%, and 2.3 (1.3-4.2; P = 0.005) for C282Y/C282Y + transferrin saturation > or =80% vs. wild type/wild type + transferrin saturation <50%. These results were most pronounced in men above 55 years of age. We did not find any association between C282Y/C282Y or iron overload and LVH or hypertension (measured as blood pressure at a single occasion or continuous blood pressure), or LVH with hypertension in the CCHS or with severity of LVH in LIFEGEN. We found that haemochromatosis genotype C282Y/C282Y and extremely elevated transferrin saturation either separately or combined were associated with increased risk of antihypertensive medication use. Therefore, testing for haemochromatosis genotype C282Y/C282Y and extreme transferrin saturation could be considered in patients with essential hypertension.

Serum insulin-like growth factor-1 (IGF-1) during CF pulmonary exacerbation: trends and biomarker correlations.

PubMed

Gifford, A H; Nymon, A B; Ashare, A

2014-04-01

Cystic fibrosis (CF) is characterized by low circulating levels of insulin-like growth factor-1 (IGF-1), a hormone produced by the liver that governs anabolism and influences immune cell function. Because treatment of CF pulmonary exacerbation (CFPE) often improves body weight and lung function, we questioned whether serum IGF-1 trends were emblematic of these responses. Initially, we compared serum levels between healthy adults with CF and controls of similar age. We then measured serum IGF-1 throughout the CFPE cycle. We also investigated correlations among IGF-1 and other serum biomarkers during CFPE. Anthopometric, spirometric, and demographic data were collected. Serum IGF-1 concentrations were measured by ELISA. CF subjects in their usual state of health had lower serum IGF-1 levels than controls. Serum IGF-1 concentrations fell significantly from baseline at the beginning of CFPE. Treatment with intravenous antibiotics was associated with significant improvement in serum IGF-1 levels, body mass index (BMI), and percent-predicted forced expiratory volume in 1 sec (FEV1 %). At early and late CFPE, serum IGF-1 was directly correlated with FEV1 %, serum iron, hemoglobin concentration, and transferrin saturation (TSAT) and indirectly correlated with alpha-1-antitrypsin. This study not only supports the paradigm that CF is characterized by IGF-1 deficiency but also that trends in lung function, nutritional status, and serum IGF-1 are related. Improvements in all three parameters after antibiotics for CFPE likely highlight the connection between lung function and nutritional status in CF. Close correlations among IGF-1 and iron-related hematologic parameters suggest that IGF-1 may participate in CF iron homeostasis, another process that is known to be influenced by CFPE. © 2013 Wiley Periodicals, Inc.

Absolute and Functional Iron Deficiency Is a Common Finding in Patients With Heart Failure and After Heart Transplantation.

PubMed

Przybylowski, P; Wasilewski, G; Golabek, K; Bachorzewska-Gajewska, H; Dobrzycki, S; Koc-Zorawska, E; Malyszko, J

2016-01-01

Anemia is relatively common in patients with heart failure and heart transplant recipients. Both absolute and functional iron deficiency may contribute to the anemia in these populations. Functional iron deficiency (defined as ferritin greater than 200 ng/mL with TSAT (Transferrin saturation) less than 20%) is characterized by the presence of adequate iron stores as defined by conventional criteria, but with insufficient iron mobilization to adequately support. The aim of this study was to determine prevalence of absolute and functional iron deficiency in patients with heart failure (n = 269) and after heart transplantation (n = 130) and their relation to parameters of iron status and inflammation. Iron status, complete blood count, and creatinine levels were assessed using standard laboratory methods. C-reactive protein, hepcidin and hemojuvelin were measured using commercially available kits. Absolute iron deficiency was present in 15% of patients with heart failure and 30% in heart transplant recipients, whereas functional iron deficiency was present in 18% of patients with heart failure and 17% in heart transplant recipients. Functional iron deficiency was associated with significantly higher C-reactive protein and hepcidin levels in heart failure patients, and higher hepcidin and lower estimate glomerular filtration rates in heart transplant recipients. Prevalence of anemia (according to the World Health Organization) was significantly higher in heart transplant recipients (40% vs 22%, P < .001), they were also younger, but with worse kidney function than patients with heart failure. Both absolute and functional iron deficiency were present in a considerable group of patients. This population should be carefully screened for possible reversible causes of inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

Higher ferritin levels, but not serum iron or transferrin saturation, are associated with Type 2 diabetes mellitus in adult men and women free of genetic haemochromatosis.

PubMed

Yeap, Bu B; Divitini, Mark L; Gunton, Jenny E; Olynyk, John K; Beilby, John P; McQuillan, Brendan; Hung, Joseph; Knuiman, Matthew W

2015-04-01

Iron overload predisposes to diabetes and higher ferritin levels have been associated with diabetes. However, it is unclear whether ferritin reflects differences in iron-related parameters between diabetic and nondiabetic persons. We examined associations of serum ferritin, iron and transferrin saturation with Type 2 diabetes in adults without genetic predisposition to iron overload. Cross-sectional analysis of community-dwelling men and women aged 17-97 years from the Busselton Health Survey, Western Australia. Men and women carrying genotypes associated with haemochromatosis (C282Y/C282Y or C282Y/H63D) were excluded. Serum ferritin, iron and transferrin saturation were assayed. There were 1834 men (122 with diabetes, 6·6%) and 2351 women (141 with diabetes, 6%). In men, higher serum ferritin was associated with diabetes after adjusting for age, smoking, alcohol, cardiovascular history, body mass index (BMI), waist, blood pressure, lipids, C-reactive protein (CRP), adiponectin, alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT) [odds ratio (OR): 1·29 per 1 unit increase log ferritin, 95% confidence interval (CI) = 1·01-1·65, P = 0·043]. In women, higher serum ferritin was associated with diabetes [fully adjusted OR: 1·31 per 1 unit increase log ferritin, 95% CI = 1·04-1·63, P = 0·020; 1·84 for tertile (T) 3 vs T1, 95% CI = 1·09-3·11]. Neither iron levels nor transferrin saturation were associated with diabetes risk in men or women. Higher ferritin was not associated with insulin resistance in nondiabetic adults. In adults, higher ferritin levels are independently associated with prevalent diabetes while iron and transferrin saturation are not. Ferritin is a robust biomarker for diabetes risk, but further investigation is needed to clarify whether this relationship is mediated via iron metabolism. © 2014 John Wiley & Sons Ltd.

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

PubMed Central

Riva, Alessia; Trombini, Paola; Mariani, Raffaella; Salvioni, Alessandra; Coletti, Sabina; Bonfadini, Silvia; Paolini, Valentina; Pozzi, Matteo; Facchetti, Rita; Bovo, Giorgio; Piperno, Alberto

2008-01-01

AIM: To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical, biochemical and histopathological findings. METHODS: We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes. The metabolic syndrome (MS) was defined according to ATPIII criteria. Iron overload was assessed by liver biopsy. Liver histology was evaluated by Ishak’s score and iron accumulation by Deugnier’s score; steatosis was diagnosed when present in ≥ 5% of hepatocytes. RESULTS: According to transferrin saturation levels, we observed significant differences in the amount of hepatic iron overload and iron distribution, as well as the number of metabolic abnormalities. Using Receiving Operating Curve analysis, we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload (P < 0.0001). Patients with ≥ 2 metabolic alterations and steatosis had lower amount of hepatic iron, lower transferrin saturation and higher sinusoidal iron than patients with < 2 MS components and absence of steatosis. CONCLUSION: In our patients, the presence of ≥ 2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome. By contrast, patients with transferrin saturation ≥ 60% had more severe iron overload, few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload. PMID:18720534

Lagtime of river systems to changes in pollutant load on the catchment: a regional scale assessment

NASA Astrophysics Data System (ADS)

Żurek, Anna J.; Różański, Kazimierz; Witczak, Stanisław

2017-04-01

Transport of conservative contaminants through groundwater systems (e.g. nitrate under oxidized conditions) is significantly delayed when compared to movement of those contaminants through surface water compartments. Characteristic time scales of groundwater movement may easily reach tens or hundreds of years. This results in large lagtimes of contaminant transport in the subsurface. These lagtimes are particularly important when response of river basins to measures aimed at recovery of good groundwater status is considered. Incorporating lagtime principles into water quality regulations may result in more realistic expectations when such policies are designed and implemented. The lagtime of contaminant transport in the subsurface with respect to transport through surface and near-surface (drainage) runoff can be separated into two components: (i) the delay associated with travel time of water (and contaminants) through the unsaturated zone, and (ii) the delay linked to time scales of groundwater flow, from the recharge area down to the discharge zone (river). Thus, the travel time of water through unsaturated and saturated zones can be considered a quantitative measure of the lagtime. Lagtime in the unsaturated zone on the territory of Poland was assessed on the basis of the existing Groundwater Vulnerability Map of Poland (GVMP) (Witczak et al., 2007; 2011). The adopted approach relies on MRT (Mean Residence Time) of water in the strata separating the saturated aquifer from the land surface, as an integrated vulnerability index. In the framework of GVMP, the MRT is calculated as turnover time of the infiltrating water in the vadose zone. The piston-flow type of water movement through the unsaturated zone is considered. The lagtime in the saturated zone (Tsat) can be approximated by travel time of water, flowing along the local hydraulic gradient to the closest river. The lagtime of river systems with respect to changes in pollutant load on the catchment is a sum of the travel time of water through the unsaturated zone (MRT) and the travel time associated with movement of water in the saturated zone (Tsat). Preliminary assessments of total lagtime (MRT + Tsat) suggest that for the territory of Poland the mean value of the total lagtime of conservative contaminant is in the order of 25 years, with the range of 10 to 60 years corresponding to one standard deviation. References: Witczak S. (Ed.) (2011). Groundwater Vulnerability Map of Poland. Ministerstwo Środowiska. Warszawa. Witczak S., Duda R., Zurek A. (2007). The Polish concept of groundwater vulnerability mapping. [In:] Witkowski A.J., Kowalczyk A., Vrba J., Groundwater Vulnerability Assessment and Mapping, Selected Papers on Hydrogeology 11, 45-59. Acknowledgements. The work was carried out as part of the project BONUS Soils2Sea and the statutory funds of the AGH University of Science and Technology (projects No.11.11.140.797 and 11.11.220.01).

Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation.

PubMed

Meyer, Sara C; O'Meara, Alix; Buser, Andreas S; Tichelli, André; Passweg, Jakob R; Stern, Martin

2013-03-01

In patients referred for allogeneic hematopoietic stem cell transplantation (HSCT), iron overload is frequent and associated with increased morbidity and mortality. Both the evolution of iron overload after transplantation and its correlation with late posttransplantation events are unknown. We studied 290 patients undergoing myeloablative allogeneic HSCT between 2000 and 2009. Serum ferritin, transferrin saturation, transferrin, iron, and soluble transferrin receptor were determined regularly between 1 and 60 months after HSCT, and values were correlated with transplantation outcome. Ferritin levels peaked in the first 3 months posttransplantation and then decreased to normal values at 5 years. Transferrin saturation and iron behaved analogously, whereas transferrin and soluble transferrin receptor increased after an early nadir. Landmark survival analysis showed that hyperferritinemia had a detrimental effect on survival in all periods analyzed (0 to 6 months P < .001; 6 to 12 months P < .001; 1 to 2 years P = .02; 2 to 5 years P = .002). This effect was independent of red blood cell transfusion dependency and graft-versus-host disease. Similar trends were seen for other iron parameters. These data show the natural dynamics of iron parameters in the setting of allogeneic HSCT and provide evidence for a prognostic role of iron overload extending beyond the immediate posttransplantation period. Interventions to reduce excessive body iron might therefore be beneficial both before and after HSCT. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Investigating the relationship between iron and depression.

PubMed

Mills, Natalie T; Maier, Robert; Whitfield, John B; Wright, Margaret J; Colodro-Conde, Lucia; Byrne, Enda M; Scott, James G; Byrne, Gerard J; Hansell, Narelle K; Vinkhuyzen, Anna A E; CouvyDuchesne, Baptiste; Montgomery, Grant W; Henders, Anjali K; Martin, Nicholas G; Wray, Naomi R; Benyamin, Beben

2017-11-01

Lower levels of circulating iron have been associated with depression. Our objective was to investigate the phenotypic and genetic relationship between measures of circulating levels of iron (serum iron, transferrin, transferrin saturation, and ferritin) and depressive symptoms. Data were available from ongoing studies at QIMR Berghofer Medical Research Institute (QIMRB), including twin adolescents (mean age 15.1 years, standard deviation (SD) 3.2 years), and twin adults (mean age 23.2 years, SD 2.2 years). In the adolescent cohort, there were 3416 participants from 1688 families. In the adult cohort there were 9035 participants from 4533 families. We estimated heritabilities of, and phenotypic and genetic correlations between, traits. We conducted analyses that linked results from published large-scale genome-wide association studies (including iron and Major Depressive Disorder) with our study samples using single SNP and multi-SNP genetic risk score analyses, and LD score regression analyses. In both cohorts, measures of iron, transferrin, transferrin saturation, and log 10 of ferritin (L10Fer) were all highly heritable, while depressive measures were moderately heritable. In adolescents, depression measures were higher in those in the middle 10th versus top 10th percentile of transferrin saturation measures (p = 0.002). Genetic profile risk scores of the iron measures were not significantly associated with depression in study participants. LD score analyses showed no significant genetic relationship between iron and depression. Genetic factors strongly influence iron measures in adolescents and adults. Using several different strategies we find no evidence for a genetic contribution to the relationship between blood measures of iron and measures of depression. Copyright © 2017 Elsevier Ltd. All rights reserved.

New insights into iron deficiency and iron deficiency anemia.

PubMed

Camaschella, Clara

2017-07-01

Recent advances in iron metabolism have stimulated new interest in iron deficiency (ID) and its anemia (IDA), common conditions worldwide. Absolute ID/IDA, i.e. the decrease of total body iron, is easily diagnosed based on decreased levels of serum ferritin and transferrin saturation. Relative lack of iron in specific organs/tissues, and IDA in the context of inflammatory disorders, are diagnosed based on arbitrary cut offs of ferritin and transferrin saturation and/or marker combination (as the soluble transferrin receptor/ferritin index) in an appropriate clinical context. Most ID patients are candidate to traditional treatment with oral iron salts, while high hepcidin levels block their absorption in inflammatory disorders. New iron preparations and new treatment modalities are available: high-dose intravenous iron compounds are becoming popular and indications to their use are increasing, although long-term side effects remain to be evaluated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Binding and Utilization of Human Transferrin by Prevotella nigrescens

PubMed Central

Duchesne, Pascale; Grenier, Daniel; Mayrand, Denis

1999-01-01

To survive and multiply within their hosts, pathogens must possess efficient iron-scavenging mechanisms. In the present study, we investigate the capacity of Prevotella nigrescens and Prevotella intermedia to use various sources of iron for growth and characterize the transferrin-binding activity of P. nigrescens. Iron-saturated human transferrin and lactoferrin, but not ferric chloride and the iron-free form of transferrin, could be used as sources of iron by P. nigrescens and P. intermedia. Neither siderophore activity nor ferric reductase activity could be detected in P. nigrescens and P. intermedia. However, both species showed transferrin-binding activity as well as the capacity to proteolytically cleave transferrin. To various extents, all strains of P. nigrescens and P. intermedia tested demonstrated transferrin-binding activity. The activity was heat and protease sensitive. The capacity of P. nigrescens to bind transferrin was decreased when cells were grown in the presence of hemin. Preincubation of bacterial cells with hemin, hemoglobin, lactoferrin, fibrinogen, immunoglobulin G, or laminin did not affect transferrin-binding activity. The transferrin-binding protein could be extracted from the cell surface of P. nigrescens by treatment with a zwitterionic detergent. Subjecting the cell surface extract to affinity chromatography on an agarose-transferrin column revealed that it contained a protein having an estimated molecular mass of 37 kDa and possessing transferrin-binding activity. The transferrin-binding activity of P. nigrescens and P. intermedia may permit the bacteria to obtain iron for survival and growth in periodontal pockets. PMID:9916061

Phosphate inhibits in vitro Fe3+ loading into transferrin by forming a soluble Fe(III)-phosphate complex: a potential non-transferrin bound iron species.

PubMed

Hilton, Robert J; Seare, Matthew C; Andros, N David; Kenealey, Zachary; Orozco, Catalina Matias; Webb, Michael; Watt, Richard K

2012-05-01

In chronic kidney diseases, NTBI can occur even when total iron levels in serum are low and transferrin is not saturated. We postulated that elevated serum phosphate concentrations, present in CKD patients, might disrupt Fe(3+) loading into apo-transferrin by forming Fe(III)-phosphate species. We report that phosphate competes with apo-transferrin for Fe(3+) by forming a soluble Fe(III)-phosphate complex. Once formed, the Fe(III)-phosphate complex is not a substrate for donating Fe(3+) to apo-transferrin. Phosphate (1-10mM) does not chelate Fe(III) from diferric transferrin under the conditions examined. Complexed forms of Fe(3+), such as iron nitrilotriacetic acid (Fe(3+)-NTA), and Fe(III)-citrate are not susceptible to this phosphate complexation reaction and efficiently deliver Fe(3+) to apo-transferrin in the presence of phosphate. This reaction suggests that citrate might play an important role in protecting against Fe(III), phosphate interactions in vivo. In contrast to the reactions of Fe(3+) and phosphate, the addition of Fe(2+) to a solution of apo-transferrin and phosphate lead to rapid oxidation and deposition of Fe(3+) into apo-transferrin. These in vitro data suggest that, in principle, elevated phosphate concentrations can influence the ability of apo-transferrin to bind iron, depending on the oxidation state of the iron. Copyright © 2012 Elsevier Inc. All rights reserved.

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.

PubMed

Kaczorowska-Hac, Barbara; Luszczyk, Marcin; Antosiewicz, Jedrzej; Ziolkowski, Wieslaw; Adamkiewicz-Drozynska, Elzbieta; Mysliwiec, Malgorzata; Milosz, Ewa; Kaczor, Jan J

2017-07-01

Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

Human granulocyte/pollen-binding protein. Recognition and identification as transferrin.

PubMed Central

Sass-Kuhn, S P; Moqbel, R; Mackay, J A; Cromwell, O; Kay, A B

1984-01-01

Normal human serum was found to contain a heat-stable protein which promoted the binding of granulocytes to timothy grass pollen (granulocyte/pollen-binding protein [GPBP]). GPBP was purified by gel filtration, anion exchange, and affinity chromatography. Virtually all of the granulocyte/pollen-binding activity was associated with a beta-1-protein having a molecular mass of approximately 77,000 D and an isoelectric point of between 5.5 and 6.1. By immunoelectrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the protein was identified as transferrin. Monospecific antisera raised against either GPBP or transferrin removed biological activity from GPBP preparations, and GPBP and transferrin gave lines of identity with these two antisera. The apparent heterogeneity in the molecular size and charge of GPBP observed during progressive purification was minimal when GPBP was saturated with ferric ions before the separation procedures. These experiments indicate that granulocyte/pollen binding is a hitherto unrecognized property of transferrin which appears to be unrelated to iron transport and raises the possibility that transferrin might have a physiological role in the removal of certain organic matter. Images PMID:6690479

Effect of Native American ancestry on iron-related phenotypes of Alabama hemochromatosis probands with HFE C282Y homozygosity

PubMed Central

Barton, James C; Barton, Ellen H; Acton, Ronald T

2006-01-01

Background In age-matched cohorts of screening study participants recruited from primary care clinics, mean serum transferrin saturation values were significantly lower and mean serum ferritin concentrations were significantly higher in Native Americans than in whites. Twenty-eight percent of 80 Alabama white hemochromatosis probands with HFE C282Y homozygosity previously reported having Native American ancestry, but the possible effect of this ancestry on hemochromatosis phenotypes was unknown. Methods We compiled observations in these 80 probands and used univariate and multivariate methods to analyze associations of age, sex, Native American ancestry (as a dichotomous variable), report of ethanol consumption (as a dichotomous variable), percentage transferrin saturation and loge serum ferritin concentration at diagnosis, quantities of iron removed by phlebotomy to achieve iron depletion, and quantities of excess iron removed by phlebotomy. Results In a univariate analysis in which probands were grouped by sex, there were no significant differences in reports of ethanol consumption, transferrin saturation, loge serum ferritin concentration, quantities of iron removed to achieve iron depletion, and quantities of excess iron removed by phlebotomy in probands who reported Native American ancestry than in those who did not. In multivariate analyses, transferrin saturation (as a dependent variable) was not significantly associated with any of the available variables, including reports of Native American ancestry and ethanol consumption. The independent variable quantities of excess iron removed by phlebotomy was significantly associated with loge serum ferritin used as a dependent variable (p < 0.0001), but not with reports of Native American ancestry or reports of ethanol consumption. Loge serum ferritin was the only independent variable significantly associated with quantities of excess iron removed by phlebotomy used as a dependent variable (p < 0.0001) (p < 0.0001; ANOVA of regression). Conclusion We conclude that the iron-related phenotypes of hemochromatosis probands with HFE C282Y homozygosity are similar in those with and without Native American ancestry reports. PMID:16533407

Haematological values in pregnant women in Port Harcourt, Nigeria II: Serum iron and transferrin, total and unsaturated iron binding capacity and some red cell and platelet indices.

PubMed

Amah-Tariah, F S; Ojeka, S O; Dapper, D V

2011-12-20

Previous studies on the normal values of serum iron, unsaturated iron binding capacity, total iron binding capacity, serum transferrin, percent transferrin saturation, red cell distribution width, and various platelet indices: Platelet count, mean platelet volume, platelet distribution width, plateletcrit and platelet larger cell ratio in pregnant subjects in Nigeria are relatively scanty. Present study aims to determine the values of these parameters in apparently healthy pregnant subjects residing in Port Harcourt south eastern Nigeria; and help establish normal reference ranges of these parameters for the population under reference. Cross sectional prospective study involving 220 female subjects attending for the first time, the ante-natal clinics of a tertiary health care facility in Port Harcourt. Subjects were divided into 73, 75 and 72 subjects in the first, second and third trimester of pregnancy respectively. Serum iron and unsaturated iron binding capacity, red cell distribution width, platelet count and platelet distribution width were determined by automated methods; total iron binding capacity, serum transferrin concentrations, percent transferrin saturation, mean platelet volume and plateletcrit were calculated using appropriate formulas. The values of serum iron, unsaturated iron binding capacity, total iron binding capacity and serum transferrin concentrations were found to show significant variations between the various trimesters of pregnancy. However, while serum iron showed significant decreases during pregnancy; unsaturated iron binding capacity, total iron binding capacity and serum transferrin concentrations were found to show significant increases during pregnancy amongst our subjects (p<0.05). By contrast the values of red cell distribution width, platelet count, mean platelet volume, platelet distribution width, plateletcrit and platelet larger cell ratio did not show any significant differences at the different trimesters of pregnancy in our subjects (p>0.05). The present study reports, for the first time, normative values for these parameters in apparently healthy pregnant subjects in Port Harcourt south eastern Nigeria. Apparently, increases in unsaturated and total iron binding capacity and serum transferrin values seen amongst our subjects with increasing gestation may perhaps be a mechanism to ensure a fetal adequate iron delivery on account of the decreasing serum iron concentration with gestation in our subjects. The study suggests that values of serum transferrin are perhaps a more useful screening tool for iron deficiency anemia during pregnancy amongst our subjects.

Ferroportin disease: pathogenesis, diagnosis and treatment

PubMed Central

Pietrangelo, Antonello

2017-01-01

Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (FPN) gene. It represents one of the commonest causes of genetic hyperferritinemia, regardless of ethnicity. FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting. The hallmark of FD is marked iron accumulation in hepatic Kupffer cells. Numerous FD-associated mutations have been reported worldwide, with a few occurring in different populations and some more commonly reported (e.g. Val192del, A77D, and G80S). FPN1 polymorphisms also represent the gene variants most commonly responsible for hyperferritinemia in Africans. Differential diagnosis includes mainly hereditary hemochromatosis, the syndrome commonly due to either HFE or TfR2, HJV, HAMP, and, in rare instances, FPN1 itself. Here, unlike FD, hyperferritinemia associates with high transferrin saturation, iron-spared macrophages, and progressive parenchymal cell iron load. Abdominal magnetic resonance imaging (MRI), the key non-invasive diagnostic tool for the diagnosis of FD, shows the characteristic iron loading SSL triad (spleen, spine and liver). A non-aggressive phlebotomy regimen is recommended, with careful monitoring of transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation. PMID:29101207

Relationship between Serum Iron Profile and Blood Groups among the Voluntary Blood Donors of Bangladesh.

PubMed

Hoque, M M; Adnan, S D; Karim, S; Al-Mamun, M A; Faruki, M A; Islam, K; Nandy, S

2016-04-01

Blood donation results in a substantial iron loss and subsequent mobilization from body stores. Chronic iron deficiency is a well-recognized complication of regular blood donation. The present study conducted to compare the level of serum ferritin, serum iron, total iron binding capacity (TIBC) and percentage transferrin saturation in different ABO and Rhesus type blood groups among the voluntary blood donors of Bangladesh. The present prospective study included 100 healthy voluntary donors attending at Department of Blood Transfusion, Dhaka Medical College, Dhaka between the periods of July 2013 to Jun 2014. From each donor 10mL venous blood sample was taken and divided into heparinized and non-heparinized tubes for determination of hemoglobin (Hb), hematocrit (Hct), serum iron (SI), total iron binding capacity (TIBC) and serum ferritin by standard laboratory methods. Percentage of transferrin saturation (TS) calculated from serum iron and TIBC. Data were analyzed with SPSS (version 16) software and comparisons between groups were made using student's t-test and one way ANOVA. In the present study mean±SD of age of the respondents was 27.2±6.5 years with a range of 18 to 49 years and 81.0% were male and 19.0% were female. Among the donors 18.0% had blood group A, 35.0% had blood group B, 14.0% had blood group AB and 33.0% had blood group O. Among the donors 91.0% had rhesus positive and 9.0% had rhesus negative. Donors with blood group O had lowest haemoglobin, serum iron and transferring saturation levels. Donors with blood group A had highest TIBC level. Donors with blood group B had lowest serum ferritin level. An independent samples 't' test showed statistically significant difference in serum ferritin and percentage transferrin saturation between blood group AB and blood group O and in percentage transferrin saturation between blood group B and blood group O. One way ANOVA showed that there is no significant difference in haemoglobin, serum iron, serum ferritin and percentage transferring saturation in different ABO and Rh blood grouping categories. Blood donors with blood group O had lowest haemoglobin, serum iron and transferring saturation levels and donors with blood group A had highest TIBC level. Blood donors with blood group B had lowest serum ferritin level. The understanding of the different blood groups ability to retain iron in their system can give an insight into their ability to handle the disease iron deficiency anaemia.

The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure.

PubMed

Ebner, Nicole; Jankowska, Ewa A; Ponikowski, Piotr; Lainscak, Mitja; Elsner, Sebastian; Sliziuk, Veronika; Steinbeck, Lisa; Kube, Jennifer; Bekfani, Tarek; Scherbakov, Nadja; Valentova, Miroslava; Sandek, Anja; Doehner, Wolfram; Springer, Jochen; Anker, Stefan D; von Haehling, Stephan

2016-02-15

Anaemia and iron deficiency (ID) are important co-morbidities in patients with chronic heart failure (HF) and both may lead to reduced exercise capacity. We enrolled 331 out-patients with stable chronic HF (mean age: 64 ± 11 years, 17% female, left ventricular ejection fraction [LVEF] 35 ± 13%, body mass index [BMI] 28.5 ± 5.2 kg/m(2), New York Heart Association [NYHA] class 2.2 ± 0.7, chronic kidney disease 35%, glomerular filtration rate 61.7 ± 20.1 mL/min). Anaemia was defined according to World Health Organization criteria (haemoglobin [Hb] < 13 g/dL in men, < 12 g/dL in women). ID was defined as serum ferritin < 100 μg/L or ferritin < 300 μg/L with transferrin saturation (TSAT) < 20%. Exercise capacity was assessed as peak oxygen consumption (peak VO2) by spiroergometry and 6-minute walk test (6MWT). A total of 91 (27%) patients died from any cause during a mean follow-up of 18 months. At baseline, 98 (30%) patients presented with anaemia and 149 (45%) patients presented with ID. We observed a significant reduction in exercise capacity in parallel to decreasing Hb levels (r = 0.24, p < 0.001). In patients with anaemia and ID (n = 63, 19%), exercise capacity was significantly lower than in patients with ID or anaemia only. Cox regression analysis showed that after adjusting for NYHA, age, hsCRP and creatinine anaemia is an independent predictor of mortality in patients with HF (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.33-0.97, p = 0.04). The impact of anaemia on reduced exercise capacity and on mortality is stronger than that of ID. Anaemia remained an independent predictor of death after adjusting for clinically relevant variables. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

An unusual case of iron deficiency anemia is associated with extremely low level of transferrin receptor.

PubMed

Hao, Shuangying; Li, Huihui; Sun, Xiaoyan; Li, Juan; Li, Kuanyu

2015-01-01

A case study of a female patient, diagnosed with iron deficiency anemia, was unresponsive to oral iron treatment and only partially responsive to parenteral iron therapy, a clinical profile resembling the iron-refractory iron deficiency anemia (IRIDA) disorder. However, the patient failed to exhibit microcytic phenotype, one of the IRIDA hallmarks. Biochemical assays revealed that serum iron, hepcidin, interluekin 6, and transferrin saturation were within the normal range of references or were comparable to her non-anemic offspring. Iron contents in serum and red blood cells and hemoglobin levels were measured, which confirmed the partial improvement of anemia after parenteral iron therapy. Strikingly, serum transferrin receptor in patient was almost undetectable, reflecting the very low activity of bone-marrow erythropoiesis. Our data demonstrate that this is not a case of systemic iron deficiency, but rather cellular iron deficit due to the low level of transferrin receptor, particularly in erythroid tissue.

[Haemochromatosis screening in 120 patients complaining with persistant fatigue].

PubMed

Vital Durand, D; François, S; Nové-Josserand, R; Durupt, S; Durieu, I; Morel, Y; Rousset, H

2004-09-01

Chronic fatigue is the more frequent symptom identified in the course of hereditary haemochromatosis. A screening for this disorder was carried out in 120 primary care patients consulting for unexplained chronic fatigue. Transferrin saturation and serum ferritin were determined in all patients. If transferrin saturation was >or= 45% and serum ferritin >or= 300 microg/l, HFE1 genotyping for mutations C282Y and H63D was completed. One hundred and twenty patients were recruited, 19-86 years old, including 62 males and 58 females. 45 patients (38%) presented with serum ferritin >or= 300 microg/l. Thirty two patients (27%) presented with transferrin saturation >or= 45%. Twenty two patients (18%) presented with these two pathological values. Four C282Y/H63D compound heterozygous, one H63D/H63D homozygous, and eight simplex heterozygous (6 H63D and 2 C282Y) genotypes were found. Patients with serum ferritin >or= 300 microg/l were predominantly male (89%), older (57 year) and plethoric (BMI: 26.4) corresponding mainly to dysmetabolic hyperferritinemia. None of these 120 patients consulting for unexplained chronic fatigue was found with hereditary haemochromatosis. Therefore observed prevalence is 0, with upper limit of 95% confidence interval at 2.5%. But the high prevalence (38%) of serum ferritin >or= 300 microg/l must be emphasized, corresponding usually to dysmetabolic hyperferritinemia.

A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED).

PubMed

Reinisch, Walter; Staun, Michael; Tandon, Rakesh K; Altorjay, Istvan; Thillainayagam, Andrew V; Gratzer, Cornelia; Nijhawan, Sandeep; Thomsen, Lars L

2013-12-01

In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA). This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of -0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response. Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was -0.37 (95% confidence interval (CI): -0.80, 0.06) with P=0.09 in the full analysis set (N=327) and -0.45 (95% CI: -0.88, -0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of -4.4 (95% CI: -7.4, -1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67%; oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP). We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose-response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.

Clinical experience with darbepoietin alfa (NESP) in children undergoing hemodialysis.

PubMed

De Palo, Tommaso; Giordano, Mario; Palumbo, Fabrizio; Bellantuono, Rosa; Messina, Giovanni; Colella, Vincenzo; Caringella, Angela D

2004-03-01

Darbepoietin alfa (NESP) is a new long-acting erythropoietin, with a half-life 3 times longer than the old epoietins. In the present study, we evaluated the efficacy of NESP in a group of children on hemodialysis. Seven children, five male and two female, with a mean age of 11.5 +/- 3 years and a mean weight of 34.1 +/- 11 kg, were enrolled in the study. All had been treated for at least 6 months with epoietin alfa at a mean dose of 106 +/- 76 IU/kg 3 times/week i.v. They were then given NESP at a mean dose of 1.59 +/- 1.19 microg/kg once a week i.v., according to the suggested conversion index (weekly epoietin alfa dose/200=weekly NESP dose). Anemia was evaluated at the end of a dialysis session. This was especially important for children less compliant with water restriction. Serum ferritin and percentage transferrin saturation (TSAT) were also monitored, as were dialysis efficacy (Kt/V), blood pressure, and heparin requirements. Before starting the new treatment, all patients had an adequate mean hemoglobin (Hb) level (11.19 +/- 1.7 g/dl) and an adequate iron status (TSAT 24.2 +/- 11.5, serum ferritin 220 +/- 105 mg/dl). Five of the seven patients were also treated with intravenous ferric gluconate (10-20 mg/kg per week). Six children were on antihypertensive treatment. After the 1st month of treatment, we observed an excessive increase in Hb, 12.3 +/- 1.7 g/dl, (P<0.05), with severe hypertension in the youngest two patients (Hb>13 g/dl). A short discontinuation of the medication, followed by restarting at a decreased dosage, allowed us to continue with the treatment. At the 2nd month of follow-up, a mean plasma Hb level of 12.2 +/- 1.2 g/dl was observed, with a NESP mean dose of 0.79 +/- 0.4 microg/kg per week. Steady state was reached at 3 months, with a mean Hb of 11.8 +/- 1.4 g/dl and a mean NESP dose of 0.51 +/- 0.18 microg/kg per week (P<0.05). These results persisted at 6 months of follow-up; only one child had a persistent increase in platelet level (373,000 vs. 555,000). Dialysis efficiency and heparin requirements during dialysis did not change significantly. The high efficacy of NESP allowed a consistent reduction in dosage. The suggested conversion index does not appear to be correct for pediatric patients. Our experience suggests that in this population the correct dose could be 0.25-0.75 microg/kg per week. Hypertension was the only major side effect reported. The influence of NESP on platelet proliferation needs to be further investigated. The single weekly administration of NESP could be effective and beneficial for both patients and clinicians.

Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis.

PubMed

Farinati, F; Cardin, R; De Maria, N; Della Libera, G; Marafin, C; Lecis, E; Burra, P; Floreani, A; Cecchetto, A; Naccarato, R

1995-04-01

Little is known about the pathogenesis of liver damage related to hepatitis C virus. The presence of steatosis or increased ferritin levels, and preliminary data on the relevance of iron as a prognostic factor prompted us to ascertain whether hepatitis C virus-related liver damage might be mediated by iron accumulation. We evaluated the degree of hepatic inflammation and steatosis, serum ferritin, transferrin saturation and iron levels, tissue iron concentrations and iron index, liver glutathione and malondialdehyde in 33 males and 20 females with chronic hepatitis C virus- or hepatitis B virus-related hepatitis (42 + 11). We also considered six patients with both alcohol abuse and hepatitis C virus, four males with chronic alcoholic liver disease and four males with genetic hemochromatosis, giving a total of 67. All diagnoses were histologically confirmed. Patients with cirrhosis were excluded. Our data show that: 1. Steatosis is more frequent in hepatitis C virus and hepatitis C virus+alcohol abuse patients; 2. In males, serum ferritin and tissue iron are significantly higher in hepatitis C virus- than in hepatitis B virus-positive patients (p < 0.01 and 0.05); transferrin saturation is higher (p < 0.05) in hepatitis C virus-positive than in hepatitis B virus-positive patients only when males and females are considered together; 3. Serum ferritin and transferrin saturation only correlate with liver iron (r = 0.833 and r = 0.695, respectively, p = 0.00001); tissue iron is significantly higher in hepatitis C virus- than in hepatitis B virus-positive patients (p < 0.05); 4. In patients with chronic hepatitis, serum ferritin is a better marker of liver iron storage than transferrin saturation, both in males and in females; 5. Hepatitis C virus-positive patients have higher malondialdehyde levels and activation of turnover of glutathione, probably in response to free-radical-mediated liver damage. Females have lower liver iron levels but similar trends. These findings suggest that hepatitis C virus-related liver damage is characterized by increased iron storage (possibly induced by the virus) which elicits a free-radical-mediated peroxidation, with consequent steatosis and activation of glutathione turnover.

Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions.

PubMed

Porter, John B; Cappellini, Maria Domenica; Kattamis, Antonis; Viprakasit, Vip; Musallam, Khaled M; Zhu, Zewen; Taher, Ali T

2017-01-01

Non-transfusion-dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n = 95), haemoglobin (Hb) E/β thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non-transferrin-bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non-splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor-15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra-hepatic iron distribution are more likely in previously transfused, splenectomised and iron-overloaded NTDT patients with TfSat >70%. © 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Anemia and Iron Deficiency in Children With Potential Celiac Disease.

PubMed

Repo, Marleena; Lindfors, Katri; Mäki, Markku; Huhtala, Heini; Laurila, Kaija; Lähdeaho, Marja-Leena; Saavalainen, Päivi; Kaukinen, Katri; Kurppa, Kalle

2017-01-01

Active screening for celiac disease frequently detects seropositive children with normal villous morphology (potential celiac disease). It remains unclear whether these subjects should be treated. We here investigated the prevalence of anemia and iron deficiency in children with potential and mucosal atrophy celiac disease. The prospective study involved 19 children with potential disease, 67 with partial or subtotal villous atrophy (P/SVA), and 16 with total villous atrophy (TVA). Twenty-three healthy children comprised the control group. The groups were compared for various clinical, histological, and laboratory parameters and hepcidin. The prevalence of abnormal parameters was as follows (controls, potential celiac disease, P/SVA, and TVA, respectively): anemia 0%, 15%, 22%, and 63%; low iron 5%, 0%, 14%, and 50%; increased transferrin receptor 1 5%, 16%, 20%, and 47%; low ferritin 0%, 21%, 35%, and 87%; and low transferrin saturation 10%, 11%, 41%, and 71%. One subject had low folate and none had low vitamin B12. The median values for hemoglobin, total iron, ferritin, and transferrin saturation were significantly lower and transferrin receptor 1 values higher in TVA group compared with other groups. After a median of 7 months on a gluten-free diet hemoglobin, total iron, ferritin, and albumin in children with P/SVA exceeded the baseline values in the potential celiac disease group. The development of anemia and iron deficiency in celiac disease is a continuum and may already be present in children with normal villous morphology, advocating an early diagnosis and possible dietary treatment of these patients.

Hemochromatosis detection in a health screening program at an Alabama forest products mill.

PubMed

Barton, James C; Cheatwood, Susan M; Key, Timothy J; Acton, Ronald T

2002-08-01

We analyzed hemochromatosis detection in a 11.5-year multiphasic health screening program at a forest products mill. There were 2199 participants: 2032 Whites (1506 men, 526 women) and 167 African Americans (124 men, 43 women); 85.0% of employees were screened. Iron and transferrin saturation were measured in a serum biochemistry profile on specimens obtained after overnight fasting; ferritin was measured in participants with elevated iron concentrations or transferrin saturation > 48%. Participants with elevated ferritin levels underwent further evaluation. Eight White men were diagnosed to have hemochromatosis (frequency 0.0039 in Whites, 0.0053 in White men). The estimated cost per case detected was $8826. Family members of two participants with hemochromatosis were also diagnosed to have hemochromatosis or iron overload. We conclude that detecting hemochromatosis in a workplace multiphasic health screening program is efficacious and economical.

Circadian variations of transferrin saturation levels in iron-overloaded patients: implications for the screening of C282Y-linked haemochromatosis.

PubMed

Guillygomarc'h, Anne; Christian, Jacquelinet; Romain, Moirand; Vincent, Quentin; Véronique, David; Deugnier, Yves

2003-01-01

The phenotypic screening for genetic haemochromatosis (GH) relies upon the determination of transferrin saturation (TS). In large-scale screening programs, the time of blood sampling can be uneasy to control. We studied the circadian variations of TS at 08.00 hours, 12.00 hours, 18.00 hours and 00.00 hours in 46 C282Y homozygous patients (GH) and 47 non-GH patients (NH), to determine whether the time of blood sampling influenced the results of screening. In both groups, there were significant circadian variations in TS, with the highest values at 08.00 hours and the lowest at 00.00 hours. For any given time-point, TS was significantly higher in the GH group when compared with the NH group (P < 0.0001). For both groups, there was a significant decrease in TS between 08.00 hours and 00.00 hours (P < 0.0001) but this decrease was not as significant in GH when compared with NH patients (interaction P < 0.0073). Receiver operating characteristics (ROC) curves generated for TS at 08.00 hours, 12.00 hours, 18.00 hours and 00.00 hours, presented the same efficiency of diagnosis of GH, with TS threshold varying between 64% at 08.00 hours and 36% at 00.00 hours. In conclusion, for screening studies of C282Y homozygosity, determination of transferrin saturation may be performed at any time during the day.

Iron Indices in Bottlenose Dolphins (Tursiops truncatus)

PubMed Central

Mazzaro, Lisa M; Johnson, Shawn P; Fair, Patricia A; Bossart, Greg; Carlin, Kevin P; Jensen, Eric D; Smith, Cynthia R; Andrews, Gordon A; Chavey, Patricia S; Venn-Watson, Stephanie

2012-01-01

Bottlenose dolphins can have iron overload (that is, hemochromatosis), and managed populations of dolphins may be more susceptible to this disease than are wild dolphins. Serum iron, total iron-binding capacity (TIBC), transferrin saturation, and ferritin were measured in 181 samples from 141 dolphins in 2 managed collections and 2 free-ranging populations. Although no iron indices increased with age among free-ranging dolphins, ferritin increased with age in managed collections. Dolphins from managed collections had higher iron, ferritin, and transferrin saturation values than did free-ranging dolphins. Dolphins with high serum iron (exceeding 300 μg/dL) were more likely to have elevated ferritin but not ceruloplasmin or haptoglobin, demonstrating that high serum levels of iron are due to a true increase in total body iron. A time-series study of 4 dolphins with hemochromatosis that were treated with phlebotomy demonstrated significant decreases in serum ferritin, iron, and TIBC between pre- and posttreatment samples; transferrin saturation initially fell but returned to prephlebotomy levels by 6 mo after treatment. Compared with those in managed collections, wild dolphins were 15 times more likely to have low serum iron (100 μg/dL or less), and this measure was associated with lower haptoglobin. In conclusion, bottlenose dolphins in managed collections are more likely to have greater iron stores than are free-ranging dolphins. Determining why this situation occurs among some dolphin populations and not others may improve the treatment of hemochromatosis in dolphins and provide clues to causes of nonhereditary hemochromatosis in humans. PMID:23561885

Fabrication of a trimer/single atom tip for gas field ion sources by means of field evaporation without tip heating.

PubMed

Kim, Kwang-Il; Kim, Young Heon; Ogawa, Takashi; Choi, Suji; Cho, Boklae; Ahn, Sang Jung; Park, In-Yong

2018-05-11

A gas field ion source (GFIS) has many advantages that are suitable for ion microscope sources, such as high brightness and a small virtual source size, among others. In order to apply a tip-based GFIS to an ion microscope, it is better to create a trimer/single atom tip (TSAT), where the ion beam must be generated in several atoms of the tip apex. Here, unlike the conventional method which uses tip heating or a reactive gas, we show that the tip surface can be cleaned using only the field evaporation phenomenon and that the TSAT can also be fabricated using an insulating layer containing tungsten oxide, which remains after electrochemical etching. Using this method, we could get TSAT over 90% of yield. Copyright © 2018. Published by Elsevier B.V.

Relationship between rabbit transferrin electrophoretic patterns and plasma iron concentrations.

PubMed

Zaragoza, P; Arana, A; Amorena, B

1987-01-01

Rabbit transferrin (Tf) was studied electrophoretically using 1141 blood samples from individuals belonging to seven populations (Spanish Common, Spanish Giant, Butterfly, Lyoné de Bourgogne, New Zealand White, Californian and New Zealand White X Californian hybrids). No Tf polymorphism was found by starch gel electrophoresis, but six patterns, differing in the presence and/or intensity of three bands ('a', anodic; 'b', intermediate; and 'c', cathodic) were observed by polyacrylamide gel electrophoresis. No genetic model could explain these patterns, since they reflect differences in plasma Tf iron content. The electrophoretic test allowed a direct observation of the relative in vivo levels of the different Tf molecular species; saturated (band 'a', Fe2Tf); semi-saturated (band 'b', Fe1Tf); and without iron (band 'c' Fe0Tf, apotransferrin). The degree of iron saturation of Tf varied among individuals and throughout the individual's life. Specifically, in pregnant females, Fe2Tf and Fe1Tf are generally observed, except in late pregnancy (from day 25 to parturition), when mainly apotransferrin is observed. Significantly, within 24 h post-partum, high levels of Fe2Tf are reached in the female's serum.

Gallium uptake by transferrin and interaction with receptor 1.

PubMed

Chikh, Zohra; Ha-Duong, Nguyêt-Thanh; Miquel, Geneviève; El Hage Chahine, Jean-Michel

2007-01-01

The kinetics and thermodynamics of Ga(III) exchange between gallium mononitrilotriacetate and human serum transferrin as well as those of the interaction between gallium-loaded transferrin and the transferrin receptor 1 were investigated in neutral media. Gallium is exchanged between the chelate and the C-site of human serum apotransferrin in interaction with bicarbonate in about 50 s to yield an intermediate complex with an equilibrium constant K (1) = (3.9 +/- 1.2) x 10(-2), a direct second-order rate constant k (1) = 425 +/- 50 M(-1) s(-1) and a reverse second-order rate constant k (-1) = (1.1 +/- 3) x 10(4) M(-1) s(-1). The intermediate complex loses a single proton with proton dissociation constant K (1a) = 80 +/- 40 nM to yield a first kinetic product. This product then undergoes a modification in its conformation which lasts about 500 s to produce a second kinetic intermediate, which in turn undergoes a final extremely slow (several hours) modification in its conformation to yield the gallium-saturated transferrin in its final state. The mechanism of gallium uptake differs from that of iron and does not involve the same transitions in conformation reported during iron uptake. The interaction of gallium-loaded transferrin with the transferrin receptor occurs in a single very fast kinetic step with a dissociation constant K (d) = 1.10 +/- 0.12 microM and a second-order rate constant k (d) = (1.15 +/- 0.3) x 10(10) M(-1) s(-1). This mechanism is different from that observed with the ferric holotransferrin and suggests that the interaction between the receptor and gallium-loaded transferrin probably takes place on the helical domain of the receptor which is specific for the C-site of transferrin and HFE. The relevance of gallium incorporation by the transferrin receptor-mediated iron-acquisition pathway is discussed.

Non-transferrin bound iron: a key role in iron overload and iron toxicity.

PubMed

Brissot, Pierre; Ropert, Martine; Le Lan, Caroline; Loréal, Olivier

2012-03-01

Besides transferrin iron, which represents the normal form of circulating iron, non-transferrin bound iron (NTBI) has been identified in the plasma of patients with various pathological conditions in which transferrin saturation is significantly elevated. To show that: i) NTBI is present not only during chronic iron overload disorders (hemochromatosis, transfusional iron overload) but also in miscellaneous diseases which are not primarily iron overloaded conditions; ii) this iron species represents a potentially toxic iron form due to its high propensity to induce reactive oxygen species and is responsible for cellular damage not only at the plasma membrane level but also towards different intracellular organelles; iii) the NTBI concept may be expanded to include intracytosolic iron forms which are not linked to ferritin, the major storage protein which exerts, at the cellular level, the same type of protective effect towards the intracellular environment as transferrin in the plasma. Plasma NTBI and especially labile plasma iron determinations represent a new important biological tool since elimination of this toxic iron species is a major therapeutic goal. The NTBI approach represents an important mechanistic concept for explaining cellular iron excess and toxicity and provides new important biochemical diagnostic tools. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders. Copyright © 2011 Elsevier B.V. All rights reserved.

Serum levels of iron in Sør-Varanger, Northern Norway--an iron mining municipality.

PubMed

Broderstad, Ann R; Smith-Sivertsen, Tone; Dahl, Inger Marie S; Ingebretsen, Ole Christian; Lund, Eiliv

2006-12-01

The purpose of this study was to investigate iron status in a population with a high proportion of miners in the northernmost part of Norway. Cross-sectional, population-based study performed in order to investigate possible health effects of pollution in the population living on both sides of the Norwegian-Russian border. All individuals living in the community of Sør-Varanger were invited for screening in 1994. In 2000, blood samples from 2949 participants (response rate 66.8 %), age range 30-69 years, were defrosted. S-ferritin and transferrin saturation were analysed in samples from 1548 women and 1401 men. About 30 % (n = 893) were employed in the iron mining industry, 476 of whom were miners and 417 had other tasks in the company. Type and duration of employment and time since last day of work at the company were used as indicators of exposure. Both s-ferritin levels and transferrin saturation were higher in men than in women. S-ferritin increased with increasing age in women, while the opposite was true for men. Iron deficiency occurred with higher frequencies in women (16 %) than in men (4 %). Iron overload was uncommon in both sexes. Adjustment for smoking and self-reported pulmonary diseases did not show any effect on iron levels. Miners had non-significant higher mean s-ferritin and transferrin saturation than non-miners. Neither duration, nor time since employment in the mine, had any impact on iron status. Our analyses did not show any associations between being a miner in the iron mining industry and serum iron levels compared to the general population.

Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo

PubMed Central

Soe-Lin, Shan; Apte, Sameer S.; Andriopoulos, Billy; Andrews, Marc C.; Schranzhofer, Matthias; Kahawita, Tanya; Garcia-Santos, Daniel; Ponka, Prem

2009-01-01

Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells. We hypothesized that macrophage Nramp1 may participate in the recycling of iron acquired from phagocytosed senescent erythrocytes. To evaluate the role of Nramp1 in vivo, the iron parameters of WT and KO mice were analyzed after acute and chronic induction of hemolytic anemia. We found that untreated KO mice exhibited greater serum transferrin saturation and splenic iron content with higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression. Furthermore, hepatocyte iron content and hepcidin mRNA levels were dramatically lower in KO mice, indicating that hepcidin levels can be regulated by low-hepatocyte iron stores despite increased transferrin saturation. After acute treatment with the hemolytic agent phenylhydrazine (Phz), KO mice experienced a significant decrease in transferrin saturation and hematocrit, whereas WT mice were relatively unaffected. After a month-long Phz regimen, KO mice retained markedly increased quantities of iron within the liver and spleen and exhibited more pronounced splenomegaly and reticulocytosis than WT mice. After injection of 59Fe-labeled heat-damaged reticulocytes, KO animals accumulated erythrophagocytosed 59Fe within their liver and spleen, whereas WT animals efficiently recycled phagocytosed 59Fe to the marrow and erythrocytes. These data imply that without Nramp1, iron accumulates within the liver and spleen during erythrophagocytosis and hemolytic anemia, supporting our hypothesis that Nramp1 promotes efficient hemoglobin iron recycling in macrophages. Our observations suggest that mutations in Nramp1 could result in a novel form of human hereditary iron overload. PMID:19321419

Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo.

PubMed

Soe-Lin, Shan; Apte, Sameer S; Andriopoulos, Billy; Andrews, Marc C; Schranzhofer, Matthias; Kahawita, Tanya; Garcia-Santos, Daniel; Ponka, Prem

2009-04-07

Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells. We hypothesized that macrophage Nramp1 may participate in the recycling of iron acquired from phagocytosed senescent erythrocytes. To evaluate the role of Nramp1 in vivo, the iron parameters of WT and KO mice were analyzed after acute and chronic induction of hemolytic anemia. We found that untreated KO mice exhibited greater serum transferrin saturation and splenic iron content with higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression. Furthermore, hepatocyte iron content and hepcidin mRNA levels were dramatically lower in KO mice, indicating that hepcidin levels can be regulated by low-hepatocyte iron stores despite increased transferrin saturation. After acute treatment with the hemolytic agent phenylhydrazine (Phz), KO mice experienced a significant decrease in transferrin saturation and hematocrit, whereas WT mice were relatively unaffected. After a month-long Phz regimen, KO mice retained markedly increased quantities of iron within the liver and spleen and exhibited more pronounced splenomegaly and reticulocytosis than WT mice. After injection of (59)Fe-labeled heat-damaged reticulocytes, KO animals accumulated erythrophagocytosed (59)Fe within their liver and spleen, whereas WT animals efficiently recycled phagocytosed (59)Fe to the marrow and erythrocytes. These data imply that without Nramp1, iron accumulates within the liver and spleen during erythrophagocytosis and hemolytic anemia, supporting our hypothesis that Nramp1 promotes efficient hemoglobin iron recycling in macrophages. Our observations suggest that mutations in Nramp1 could result in a novel form of human hereditary iron overload.

Efficacy of a microencapsulated iron pyrophosphate-fortified fruit juice: a randomised, double-blind, placebo-controlled study in Spanish iron-deficient women.

PubMed

Blanco-Rojo, Ruth; Pérez-Granados, Ana M; Toxqui, Laura; González-Vizcayno, Carmen; Delgado, Marco A; Vaquero, M Pilar

2011-06-01

Fe-deficiency anaemia is a worldwide health problem. We studied the influence of consuming an Fe-fortified fruit juice on Fe status in menstruating women. A randomised, double-blind, placebo-controlled study of 16 weeks of duration was performed. Subjects were randomised into two groups: the P group (n 58) or the F group (n 64), and consumed, as a supplement to their usual diet, 500 ml/d of a placebo fruit juice or an Fe-fortified fruit juice, respectively. The Fe-fortified fruit juice, containing microencapsulated iron pyrophosphate, provided 18 mg Fe/d (100 % of the RDA). At baseline and monthly, dietary intake, body weight and Fe parameters were determined: total erythrocytes, haematocrit, mean corpuscular volume (MCV), red blood cell distribution width (RDW), Hb, serum Fe, serum ferritin, serum transferrin, transferrin saturation, soluble transferrin receptor (sTfR) and zinc protoporphyrin (ZnPP). The fruit juice consumption involved increased intake of carbohydrates and vitamin C, and increased BMI within normal limits. Ferritin was higher in the F group after week 4 (P < 0·05) and became 80 % higher than in the P group after week 16 (P < 0·001), and transferrin decreased in the F group compared with the P group after week 4 (P < 0·001). RDW was higher at weeks 4 and 8 in the F group compared with the P group (P < 0·05). Transferrin saturation increased after week 8, and haematocrit, MCV and Hb increased after week 12, in the F group compared with the P group. Serum Fe did not change. sTfR and ZnPP decreased in the F group at week 16 (P < 0·05). Iron pyrophosphate-fortified fruit juice improves Fe status and may be used to prevent Fe-deficiency anaemia.

Decreased Serum Hepcidin Concentration Correlates with Brain Iron Deposition in Patients with HBV-Related Cirrhosis

PubMed Central

Liu, Jian-Ying; He, Yi-Feng; Dai, Zhi; Chen, Cai-Zhong; Cheng, Wei-Zhong; Zhou, Jian; Wang, Xin

2013-01-01

Purpose Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. Methods Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. Results Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. Conclusions Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential. PMID:23776499

Evaluation of the bioactivity of recombinant human lactoferrins toward murine osteoblast-like cells for bone tissue engineering.

PubMed

Amini, Ashley A; Nair, Lakshmi S

2013-05-01

Lactoferrin (LF), which belongs to the iron-binding transferrin family, is an important regulator of the levels of free iron in the body fluids. LF has raised significant interest as a bioactive protein due to its wide array of physiological effects on many different cell types, including osteoblasts and osteoclasts. The glycoprotein's degree of iron saturation has a pivotal influence on its physical structure. The objective of this study is to investigate the biological effects of apo (low iron saturation), pis (partially iron saturated), and holo (high iron saturation) recombinant human LF (rhLF) on MC3T3-E1 cells to identify the suitable candidate for bone tissue engineering application. Our studies demonstrated a dose-dependent mitogenic response of MC3T3 to rhLF treatment irrespective of the iron concentration. Furthermore, rhLF induced the cells to produce transcription factors, chemokines, and cytokines as determined by β-catenin activation, phosphorylation of Akt, vascular endothelial growth factor, and interleukin (IL-6) expression. The iron saturation of rhLF did not have any significant effect on these biological activities of MC3T3 cells. In addition, the overall pattern of gene regulation in MC3T3-E1 cells upon rhLF treatment was followed by a global microarray analysis. Among the 45,200 genes tested, only 251 genes were found to be regulated by rhLFs of different iron concentrations. Of these, the transferrin receptor (Tfrc) was the only gene differentially regulated by the iron saturated and iron depleted (apo) rhLFs. In conclusion, the study demonstrated that rhLF is a bioactive protein and that the iron saturation of rhLF may not play a significant role in modulating osteoblast functions.

Impact of daily consumption of iron fortified ready-to-eat cereal and pumpkin seed kernels (Cucurbita pepo) on serum iron in adult women.

PubMed

Naghii, Mohammad Reza; Mofid, Mahmood

2007-01-01

Iron deficiency, anemia, is the most prevalent nutritional problem in the world today. The objective of this study was to consider the effectiveness of consumption of iron fortified ready-to-eat cereal and pumpkin seed kernels as two sources of dietary iron on status of iron nutrition and response of hematological characteristics of women at reproductive ages. Eight healthy female, single or non pregnant subjects, aged 20-37 y consumed 30 g of iron fortified ready-to-eat cereal (providing 7.1 mg iron/day) plus 30 g of pumpkin seed kernels (providing 4.0 mg iron/day) for four weeks. Blood samples collected on the day 20 of menstrual cycles before and after consumption and indices of iron status such as reticulocyte count, hemoglobin (Hb), hematocrit (Ht), serum ferritin, iron, total iron-binding capacity (TIBC), transferrin and transferrin saturation percent were determined. Better response for iron status was observed after consumption period. The statistical analysis showed a significant difference between the pre and post consumption phase for higher serum iron (60 +/- 22 vs. 85 +/- 23 ug/dl), higher transferrin saturation percent (16.8 +/- 8.0 vs. 25.6 +/- 9.0%), and lower TIBC (367 +/- 31 vs. 339 +/- 31 ug/dl). All individuals had higher serum iron after consumption. A significant positive correlation (r=0.981, p=0.000) between the differences in serum iron levels and differences in transferrin saturation percentages and a significant negative correlation (r=-0.916, p<0.001) between the differences in serum iron levels and differences in TIBC was found, as well. Fortified foods contribute to maintaining optimal nutritional status and minimizing the likelihood of iron insufficiencies and use of fortified ready-to-eat cereals is a common strategy. The results showed that adding another food source of iron such as pumpkin seed kernels improves the iron status. Additional and longer studies using these two food products are recommended to further determine the effect of iron fortification on iron nutrition and status among the target population, and mainly in young children, adolescents, women of reproductive ages and pregnant women.

Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients.

PubMed

Floege, Jürgen; Covic, Adrian C; Ketteler, Markus; Mann, Johannes F E; Rastogi, Anjay; Spinowitz, Bruce; Chong, Edward M F; Gaillard, Sylvain; Lisk, Laura J; Sprague, Stuart M

2015-06-01

Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study. In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0-3.0 g/day (2-6 tablets/day; n = 710) or sevelamer 2.4-14.4 g/day (3-18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study. Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n = 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean ± standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02 ± 0.52 mmol/L with sucroferric oxyhydroxide and 0.09 ± 0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13-1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for sucroferric oxyhydroxide (4.0 ± 1.5) versus sevelamer (10.1 ± 6.6). Patient adherence was 86.2% with sucroferric oxyhydroxide versus 76.9% with sevelamer. Mean serum ferritin concentrations increased over the extension study in both treatment groups, but transferrin saturation (TSAT), iron and hemoglobin concentrations were generally stable. Gastrointestinal-related adverse events were similar and occurred early with both treatments, but decreased over time. The serum phosphorus-lowering effect of sucroferric oxyhydroxide was maintained over 1 year and associated with a lower pill burden, compared with sevelamer. Sucroferric oxyhydroxide was generally well tolerated long-term and there was no evidence of iron accumulation. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.

Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non–transferrin-bound iron

PubMed Central

Brittenham, Gary M.; Billote, Genia B.; Francis, Richard O.; Ginzburg, Yelena Z.; Hendrickson, Jeanne E.; Jhang, Jeffrey; Schwartz, Joseph; Sharma, Shruti; Sheth, Sujit; Sireci, Anthony N.; Stephens, Hannah L.; Stotler, Brie A.; Wojczyk, Boguslaw S.; Zimring, James C.; Spitalnik, Steven L.

2011-01-01

Transfusions of RBCs stored for longer durations are associated with adverse effects in hospitalized patients. We prospectively studied 14 healthy human volunteers who donated standard leuko-reduced, double RBC units. One unit was autologously transfused “fresh” (3-7 days of storage), and the other “older” unit was transfused after 40 to 42 days of storage. Of the routine laboratory parameters measured at defined times surrounding transfusion, significant differences between fresh and older transfusions were only observed in iron parameters and markers of extravascular hemolysis. Compared with fresh RBCs, mean serum total bilirubin increased by 0.55 mg/dL at 4 hours after transfusion of older RBCs (P = .0003), without significant changes in haptoglobin or lactate dehydrogenase. In addition, only after the older transfusion, transferrin saturation increased progressively over 4 hours to a mean of 64%, and non–transferrin-bound iron appeared, reaching a mean of 3.2μM. The increased concentrations of non–transferrin-bound iron correlated with enhanced proliferation in vitro of a pathogenic strain of Escherichia coli (r = 0.94, P = .002). Therefore, circulating non–transferrin-bound iron derived from rapid clearance of transfused, older stored RBCs may enhance transfusion-related complications, such as infection. The trial was registered with www.clinicaltrials.gov as #NCT01319552. PMID:22021369

Binding of various ovotransferrin fragments to chick-embryo red cells.

PubMed Central

Oratore, A; D'Andrea, G; Moreton, K; Williams, J

1989-01-01

1. The ability of N- and C-terminal half-molecule fragments of hen ovotransferrin to interact with chick red blood cells (CERBC) has been studied under conditions that allow binding of the transferrin to transferrin receptors to take place, but not the delivery of iron to the cell. Two kinds of half-molecule fragments were used: (a) those which can associate with one another to give a dimer resembling native transferrin and (b) those which cannot associate in this way because they lack a few amino acid residues from their C-terminal ends. 2. Neither N nor C half-molecules alone can bind to the CERBC, but, when both are present, tight binding occurs. 3. Whether or not the half-molecules can associate with one another makes little difference to receptor binding. 4. Given that one of the half-molecules is iron-saturated, the presence or absence of iron in the contralateral half-molecule again makes little difference to receptor binding. PMID:2920021

Hemojuvelin: a supposed role in iron metabolism one year after its discovery.

PubMed

Celec, Peter

2005-07-01

The discovery of hemojuvelin and its association with juvenile hemochromatosis are important not only for the diagnostics of this rare severe disease but also for the understanding of the complex mechanism of iron metabolism regulation. Currently, the physiological role of hemojuvelin is obscure. Recent experimental and clinical studies indicate that hemojuvelin will probably be a regulator of hepcidin, similar to HFE and transferrin receptor 2. However, in contrast to transferrin receptor 2, which is relevant in the hepcidin response to changes in transferrin saturation, HFE and especially hemojuvelin seem to be involved in the inflammation-induced hepcidin expression. Hepcidin, generally accepted as a hormone targeting enterocytes and macrophages, decreases iron absorption from the intestinal lumen and iron release from phagocytes. This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease. Further basic and clinical research is needed to uncover the details of hemojuvelin pathophysiology required for potential pharmacological interventions.

Iron deficiency across chronic kidney disease stages: Is there a reverse gender pattern?

PubMed

Aoun, Mabel; Karam, Rita; Sleilaty, Ghassan; Antoun, Leony; Ammar, Walid

2018-01-01

In non-dialysis chronic kidney disease patients, looking for iron deficiency is highly variable in practice and there is a great variability regarding the cutoffs used to treat iron deficiency. The aim of this study is to investigate the degree of iron deficiency in non-dialysis chronic kidney disease patients on erythropoiesis-stimulating agents. We included all non-dialysis chronic kidney disease patients that applied to the Lebanese Ministry of Public Health for erythropoiesis-stimulating agents' coverage during a 5-month period. Iron requirement was assessed based on two guidelines' target-to-treat cutoffs: 1-ferritin <100 ng/ml and/or TSAT < 20% (KDOQI 2006), 2- ferritin ≤500 ng/ml and TSAT ≤30% (KDIGO 2012). A total of 238 CKD patients were included over 5 months. All patients had a ferritin level in their record and 64% had an available TSAT. Median age was 71.0 (59.8-79.3) years and 61.8% were female. All had an eGFR<60 ml/min. The proportion of patients found to require iron therapy ranged between 48 and 78% with a trend towards higher values when using KDIGO-based criteria. Using ANCOVA test, inverse normal transformations of ferritin and TSAT showed a reverse pattern between men and women with women being more iron deficient in the early stage. Iron deficiency is highly prevalent in non-dialysis chronic kidney disease patients on erythropoiesis-stimulating agents' therapy. These findings reflect a lack in effective iron supplementation when managing anemia in pre-dialysis patients, especially in men at advanced stages. Renal societies should spread awareness about iron deficiency screening in those patients.

Maternal iron status during pregnancy and respiratory and atopic outcomes in the offspring: a Mendelian randomisation study

PubMed Central

Bédard, Annabelle; Lewis, Sarah J; Burgess, Stephen; Henderson, A John; Shaheen, Seif O

2018-01-01

Introduction Limited evidence from birth cohort studies suggests that lower prenatal iron status may be a risk factor for childhood respiratory and atopic outcomes, but these observational findings may be confounded. Mendelian randomisation (MR) can potentially provide unconfounded estimates of causal effects by using common genetic variants as instrumental variables. We aimed to study the relationship between prenatal iron status and respiratory and atopic outcomes in the offspring using MR. Methods In the Avon Longitudinal Study of Parents and Children birth cohort, we constructed four maternal genotypic risk scores by summing the total number of risk alleles (associated with lower iron status) across single nucleotide polymorphisms known to be associated with at least one of four iron biomarkers (serum iron, ferritin, transferrin and transferrin saturation). We used MR to study their associations with respiratory and atopic outcomes in children aged 7–9 years (n=6002). Results When analyses were restricted to mothers without iron supplementation during late pregnancy, negative associations were found between the maternal transferrin saturation score and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age, height and gender-adjusted SD units per SD increase in genotypic score: −0.05 (−0.09, −0.01) p=0.03, and −0.04 (−0.08, 0.00) p=0.04, respectively). Conclusion Using MR we have found weak evidence suggesting that low maternal iron status during pregnancy may cause impaired childhood lung function. PMID:29636978

Indole 3-acetic acid, indoxyl sulfate and paracresyl-sulfate do not influence anemia parameters in hemodialysis patients.

PubMed

Bataille, Stanislas; Pelletier, Marion; Sallée, Marion; Berland, Yvon; McKay, Nathalie; Duval, Ariane; Gentile, Stéphanie; Mouelhi, Yosra; Brunet, Philippe; Burtey, Stéphane

2017-07-26

The main reason for anemia in renal failure patients is the insufficient erythropoietin production by the kidneys. Beside erythropoietin deficiency, in vitro studies have incriminated uremic toxins in the pathophysiology of anemia but clinical data are sparse. In order to assess if indole 3-acetic acid (IAA), indoxyl sulfate (IS), and paracresyl sulfate (PCS) -three protein bound uremic toxins- are clinically implicated in end-stage renal disease anemia we studied the correlation between IAA, IS and PCS plasmatic concentrations with hemoglobin and Erythropoietin Stimulating Agents (ESA) use in hemodialysis patients. Between June and July 2014, we conducted an observational cross sectional study in two hemodialysis center. Three statistical approaches were conducted. First, we compared patients treated with ESA and those not treated. Second, we performed linear regression models between IAA, IS, and PCS plasma concentrations and hemoglobin, the ESA dose over hemoglobin ratio (ESA/Hemoglobin) or the ESA resistance index (ERI). Third, we used a polytomous logistic regression model to compare groups of patients with no/low/high ESA dose and low/high hemoglobin statuses. Overall, 240 patients were included in the study. Mean age ± SD was 67.6 ± 16.0 years, 55.4% were men and 42.5% had diabetes mellitus. When compared with ESA treated patients, patients with no ESA had higher hemoglobin (mean 11.4 ± 1.1 versus 10.6 ± 1.2 g/dL; p <0.001), higher transferrin saturation (TSAT, 31.1 ± 16.3% versus 23.1 ± 11.5%; p < 0.001), less frequently an IV iron prescription (52.1 versus 65.7%, p = 0.04) and were more frequently treated with hemodiafiltration (53.5 versus 36.7%). In univariate analysis, IAA, IS or PCS plasma concentrations did not differ between the two groups. In the linear model, IAA plasma concentration was not associated with hemoglobin, but was negatively associated with ESA/Hb (p = 0.02; R = 0.18) and with the ERI (p = 0.03; R = 0.17). IS was associated with none of the three anemia parameters. PCS was positively associated with hemoglobin (p = 0.03; R = 0.14), but negatively with ESA/Hb (p = 0.03; R = 0.17) and the ERI (p = 0.02; R = 0.19). In multivariate analysis, the association of IAA concentration with ESA/Hb or ERI was not statistically significant, neither was the association of PCS with ESA/Hb or ERI. Identically, in the subgroup of 76 patients with no inflammation (CRP <5 mg/L) and no iron deficiency (TSAT >20%) linear regression between IAA, IS or PCS and any anemia parameter did not reach significance. In the third model, univariate analysis showed no intergroup significant differences for IAA and IS. Regarding PCS, the Low Hb/High ESA group had lower concentrations. However, when we compared PCS with the other significant characteristics of the five groups to the Low Hb/high ESA (our reference group), the polytomous logistic regression model didn't show any significant difference for PCS. In our study, using three different statistical models, we were unable to show any correlation between IAA, IS and PCS plasmatic concentrations and any anemia parameter in hemodialysis patients. Indolic uremic toxins and PCS have no or a very low effect on anemia parameters.

Anaemia management protocols in the care of haemodialysis patients: examining patient outcomes.

PubMed

Saunders, Sushila; MacLeod, Martha L P; Salyers, Vince; MacMillan, Peter D; Ogborn, Malcolm R

2013-08-01

To determine whether the use of a nurse-driven protocol in the haemodialysis setting is as safe and effective as traditional physician-driven approaches to anaemia management. The role of haemodialysis nurses in renal anaemia management has evolved through the implementation of nurse-driven protocols, addressing the trend of exceeding haemoglobin targets and rising costs of erythropoietin-stimulating agents. Retrospective, non-equivalent case control group design. The sample was from three haemodialysis units in a control group (n = 64) and three haemodialysis units in a protocol group (n = 43). The protocol group used a nurse-driven renal anaemia management protocol, while the control group used a traditional physician-driven approach to renal anaemia management. All retrospective data were obtained from a provincial renal database. Data were analysed using chi-square tests and t-tests. Patient outcomes examined were haemoglobin levels, transferrin saturation levels, erythropoietin-stimulating agents use and intravenous iron use. Cost comparisons were determined using average use of erythropoietin-stimulating agents and intravenous iron. Control and protocol groups reached haemoglobin target levels. In the protocol group, 75% reached transferrin saturation target levels in comparison with 25% of the control group. Use and costs for iron was higher in the control group, while use and costs for erythropoietin was higher in the protocol group. The higher usage of erythropoietin-stimulating agents was potentially related to comorbid conditions amongst the protocol group. A nurse-driven protocol approach to renal anaemia management was as effective as the physician-driven approach in reaching haemoglobin and transferrin saturation levels. Further examination of the use and dosing of erythropoietin-stimulating agents and intravenous iron, their impact on haemoglobin levels related to patient comorbidities and subsequent cost effectiveness of protocols is required. Using a nurse-driven protocol in practice supports the independent nursing role while contributing to safe patient outcomes. © 2013 Blackwell Publishing Ltd.

Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis

PubMed Central

Sika, Mohammed; Koury, Mark J.; Chuang, Peale; Schulman, Gerald; Smith, Mark T.; Whittier, Frederick C.; Linfert, Douglas R.; Galphin, Claude M.; Athreya, Balaji P.; Nossuli, A. Kaldun Kaldun; Chang, Ingrid J.; Blumenthal, Samuel S.; Manley, John; Zeig, Steven; Kant, Kotagal S.; Olivero, Juan Jose; Greene, Tom; Dwyer, Jamie P.

2015-01-01

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of −2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin. PMID:25060056

Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition.

PubMed

Sheokand, Navdeep; Kumar, Santosh; Malhotra, Himanshu; Tillu, Vikas; Raje, Chaaya Iyengar; Raje, Manoj

2013-06-01

The long held view is that mammalian cells obtain transferrin (Tf) bound iron utilizing specialized membrane anchored receptors. Here we report that, during increased iron demand, cells secrete the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which enhances cellular uptake of Tf and iron. These observations could be mimicked by utilizing purified GAPDH injected into mice as well as when supplemented in culture medium of model cell lines and primary cell types that play a key role in iron metabolism. Transferrin and iron delivery was evaluated by biochemical, biophysical and imaging based assays. This mode of iron uptake is a saturable, energy dependent pathway, utilizing raft as well as non-raft domains of the cell membrane and also involves the membrane protein CD87 (uPAR). Tf internalized by this mode is also catabolized. Our research demonstrates that, even in cell types that express the known surface receptor based mechanism for transferrin uptake, more transferrin is delivered by this route which represents a hidden dimension of iron homeostasis. Iron is an essential trace metal for practically all living organisms however its acquisition presents major challenges. The current paradigm is that living organisms have developed well orchestrated and evolved mechanisms involving iron carrier molecules and their specific receptors to regulate its absorption, transport, storage and mobilization. Our research uncovers a hidden and primitive pathway of bulk iron trafficking involving a secreted receptor that is a multifunctional glycolytic enzyme that has implications in pathological conditions such as infectious diseases and cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

Hepcidin Response to Iron Therapy in Patients with Non-Dialysis Dependent CKD: An Analysis of the FIND-CKD Trial.

PubMed

Gaillard, Carlo A; Bock, Andreas H; Carrera, Fernando; Eckardt, Kai-Uwe; Van Wyck, David B; Bansal, Sukhvinder S; Cronin, Maureen; Meier, Yvonne; Larroque, Sylvain; Roger, Simon D; Macdougall, Iain C

2016-01-01

Hepcidin is the key regulator of iron homeostasis but data are limited regarding its temporal response to iron therapy, and response to intravenous versus oral iron. In the 56-week, open-label, multicenter, prospective, randomized FIND-CKD study, 626 anemic patients with non-dialysis dependent chronic kidney disease (ND-CKD) and iron deficiency not receiving an erythropoiesis stimulating agent were randomized (1:1:2) to intravenous ferric carboxymaltose (FCM), targeting higher (400-600μg/L) or lower (100-200μg/L) ferritin, or to oral iron. Serum hepcidin levels were measured centrally in a subset of 61 patients. Mean (SD) baseline hepcidin level was 4.0(3.5), 7.3(6.4) and 6.5(5.6) ng/mL in the high ferritin FCM (n = 17), low ferritin FCM (n = 16) and oral iron group (n = 28). The mean (SD) endpoint value (i.e. the last post-baseline value) was 26.0(9.1),15.7(7.7) and 16.3(11.0) ng/mL, respectively. The increase in hepcidin from baseline was significantly smaller with low ferritin FCM or oral iron vs high ferritin FCM at all time points up to week 52. Significant correlations were found between absolute hepcidin and ferritin values (r = 0.65, p<0.001) and between final post-baseline increases in both parameters (r = 0.70, p<0.001). The increase in hepcidin levels over the 12-month study generally mirrored the cumulative iron dose in each group. Hepcidin and transferrin saturation (TSAT) absolute values showed no correlation, although there was an association between final post-baseline increases (r = 0.42, p<0.001). Absolute values (r = 0.36, p = 0.004) and final post-baseline increases of hepcidin and hemoglobin (p = 0.30, p = 0.030) correlated weakly. Baseline hepcidin levels were not predictive of a hematopoietic response to iron therapy. In conclusion, hepcidin levels rose in response to either intravenous or oral iron therapy, but the speed and extent of the rise was greatest with intravenous iron targeting a higher ferritin level. However neither the baseline level nor the change in hepcidin was able to predict response to therapy in this cohort.

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production.

PubMed

Desgrippes, Romain; Lainé, Fabrice; Morcet, Jeff; Perrin, Michèle; Manet, Ghislain; Jezequel, Caroline; Bardou-Jacquet, Edouard; Ropert, Martine; Deugnier, Yves

2013-05-01

An excess of visceral adipose tissue could be involved as a modulator of the penetrance of HFE hemochromatosis since fat mass is associated with overexpression of hepcidin and low transferrin saturation was found to be associated with being overweight in women. This study was aimed at assessing the relationship between body mass index (BMI), a surrogate marker of insulin resistance, and iron burden in HFE hemochromatosis. In all, 877 patients from a cohort of C282Y homozygotes were included in the study when BMI at diagnosis and amount of iron removed (AIR) by phlebotomy were available. No relationship between AIR and BMI was found in men, whereas 15.1% (52/345) of women with AIR <6 g had BMI ≥28 versus 3.9% (2/51) of women with AIR ≥6 g (P = 0.03). At multivariate analysis, BMI was an independent factor negatively associated with AIR (odds ratio: 0.13; 95% confidence interval [CI]: 0.03-0.71) together with serum ferritin, serum transferrin, transferrin saturation, hemoglobin, and alanine aminotransferase. In a control group of 30 C282Y homozygous women, serum hepcidin was significantly higher in overweight (14.3 mmoL/L ± 7.1) than in lean (7.9 mmoL/L ± 4.3) women (P = 0.0005). In C282Y homozygous women, BMI ≥28 kg/m(2) is independently associated with a lower amount of iron removed by phlebotomy. BMI is likely a modulator factor of the phenotypic expression of C282Y homozygosity, likely through an increase of circulating levels of hepcidin. Copyright © 2013 American Association for the Study of Liver Diseases.

Stiffened yeast telomerase RNA supports RNP function in vitro and in vivo

PubMed Central

Lebo, Kevin J.; Zappulla, David C.

2012-01-01

The 1157-nt Saccharomyces cerevisiae telomerase RNA, TLC1, in addition to providing a 16-nt template region for reverse transcription, has been proposed to act as a scaffold for protein subunits. Although accessory subunits of the telomerase ribonucleoprotein (RNP) complex function even when their binding sites are relocated on the yeast telomerase RNA, the physical nature of the RNA scaffold has not been directly analyzed. Here we explore the structure–function organization of the yeast telomerase RNP by extensively stiffening the three long arms of TLC1, which connect essential and important accessory protein subunits Ku, Est1, and Sm7, to its central catalytic hub. This 956-nt triple-stiff-arm TLC1 (TSA-T) reconstitutes active telomerase with TERT (Est2) in vitro. Furthermore, TSA-T functions in vivo, even maintaining longer telomeres than TLC1 on a per RNA basis. We also tested functional contributions of each stiffened arm within TSA-T and found that the stiffened Est1 and Ku arms contribute to telomere lengthening, while stiffening the terminal arm reduces telomere length and telomerase RNA abundance. The fact that yeast telomerase tolerates significant stiffening of its RNA subunit in vivo advances our understanding of the architectural and functional organization of this RNP and, more broadly, our conception of the world of lncRNPs. PMID:22850424

Iron Status of Pregnant Women in Rural and Urban Communities of Cross River State, South-South Nigeria.

PubMed

Okafor, I M; Okpokam, D C; Antai, A B; Usanga, E A

2017-03-06

Anaemia in pregnancy is a major public health problem in Nigeria. Iron deficiency is one of the major causes of anaemia in pregnancy.  Inadequate iron intake during pregnancy can be dangerous to both baby and mother. Iron status of pregnant women was assessed in two rural and one urban communities in Cross River State Nigeria. Packed cell volume, haemoglobin, mean cell haemoglobin, mean cell haemoglobin concentration, red cell count, serum iron, total iron binding capacity, transferrin saturation, serum ferritin, soluble transferrin receptor and soluble transferrin receptor/ferritin ratio were measured in plasma/serum of 170 pregnant women within the age range of 15-45 years. Seventy participants were from antenatal clinic of University of Calabar Teaching Hospital Calabar (urban community), 50 from St Joseph Hospital Ikot Ene (rural community) in Akpabuyo Local Government Area and the remaining 50 from University of Calabar Teaching Hospital   extension clinic in Okoyong (rural community), Odukpani Local Government Area of Cross River state. The prevalence of   anaemia, iron deficiency, iron depletion and iron deficiency anaemia were found to be significantly higher among pregnant women from the two rural communities when compared to the urban community. it was also observed that  the prevalence of  anaemia, iron deficiency, iron depletion and iron deficiency anaemia   were significantly higher (p<0.05) among pregnant women from Akpabuyo   38(76.00%),   20(40.00%),   23(46.0%)   ,   16(32.00%)   respectively followed   by  Okoyong 24(48.0%),  20(40.0%),  16(32.0%),  6(12.0)     and  then  those  from     Calabar  14(20%), 12(17.90%) , 14(20.0%).  The mean haemoglobin and haematocrit were significantly reduced in pregnant women from the two rural communities. Serum iron, serum ferritin and transferrin saturation showed no significant difference while total iron binding capacity and soluble transferrin receptor significantly increased among pregnant women from Okoyong when compared to those from Calabar. It was also shown that pregnant women in their third trimesters and multigravidae had the highest prevalence of iron depletion and iron deficiency anaemia while prevalence of iron deficiency and anaemia were higher in primigravidae and the pregnant women in their second trimester. In conclusion, this study has shown that the prevalence of anaemia and iron deficiency anaemia are higher among pregnant women in the rural communities when compared to those in the urban areas.

Non-HFE iron overload as a surrogate marker of disease severity in patients of liver cirrhosis.

PubMed

Noor, Mohd Talha; Tiwari, Manish; Kumar, Ravindra

2016-01-01

Decompensated liver cirrhosis is an important cause of mortality worldwide. Various modifiable and non-modifiable factors are involved in the pathogenesis of cirrhosis and its complications. This study was aimed to evaluate the association of iron overload and disease severity in patients of liver cirrhosis and its association with HFE gene mutation. Forty-nine patients with decompensated liver cirrhosis were recruited. Clinical and laboratory parameters were compared in patients with and without iron overload. C282Y and H63D gene mutation analysis was performed in all patients with iron overload. Iron overload was found in 20 (40.82%) patients. A significant positive correlation of transferrin saturation with Child-Turcotte-Pugh (CTP) score (r = 0.705, p < 0.001) and model for end-stage liver disease (MELD) score (r = 0.668, p < 0.001) was found. Transferrin saturation was also independently associated with high CTP and MELD score on multivariate analysis. Mortality over 3 months was significantly more common in iron-overloaded patients (p = 0.028). C282Y homozygosity or C282Y/H63D compound heterozygosity was not found in any of the patients with iron overload. Iron overload was significantly associated with disease severity and reduced survival in patients of decompensated liver cirrhosis.

Late magmatic stage of the zoned Caleu pluton (Central Chile): insights from zircon crystallization conditions

NASA Astrophysics Data System (ADS)

Molina, P. G.; Parada, M.; Gutierrez, F. J.; Chang-Qiang, M.; Jianwei, L.; Yuanyuan, L.

2012-12-01

The Caleu pluton consists of three N-S elongated lithological zones: Gabbro-Diorite Zone (GDZ), Tonalite Zone (TZ) and Granodiorite Zone (GZ); western, middle and eastern portions of the pluton, respectively. The zones are thought to be previously differentiated in a common, isotopically depleted (Sr-Nd), subjacent magma reservoir at a 4 kbar equivalent depth. The emplacement should have occurred at the climax of the Cretaceous rifting. We present preliminary results of U238/Pb206 zircon geochronology; zircon saturation, Tsat(Zrn), and crystallization temperatures (Ti-in-Zrn); as well as relative oxidation states at time of crystallization, based on: (i) the sluggish REE and HFSE subsolidus diffusivities in zircon; (ii) the behavior of Ti4+↔Si4+ and Ce4+↔Zr4+ isovalent replacement, in addition to a constrained TiO2 activity in almost all typical crustal rocks; and (iii) relative oxidation states at time of crystallization, respectively. The latter are obtained by interpolation of the partition coefficients of trivalent (REE) and tetravalent (HFSE) curves in Onuma diagrams for each zircon, and then estimating relative Ce(IV)/Ce(III) ratios. Results obtained from 4 samples (a total of 77 zircon grains) collected from the three mentioned lithological zones indicate U/Pb ages of approximately 99.5 ±1.5 Ma, 96.8 ±0.6 Ma, and 94.4 +2.2 -0.8 Ma; and Ti-in Zrn ranges of ca. 720-870°C, ca. 680-820°C and ca. 750-840°C, for the GDZ, TZ and GZ samples, respectively. On the other hand Tsat(Zrn) of ca. 750-780°C in the TZ, and ca. 830-890°C in the GZ, were obtained. As expected saturation temperatures are similar or higher than Ti-in-Zrn obtained in zircon grains of TZ and GZ, respectively. Cathodoluminiscence images in zircon suggest a magmatic origin, due to absence of complex zoning patterns and fairly well conserved morphologies. Exceptionally the GDZ sample zircons show evidence of inheritance, indicating a xenocrystic and/or antecrystic origin. A relative Ce(IV)/Ce(III) decrease with temperature gives rise to separate trends for each zone, suggesting an independent unbuffered development at time of zircon formation. Taking into account variations in zircon ages, morphologies and crystallization ranges in the collected samples, it is suggested that zircon crystallization took place independent of the magma composition. Furthermore, old inherited zircon grains in the GDZ could be antecrysts, or products of a restricted and not major host rock assimilation, owing to the impossibility of basaltic magmas to saturate zircon crystals, and the isotopically depleted signature. This study is financed by CONICYT-FONDAP grant 15090013, Centro de Excelencia en Geotermia de los Andes (CEGA); and the CONICYT PBCT-PDA07, Programa Bicentenario de Ciencia y Tecnología.

Glutamate-Mediated Primary Somatosensory Cortex Excitability Correlated with Circulating Copper and Ceruloplasmin

PubMed Central

Tecchio, Franca; Assenza, Giovanni; Zappasodi, Filippo; Mariani, Stefania; Salustri, Carlo; Squitti, Rosanna

2011-01-01

Objective. To verify whether markers of metal homeostasis are related to a magnetoencephalographic index representative of glutamate-mediated excitability of the primary somatosensory cortex. The index is identified as the source strength of the earliest component (M20) of the somatosensory magnetic fields (SEFs) evoked by right median nerve stimulation at wrist. Method. Thirty healthy right-handed subjects (51 ± 22 years) were enrolled in the study. A source reconstruction algorithm was applied to assess the amount of synchronously activated neurons subtending the M20 and the following SEF component (M30), which is generated by two independent contributions of gabaergic and glutamatergic transmission. Serum copper, ceruloplasmin, iron, transferrin, transferrin saturation, and zinc levels were measured. Results. Total copper and ceruloplasmin negatively correlated with the M20 source strength. Conclusion. This pilot study suggests that higher level of body copper reserve, as marked by ceruloplasmin variations, parallels lower cortical glutamatergic responsiveness. PMID:22145081

Comparisons of vegetarian and beef-containing diets on hematological indexes and iron stores during a period of resistive training in older men

PubMed Central

Wells, Amanda M.; Haub, Mark D.; Fluckey, James; Williams, D. Keith; Chernoff, Ronni; Campbell, Wayne W.

2008-01-01

Objective To test the hypothesis that older men who consumed a vegetarian (lacto-ovo) diet would develop a lower iron status compared with older men who consumed a beef-containing diet during a period of resistive training (RT). Design Experimental, repeated measures study. Subjects Twenty-one healthy men aged 59 to 78 years, with a BMI range of 24 to 33 kg/m2, completed the study. Intervention All men consumed a vegetarian diet for 2 weeks (baseline). After this, the men were randomly assigned to one of two dietary groups. Eleven men consumed a beef-containing diet, and 10 men continued to consume a vegetarian diet for 12 weeks. During this time all subjects participated in RT three days per week, designated as RT1 to RT12. Main outcome measures Serum ferritin and serum iron concentrations, transferrin saturation, transferrin receptor, total iron binding capacity, and selected hematological variables, as well as selected nutrient intakes and estimated iron bioavailability from three-day diet records, were determined at baseline, RT5, and RT12. Statistical analyses A general linear model repeated-measures ANOVA was used to examine the effects of group, time, and group×time interactions for iron status and dietary data. Results Total iron intake was not different between the two groups; however, the beef group had a three to four times greater intake of bioavailable iron (P<.01) than the vegetarian group. Serum iron, total iron binding capacity, transferrin saturation, and transferrin receptor were not significantly different between the beef and vegetarian groups, or changed over time with RT. Serum ferritin decreased over time in both the beef and vegetarian groups during RT (P<.01). Re-introduction of beef into the diets of the beef group increased hemoglobin concentration and hematocrit compared with the vegetarian group during the 12 weeks of RT (group×time, P<.05). These changes were within clinically normal limits. Applications/Conclusions Older men who consume a beef-containing, higher-bioavailable-iron diet, compared with a vegetarian, lower-bioavailable-iron diet, have an increased hematological profile during a 12-week period of RT. Older men who consume either a beef-containing or a vegetarian diet maintain a hematological profile within clinically normal limits during 12 weeks of RT. PMID:12728219

Iron deficiency anaemia.

PubMed

Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

2016-02-27

Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Novel Approach to Improving Utilization of Laboratory Testing.

PubMed

Zhou, Yaolin; Procop, Gary W; Riley, Jacquelyn D

2018-02-01

- The incorporation of best practice guidelines into one's institution is a challenging goal of utilization management, and the successful adoption of such guidelines depends on institutional context. Laboratorians who have access to key clinical data are well positioned to understand existing local practices and promote more appropriate laboratory testing. - To apply a novel approach to utilization management by reviewing international clinical guidelines and current institutional practices to create a reliable mechanism to improve detection and reduce unnecessary tests in our patient population. - We targeted a frequently ordered genetic test for HFE-related hereditary hemochromatosis, a disorder of low penetrance. After reviewing international practice guidelines, we evaluated 918 HFE tests and found that all patients with new diagnoses had transferrin saturation levels that were significantly higher than those of patients with nonrisk genotypes (72% versus 42%; P < .001). - Our "one-button" order that restricts HFE genetic tests to patients with transferrin saturation greater than 45% is consistent with published practice guidelines and detected 100% of new patients with HFE-related hereditary hemochromatosis. - Our proposed algorithm differs from previously published approaches in that it incorporates both clinical practice guidelines and local physician practices, yet requires no additional hands-on effort from pathologists or clinicians. This novel approach to utilization management embraces the role of pathologists as leaders in promoting high-quality patient care in local health care systems.

The significance of folic acid, tissue iron stores, and tissue viability in determining iron uptake from serum by thyroid tissue slices

PubMed Central

Buchanan, W. M.

1971-01-01

This paper describes an attempt to measure in vitro iron uptake from serum by human thyroid slices and to relate the uptake to tissue iron stores, folic acid status, and tissue viability. It is an extension of work previously reported (Buchanan, 1969). Thyroids were obtained from patients undergoing partial thyroidectomy for colloid goitre and serum from clinically normal healthy adults. The haemoglobin, serum iron, and folic acid levels of both thyroid and serum donors were measured and thyroids examined histologically for the presence of stainable iron. Viable and non-viable tissue slices were incubated in sera treated with radioactive iron so as to produce high and normal levels of transferrin saturation. Iron was taken up both from sera with normal and high transferrin saturation but the amount was, in almost all cases, greater from the more highly saturated. The uptake by non-viable tissue was appreciable but did not vary to any great extent from one serum to the next, and was attributed to simple diffusion of ionic iron into the tissue. There was, however, marked variation in uptake from different sera by viable tissue. It was concluded therefore that viability is a factor affecting the uptake. As the variation in uptake by viable tissue incubated in a single serum was significantly less than tissue incubated in a number of different sera it was further concluded that there was also a factor in the serum itself affecting iron uptake. The nature of the factor was not elucidated but neither folic acid nor levels of iron stores appeared to influence uptake because no correlation was found between iron uptake and iron stores or folic acid. Images PMID:5556118

Anatomy of an ancient subduction interface at 40 km depth: Insights from P-T-t-d data, and geodynamic implications (Dent Blanche, Western Alps)

NASA Astrophysics Data System (ADS)

Angiboust, Samuel; Glodny, Johannes; Oncken, Onno; Chopin, Christian

2014-05-01

An exhumed metamorphic suture zone over 40 km long is exposed in the Dent Blanche Region of the Western Alps belt, along the Swiss-Italian border. In this region, the metasediment-bearing ophiolitic remnants of the Liguro-Piemontese ocean (Tsaté complex) are overthrusted by a continental, km-sized complex (Dent Blanche Tectonic System: DBTS) of Austro-Alpine affinity. The DBTS represents a strongly deformed composite terrane with independent tectonic slices of continental and oceanic origin. In order to better understand the nature and the geodynamic meaning of the shear zone at the base of the DBTS (Dent Blanche Thrust, DBT) we re-evaluated the pressure-temperature-time-deformation (P-T-t-d) history of these two units using modern thermobarometric tools, Rb/Sr deformation ages and field relationships. Our results show that the Tsaté complex is formed by a stack of km-thick calcschists-bearing tectonic slices, having experienced variable maximum burial temperatures of between 360°C and 490°C at depths of ca. 25-40 km, between 41 Ma and 37 Ma. The Arolla gneissic mylonites constituting the base of the DBTS experienced a continuous record of protracted high-pressure (12-14 kbar), top-to-NW D1 deformation at 450-500°C between 43 and 55 Ma. Some of these primary, peak metamorphic fabrics have been sheared (top-to-SE D2) and backfolded during exhumation and collisional overprint (20 km depth, 35-40 Ma) leading to the regional greenschist facies retrogression particularly prominent within Tsaté metasediments. The final juxtaposition of the DBTS with the Tsaté complex occurred between 350 and 500°C during this later, exhumation-related D2 event. Although some exhumation-related deformation partially reworked D1 primary features, we emphasize that the DBT can be viewed as a remnant of the Alpine early Eocene blueschist-facies subduction interface region. The DBT therefore constitutes the deeper equivalent of some shallower portions of the Alpine subduction interface exposed 200 km eastwards in eastern Switzerland (e.g. Bachmann et al., 2009). Our results shed light on deep (25-45 km) subduction zone structures and dynamics and are therefore of major interest for geophysical studies imaging the plate interface region in active subduction zones.

Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency.

PubMed

Ponikowski, Piotr; van Veldhuisen, Dirk J; Comin-Colet, Josep; Ertl, Georg; Komajda, Michel; Mareev, Viacheslav; McDonagh, Theresa A; Parkhomenko, Alexander; Tavazzi, Luigi; Levesque, Victoria; Mori, Claudio; Roubert, Bernard; Filippatos, Gerasimos; Ruschitzka, Frank; Anker, Stefan D

2014-09-01

Iron deficiency (ID) is a common co-morbidity associated with chronic heart failure (CHF), which has unfavourable clinical and prognostic consequences. In Ferinject Assessment in Patients with IRon Deficiency and Chronic Heart Failure (FAIR-HF), the treatment with i.v. ferric carboxymaltose (FCM) improved symptoms and quality of life over a 24 week period. Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) was designed to test a simplifieddosage scheme of FCM during a longer follow-up period. CONFIRM-HF, a double-blind, multi-centre, prospective, randomized, two-arm study, enrolled ambulatory patients with symptomatic CHF [New York Heart Association (NYHA) class II/III] with left ventricular ejection fraction ≤45%, BNP >100 pg/mL, or NT-proBNP >400 pg/mL, presence of ID [defined as ferritin <100 ng/mL, or ferritin 100-300 ng/mL if transferrin saturation (TSAT) <20%], and haemoglobin (Hb) <15 g/dL. Patients were randomized 1:1 to treatment with FCM or placebo for 52 weeks. Primary endpoint is change in 6-minute walk test (6MWT) distance from baseline to Week 24. Secondary endpoints are: change in 6MWT from baseline to Weeks 6, 12, 36, and 52; Patient Global Assessment score at Weeks 6, 12, 24, 36, and 52; and change from baseline to Weeks 6, 12, 24, 36, and 52 in NYHA class, fatigue score, and quality of life. Safety endpoints include overall safety over the treatment period of 52 weeks. Study medication was administered in single doses as undiluted bolus injection of up to 1000 mg of iron or normal saline at Day 0 and Week 6 up to iron repletion. Further doses of study medication could be administered at Weeks 12, 24, and 36 if a patient still had ID. Overall, 304 patients were recruited in 41 centres in nine countries. This study will provide further information on the efficacy and safety of iron therapy with i.v. FCM in CHF patients with ID over a 1 year period using a simplified dosing scheme. © 2014 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Can soluble transferrin receptor be used in diagnosing iron deficiency anemia and assessing iron response in infants with moderate acute malnutrition?

PubMed

Büyükkaragöz, Bahar; Akgun, Necat A; Bulus, Ayse D; Durmus Aydogdu, Sultan; Bal, Cengiz

2017-04-01

To evaluate the efficacy of soluble transferrin receptor (sTfR) in diagnosing iron deficiency anemia (IDA) and evaluating iron response in infants with moderate acute malnutrition (MAM). Infants with hemoglobin (Hb) levels lower than threshold values for anemia for their ages and hypochromic/ microcytic anemia on peripheral smear were recruited. MAM was defined as weight/height z score < -2 to -3. Complete blood count (CBC), iron parameters and sTfR were compared among 41 infants with MAM and anemia (MA group), 32 infants with anemia without MAM (group A), and healthy controls (n= 30). Following anemia and malnutrition treatment, tests were repeated. Besides hematological indices compatible with IDA, serum iron (Fe) and transferrin saturation (TS) were significantly lower, while transferrin was significantly higher in MA and A groups compared to controls (p <0.001). Ferritin and C-reactive protein (CRP) were significantly higher in MA group (p <0.05 ferritin, p 0.01 for CRP). Mean sTfR was similar in both MA and A groups (p >0.05) and significantly higher than controls (p <0.001). Following iron treatment, sTfR decreased in both MA and A groups (p <0.001) to similar values as controls. sTfR was negatively correlated to Hb throughout the study (for MA group, r= -0.350, p <0.05; for A group, r= -0.683, p <0.01). As sTfR values in both MA and A groups decreased following iron treatment, we believe that this parameter was not influenced by MAM or inflammation; and it alone can be used to detect IDA and monitor treatment response in infants with MAM.

Iron metabolism and oxidative profile of dogs naturally infected by Ehrlichia canis: Acute and subclinical disease.

PubMed

Bottari, Nathieli B; Crivellenti, Leandro Z; Borin-Crivellenti, Sofia; Oliveira, Jéssica R; Coelho, Stefanie B; Contin, Catarina M; Tatsch, Etiane; Moresco, Rafael N; Santana, Aureo E; Tonin, Alexandre A; Tinucci-Costa, Mirela; Da Silva, Aleksandro S

2016-03-01

The aim of this study was to evaluate the oxidant profile and iron metabolism in serum of dogs infected by Ehrlichia canis. Banked sera samples of dogs were divided into two groups: negative control (n = 17) and infected by E. canis on acute (n = 24), and subclinical (n = 18) phases of the disease. The eritrogram, leucogram, and platelet counts were evaluate as well as iron, ferritin, and transferrin levels, latent iron binding capacity (LIBC), and transferrin saturation index (TSI) concentration. In addition, the advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP) in sera were also analyzed. Blood samples were examined for the presence of E. canis by PCR techniques. History and clinical signals were recorded for each dog. During the acute phase of the disease, infected animals showed thrombocytopenia and anemia when compared to healthy animals (P < 0.05) as a consequence of lower iron levels. Ferritin and transferrin levels were higher in both phases (acute and subclinical) of the disease. The AOPP and FRAP levels increased in infected animals on the acute phase; however, the opposite occurred in the subclinical phase. We concluded that dogs naturally infected by E. canis showed changes in the iron metabolism and developed an oxidant status in consequence of disease pathophysiology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modeling Droplet Heat and Mass Transfer during Spray Bar Pressure Control of the Multipurpose Hydrogen Test Bed (MHTB) Tank in Normal Gravity

NASA Technical Reports Server (NTRS)

Kartuzova, O.; Kassemi, M.

2016-01-01

A CFD model for simulating pressure control in cryogenic storage tanks through the injection of a subcooled liquid into the ullage is presented and applied to the 1g MHTB spray bar cooling experiments. An Eulerian-Lagrangian approach is utilized to track the spray droplets and capture the interaction between the discrete droplets and the continuous ullage phase. The spray model is coupled with the VOF model by performing particle tracking in the ullage, removing particles from the ullage when they reach the interface, and then adding their contributions to the liquid. A new model for calculating the droplet-ullage heat and mass transfer is developed. In this model, a droplet is allowed to warm up to the saturation temperature corresponding to the ullage vapor pressure, after which it evaporates while remaining at the saturation temperature. The droplet model is validated against the results of the MHTB spray-bar cooling experiments with 50% and 90% tank fill ratios. The predictions of the present T-sat based model are compared with those of a previously developed kinetic-based droplet mass transfer model. The predictions of the two models regarding the evolving tank pressure and temperature distributions, as well as the droplets' trajectories and temperatures, are examined and compared in detail. Finally, the ullage pressure and local vapor and liquid temperature evolutions are validated against the corresponding data provided by the MHTB spray bar mixing experiment.

Iron status and its association with coronary heart disease: systematic review and meta-analysis of prospective studies.

PubMed

Das De, Sudeep; Krishna, Sreedhar; Jethwa, Ankeet

2015-02-01

Observations in the past have hypothesized an association between body iron status and coronary heart disease (CHD). Epidemiological studies to date have however been inconclusive without the existence of strongly positive or strongly negative associations between iron status and coronary heart disease. To investigate the association between iron status and coronary heart disease. A systematic review was performed using the databases PubMed and Cochrane Library. Search terms included iron, ferritin, transferrin, total iron binding capacity, coronary heart disease and angina. Only prospective studies investigating the association of body iron status and coronary heart disease were included. All participants were free from coronary heart disease at baseline. There were no language or geographic restrictions imposed on the search strategy. Independent extraction of articles by 2 authors using predefined data fields. All pooled analyses were based on random-effects models. A total of 17 studies were identified for analysis, involving a total of 9236 cases of coronary heart disease and 156,427 participants. Several studies reported more than 1 marker of iron status. For serum ferritin, comparison of individuals in the top third versus the bottom third of baseline measurements yielded a combined risk ratio of 1.03 (95%CI, 0.87-1.23) for CHD/MI. For transferrin saturation, the combined risk ratio for CHD/MI was 0.82 (95% CI, 0.75-0.89) for individuals in the top third versus the bottom third of baseline measurements. Comparison of individuals in top and bottom thirds of baseline measurements yielded non-significant risk ratios of studies involving total iron-binding capacity (combined risk ratio, 0.99; 95% CI 0.86-1.13) and serum iron (combined risk ratio, 0.87; 95% CI 0.73-1.04). For serum iron, the combined risk ratio for CHD/MI after excluding the study by Morrisson et al. [1] was 0.80 (95% CI, 0.73-0.87). The results suggest that there is a negative association of transferrin levels and coronary heart disease with high transferrin saturations being associated with a lower risk of CHD/MI. There was also a negative association of serum iron and CHD/MI after one study [1] was excluded. There is no significant association between the other markers of iron status and CHD. It is however difficult to infer causality from these findings due to limitations in terms of reverse causality bias and residual confounding. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium.

PubMed Central

Chitambar, C R; Seligman, P A

1986-01-01

We have previously shown that human leukemic cells proliferate normally in serum-free media containing various transferrin forms, but the addition of transferrin-gallium leads to inhibition of cellular proliferation. Because gallium has therapeutic potential, the effects of transferrin-gallium on leukemic cell proliferation, transferrin receptor expression, and cellular iron utilization were studied. The cytotoxicity of gallium is considerably enhanced by its binding to transferrin and cytotoxicity can be reversed by transferrin-iron but not by other transferrin forms. Exposure to transferrin-gallium leads to a marked increase in cell surface transferrin binding sites, but despite this, cellular 59Fe incorporation is inappropriately low. Although shunting of transferrin-gallium to another cellular compartment has not been ruled out, other studies suggest that transferrin-gallium impairs intracellular release of 59Fe from transferrin by interfering with processes responsible for intracellular acidification. These studies, taken together, demonstrate that inhibition of cellular iron incorporation by transferrin-gallium is a prerequisite for inhibition of cellular proliferation. PMID:3465751

Reference Intervals of Hematology and Clinical Chemistry Analytes for 1-Year-Old Korean Children

PubMed Central

Lee, Hye Ryun; Roh, Eun Youn; Chang, Ju Young

2016-01-01

Background Reference intervals need to be established according to age. We established reference intervals of hematology and chemistry from community-based healthy 1-yr-old children and analyzed their iron status according to the feeding methods during the first six months after birth. Methods A total of 887 children who received a medical check-up between 2010 and 2014 at Boramae Hospital (Seoul, Korea) were enrolled. A total of 534 children (247 boys and 287 girls) were enrolled as reference individuals after the exclusion of data obtained from children with suspected iron deficiency. Hematology and clinical chemistry analytes were measured, and the reference value of each analyte was estimated by using parametric (mean±2 SD) or nonparametric methods (2.5-97.5th percentile). Iron, total iron-binding capacity, and ferritin were measured, and transferrin saturation was calculated. Results As there were no differences in the mean values between boys and girls, we established the reference intervals for 1-yr-old children regardless of sex. The analysis of serum iron status according to feeding methods during the first six months revealed higher iron, ferritin, and transferrin saturation levels in children exclusively or mainly fed formula than in children exclusively or mainly fed breast milk. Conclusions We established reference intervals of hematology and clinical chemistry analytes from community-based healthy children at one year of age. These reference intervals will be useful for interpreting results of medical check-ups at one year of age. PMID:27374715

Reference Intervals of Hematology and Clinical Chemistry Analytes for 1-Year-Old Korean Children.

PubMed

Lee, Hye Ryun; Shin, Sue; Yoon, Jong Hyun; Roh, Eun Youn; Chang, Ju Young

2016-09-01

Reference intervals need to be established according to age. We established reference intervals of hematology and chemistry from community-based healthy 1-yr-old children and analyzed their iron status according to the feeding methods during the first six months after birth. A total of 887 children who received a medical check-up between 2010 and 2014 at Boramae Hospital (Seoul, Korea) were enrolled. A total of 534 children (247 boys and 287 girls) were enrolled as reference individuals after the exclusion of data obtained from children with suspected iron deficiency. Hematology and clinical chemistry analytes were measured, and the reference value of each analyte was estimated by using parametric (mean±2 SD) or nonparametric methods (2.5-97.5th percentile). Iron, total iron-binding capacity, and ferritin were measured, and transferrin saturation was calculated. As there were no differences in the mean values between boys and girls, we established the reference intervals for 1-yr-old children regardless of sex. The analysis of serum iron status according to feeding methods during the first six months revealed higher iron, ferritin, and transferrin saturation levels in children exclusively or mainly fed formula than in children exclusively or mainly fed breast milk. We established reference intervals of hematology and clinical chemistry analytes from community-based healthy children at one year of age. These reference intervals will be useful for interpreting results of medical check-ups at one year of age.

Effectiveness of fortification of corn flour-derived products with hydrogen-reduced elemental iron on iron-deficiency anaemia in children and adolescents in southern Brazil.

PubMed

Miglioranza, Lúcia H S; Breganó, José Wander; Dichi, Isaias; Matsuo, Tiemi; Dichi, Jane Bandeira; Barbosa, Décio Sabbatini

2009-02-01

To find the ideal combination of Fe fortifier and its food vehicle is an essential measure in developing countries. However, its cost also plays an important role. In the present study, the effect on blood parameter values of corn flour-derived products fortified with powdered elemental Fe in the form of H2-reduced Fe was investigated in children and adolescents. One hundred and sixty-two individuals (eighty-six boys and seventy-six girls) from public educational centres in Londrina, Paraná (southern Brazil) participated in the study. Fe-deficiency anaemia (IDA) was defined when Hb and serum ferritin values fell below 12 g/dl and 20 microg/l, respectively; Fe deficiency (ID) was considered when serum ferritin was below 20 microg/l. The prevalence of ID and IDA decreased from 18.0 % and 14.9 %, values found at the beginning of the study, to respectively 5.6 % and 1.2 % after 6 months. Changes from altered to normal values occurred more often than normal to altered values with transferrin saturation (14.2 % v. 6.8 %; P < 0.04) and ferritin (12.4 % v. 0 %; P < 0.001). Hb, transferrin saturation and ferritin showed differences between normal and altered parameters after 6 months (P < 0.001). A pronounced reduction in the prevalence of ID and IDA was observed in children and adolescents following 6 months' ingestion of corn flour-derived products enriched with elemental Fe.

Comparative study of the oral absorption of microencapsulated ferric saccharate and ferrous sulfate in humans.

PubMed

Contreras, Carlos; Barnuevo, María Dolores; Guillén, Isabel; Luque, Antonio; Lázaro, Elisabet; Espadaler, Jordi; López-Román, Javier; Villegas, José A

2014-01-01

Our objective was to compare the absorption of microencapsulated ferric saccharate (MFS) and ferrous sulfate (FS) in a fortified milk product, using a crossover design. Seventeen non-iron-deficient healthy adults from both sexes participated in the study. On each intervention day (days 1 and 8), after an overnight fast, the volunteers consumed one type of product (test or control) and blood sampling was carried out at different times. The interventions days were separated by 7-day washout periods. This study was double blinded, crossover and randomized for nature of the test meals. The primary outcomes of the study were total serum iron and transferrin saturation. No significant differences could be observed in serum iron concentration during the 6-h postprandial study due to the type of milk product consumed, and there was neither an effect of time nor an interaction between the type of milk product and time. Transferrin saturation significantly increased after the intake of both products (P < 0.005), reaching a peak value between hours 2 and 4. No significant differences were detected between MFS and FS, indicating that iron absorption from MFS is equivalent to absorption from FS. MFS is a new ingredient that allows the fortification of a wide range of food products, including heat-processed and non-acidic products with similar absorption to FS, designed to produce neither organoleptic changes nor off-color development during storage of fortified food.

Anemia, Iron Deficiency and Iodine Deficiency among Nepalese School Children.

PubMed

Khatiwada, Saroj; Lamsal, Madhab; Gelal, Basanta; Gautam, Sharad; Nepal, Ashwini Kumar; Brodie, David; Baral, Nirmal

2016-07-01

To assess iodine and iron nutritional status among Nepalese school children. A cross-sectional, community based study was conducted in the two districts, Ilam (hilly region) and Udayapur (plain region) of eastern Nepal. A total of 759 school children aged 6-13 y from different schools within the study areas were randomly enrolled. A total of 759 urine samples and 316 blood samples were collected. Blood hemoglobin level, serum iron, total iron binding capacity and urinary iodine concentration was measured. Percentage of transferrin saturation was calculated using serum iron and total iron binding capacity values. The mean level of hemoglobin, serum iron, total iron binding capacity, transferrin saturation and median urinary iodine excretion were 12.29 ± 1.85 g/dl, 70.45 ± 34.46 μg/dl, 386.48 ± 62.48 μg/dl, 19.94 ± 12.07 % and 274.67 μg/L respectively. Anemia, iron deficiency and iodine deficiency (urinary iodine excretion <100 μg/L) were present in 34.5 %, 43.4 % and 12.6 % children respectively. Insufficient urinary iodine excretion (urinary iodine excretion <100 μg/L) was common in anemic and iron deficient children. Iron deficiency and anemia are common in Nepalese children, whereas, iodine nutrition is more than adequate. Low urinary iodine excretion was common in iron deficiency and anemia.

Iron metabolism in critically ill patients developing anemia of inflammation: a case control study.

PubMed

Boshuizen, Margit; Binnekade, Jan M; Nota, Benjamin; van de Groep, Kirsten; Cremer, Olaf L; Tuinman, Pieter R; Horn, Janneke; Schultz, Marcus J; van Bruggen, Robin; Juffermans, Nicole P

2018-05-02

Anemia occurring as a result of inflammatory processes (anemia of inflammation, AI) has a high prevalence in critically ill patients. Knowledge on changes in iron metabolism during the course of AI is limited, hampering the development of strategies to counteract AI. This case control study aimed to investigate iron metabolism during the development of AI in critically ill patients. Iron metabolism in 30 patients who developed AI during ICU stay was compared with 30 septic patients with a high Hb and 30 non-septic patients with a high Hb. Patients were matched on age and sex. Longitudinally collected plasma samples were analyzed for levels of parameters of iron metabolism. A linear mixed model was used to assess the predictive values of the parameters. In patients with AI, levels of iron, transferrin and transferrin saturation showed an early decrease compared to controls with a high Hb, already prior to the development of anemia. Ferritin, hepcidin and IL-6 levels were increased in AI compared to controls. During AI development, erythroferrone decreased. Differences in iron metabolism between groups were not influenced by APACHE IV score. The results show that in critically ill patients with AI, iron metabolism is already altered prior to the development of anemia. Levels of iron regulators in AI differ from septic controls with a high Hb, irrespective of disease severity. AI is characterized by high levels of hepcidin, ferritin and IL-6 and low levels of iron, transferrin and erythroferrone.

Hematological Profile and Martial Status in Rugby Players during Whole Body Cryostimulation

PubMed Central

Lombardi, Giovanni; Lanteri, Patrizia; Porcelli, Simone; Mauri, Clara; Colombini, Alessandra; Grasso, Dalila; Zani, Viviana; Bonomi, Felice Giulio; Melegati, Gianluca; Banfi, Giuseppe

2013-01-01

Cold-based therapies are commonly applied to alleviate pain symptoms secondary to inflammatory diseases, but also to treat injuries or overuse, as done in sports rehabilitation. Whole body cryotherapy, a relatively new form of cold therapy, consists of short whole-body exposure to extremely cold air (−110°C to −140°C). Cryostimulation is gaining wider acceptance as an effective part of physical therapy to accelerate muscle recovery in rugby players. The aim of this study was to evaluate the effect of repeated cryostimulation sessions on the hematological profile and martial status markers in professional rugby players. Twenty-seven professional rugby players received 2 daily cryostimulation treatments for 7 consecutive days. Blood samples were collected before and after administration of the cryotherapic protocol and hematological profiles were obtained. No changes in the leukocyte count or composition were seen. There was a decrease in the values for erythrocytes, hematocrit, hemoglobin and mean corpuscular hemoglobin content, and an increase in mean corpuscular volume and red cell distribution width. Platelet count and mean volume remained unchanged. Serum transferrin and ferritin decreased, while soluble transferrin receptor increased. Serum iron and transferrin saturation were unchanged, as was reticulocyte count, whereas the immature reticulocyte fraction decreased substantially. In conclusion, in this sample of professional rugby players, cryostimulation modified the hematological profile, with a reduction in erythrocyte count and hemoglobinization paralleled by a change in martial status markers. PMID:23383348

[Molecular genetic diagnostics and screening of hereditary hemochromatosis].

PubMed

Zlocha, J; Kovács, L; Pozgayová, S; Kupcová, V; Durínová, S

2006-06-01

Hereditary hemochromatosis is considered one of the most common hereditary diseases in population of Caucasian origin. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in up to 80% of study patients with type 1 hereditary hemochromatosis. The purpose of the paper was to confirm the importance of genetic testing for HFE mutations in making the diagnosis of hemochromatosis and find out a suitable diagnostic algorithm for the indication of this form of diagnostics in patients suspected of hereditary hemochromatosis. The examination of C282Y mutation was conducted in 500 subjects. The most frequent indications for DNA analysis were hepatopathy of unknown ethiology, liver cirrhosis, diabetes mellitus, bronze skin pigmentation in connection with high serum iron concentration, elevated transferrin saturation and elevated serum ferritin levels. In our group of patients, 29 homozygotes and 75 heterozygotes for C282Y mutation were identified, 10 patients carried both C282Y and H63D mutations of HFE gene (compound heterozygotes), whereas in 386 subjects the mutation was not found. The genotype-phenotype correlation showed that 22 homozygotes had liver affection proved by imaging and/or histologic methods. Except the liver disorders, the most common symptoms of these patients were type 2 diabetes mellitus or glucose tolerance disorder (10 patients), arthritis or joint pain (9 patients) and cardiovascular disorders, such as cardiomyopathy (2 patients). Bronze skin pigmentation was present in 9 homozygotes. Transferin saturation values were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.05) or wild type subjects (p < 0.001) respectively. Also serum ferritin levels were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.001) and wild type subjects (p < 0.001) respectively. Our observations confirm that DNA analysis significantly contributes to differential diagnostics of this severe, but in early recognition curable disease. Early detection and phlebotomy treatment prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. DNA analysis is recommended in patients whose transferrin saturation is 45% or more on a repeated test. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with secondary iron overload, especially patients with chronic liver disorders and chronic anemia. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified.

Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes

PubMed Central

Chicharro, J; Hoyos, J; Gomez-Gallego, F; Villa, J; Bandres, F; Celaya, P; Jimenez, F; Alonso, J; Cordova, A; Lucia, A

2004-01-01

Background: Hereditary haemochromatosis, a disease that affects iron metabolism, progresses with a greater or lesser tendency to induce iron overload, possibly leading to severe organ dysfunction. Most elite endurance athletes take iron supplements during their active sporting life, which could aggravate this condition. Objective: To determine the prevalence and discuss potential clinical implications of mutations of HFE (the gene responsible for hereditary haemochromatosis) in endurance athletes. Methods: Basal concentrations of iron, ferritin, and transferrin and transferrin saturation were determined in the period before competition in 65 highly trained athletes. Possible mutations in the HFE gene were evaluated in each subject by extracting genomic DNA from peripheral blood. The restriction enzymes SnaBI and BclI were used to detect the mutations 845G→A (C282Y) and 187C→G (H63D). Results: Our findings indicate a high prevalence of HFE gene mutations in this population (49.2%) compared with sedentary controls (33.5%). No association was detected in the athletes between mutations and blood iron markers. Conclusions: The findings support the need to assess regularly iron stores in elite endurance athletes. PMID:15273174

Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency.

PubMed

Suzuki, Tomoyasu; Hanawa, Haruo; Jiao, Shuang; Ohno, Yukako; Hayashi, Yuka; Yoshida, Kaori; Kashimura, Takeshi; Obata, Hiroaki; Minamino, Tohru

2014-04-01

Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC. LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4. We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin. Copyright © 2014 Elsevier Inc. All rights reserved.

Presence of hemochromatosis-associated mutations in Hispanic patients with iron overload.

PubMed

Nieves-Santiago, Paul; Cancel, Dilany; Canales, Dialma; Toro, Doris H

2011-09-01

To determine the characteristics of the Puerto Rico Veteran population with iron overload in terms of demographic features, clinical manifestations, and the presence of hereditary hemochromatosis (HH) mutations, and to compare such characteristics in patients with and without HH mutations. A retrospective study was conducted in patients with iron overload (transferrin saturation > or = 45%) who were tested for HH mutations from January 2003 to June 2007. Data collected included age, gender, body mass index, hemoglobin level, platelet count, ferritin level, transferrin saturation, ceruloplasmin, alfa-1 antitrypsin, anti-nuclear antibodies, aspartate aminotransferase, alanine aminotransferase, alfa-fetoprotein, viral hepatitis profile, imaging studies, and comorbid conditions. Patients were grouped according to the results of the commercially available HH DNA mutation analysis as homozygote, heterozygote, compound heterozygote, or negative. 94 patients were studied. Most patients were male (90/94); the mean age was 60 years. Of the study group, 36% (34/94) was found positive for HH mutations. The most common mutation was H63D, which was found in 85% (29/34) of patients; 4 homozygotes and 25 heterozygotes. C282Y mutation was identified in only 12% (4/34) of patients, of which one was homozygote. A compound heterozygote (C282Y/ H63D) was also identified. After analyzing the data for confounding factors, 6 of 29 heterozygotes had no other risk factors for liver disease other than the H63D mutation. The predominance of H63D mutations in our population deserves further investigation since it considerably differs from other studied populations with iron overload in which C282Y is the most common mutation.

Nutritional anemia in pregnancy: a study at the maternity hospital, Kuala Lumpur.

PubMed

Tee E Siong; Kandiah, M; Ali, J; Kandiah, V; Zahari, M R; Kuladevan, R; Hamzah, Z

1984-06-01

The study presents recent data on the prevalence and pattern of nutritional anemia in the Maternity Hospital, Kuala Lumpur. A total of 309 pregnant women in their 3rd trimester, of Malay, Chinese and Indian origin from the lower socio-economic strata were randomly selected for the study. Hematological indices (including Hb, PCV, MCHC, and TRBC), serum iron, transferrin saturation and ferritin, serum folate as well as protein and albumin were determined. Based on Hb and PCV values, 30-40% of the women could be considered anemic; approximately 50% of them presented with unsatisfactory serum iron, transferrin saturation and ferritin values; 60.9% had low serum folate levels; and about 30% may be considered to be of poor protein nutriture. Anemia in the study population was seen to be related mostly to iron and to a lesser extent, folate deficiency. Hematological, iron, folate and protein status was observed to be the poorest amongst the Indian women, better in the Malay group and generally the best amongst the Chinese women. Birth records of 169 of these women revealed that all of them had live births. Nearly all the infants were delivered by normal vaginal delivery (NVD). The mean gestational age was 38.6 weeks. One of the infants had a birth weight of 2.0 kg; incidence of low birth weight, 2.5 kg, was 8.3%. Although there was a trend of deteriorating hematological, iron and protein status of women from the 0, 1-3 and 4 parity groups, these differences were not statistically significant.

Erythrocytapheresis compared with whole blood phlebotomy for the treatment of hereditary haemochromatosis

PubMed Central

Sundic, Tatjana; Hervig, Tor; Hannisdal, Signe; Assmus, Jörg; Ulvik, Rune J.; Olaussen, Richard W.; Berentsen, Sigbjørn

2014-01-01

Background Hereditary haemochromatosis may result in severe organ damage which can be prevented by therapy. We studied the possible advantages and disadvantages of erythrocytapheresis as compared with phlebotomy in patients with hereditary haemochromatosis. Materials and methods In a prospective, randomised, open-label study, patients with hereditary haemochromatosis were randomised to bi-weekly apheresis or weekly whole blood phlebotomy. Primary end-points were decrease in ferritin levels and transferrin saturation. Secondary endpoints were decrease in haemoglobin levels, discomfort during the therapeutic procedure, costs and technicians’ working time. Results Sixty-two patients were included. Thirty patients were randomised to apheresis and 32 to whole blood phlebotomy. Initially, ferritin levels declined more rapidly in the apheresis group, and the difference became statistically highly significant at 11 weeks; however, time to normalisation of ferritin level was equal in the two groups. We observed no significant differences in decline of transferrin saturation, haemoglobin levels or discomfort. The mean cumulative technician time consumption until the ferritin level reached 50 μg/L was longer in the apheresis group, but the difference was not statistically significant. The cumulative costs for materials until achievement of the desired ferritin levels were three-fold higher in the apheresis group. Conclusion Treatment of hereditary haemochromatosis with erythrocytapheresis instead of whole blood phlebotomy results in a more rapid initial decline in ferritin levels and a reduced number of procedures per patient, but not in earlier achievement of target ferritin level. The frequency of discomfort was equally low with the two methods. The costs and, probably, technician time consumption were higher in the apheresis group. PMID:24333062

Invariant Natural Killer T Cells are Reduced in Hereditary Hemochromatosis Patients.

PubMed

Maia, M L; Pereira, C S; Melo, G; Pinheiro, I; Exley, M A; Porto, G; Macedo, M F

2015-01-01

Invariant natural killer T (iNKT) cells are CD1d restricted-T cells that react to lipid antigens. iNKT cells were shown to be important in infection, autoimmunity and tumor surveillance. Alterations in the number and function of these cells were described in several pathological conditions including autoimmune and/or liver diseases. CD1d is critical for antigen presentation to iNKT cells, and its expression is increased in liver diseases. The liver is the major organ affected in Hereditary Hemochromatosis (HH), an autosomal recessive disorder caused by excessive iron absorption. Herein, we describe the study of iNKT cells of HH patients. Twenty-eight HH patients and 24 control subjects from Santo António Hospital, Porto, were included in this study. Patient's iron biochemical parameters (serum transferrin saturation and ferritin levels) and the liver function marker alanine transaminase (ALT) were determined at the time of study. Peripheral blood iNKT cells were analyzed by flow cytometry using an anti-CD3 antibody and the CD1d tetramer loaded with PBS57. We found a decrease in the percentage and number of circulating iNKT cells from HH patients when compared with control population independently of age. iNKT cell defects were more pronounced in untreated patients, relating with serum ferritin and transferrin saturation levels. No correlation was found with ALT, a marker of active liver dysfunction. Altogether, our results demonstrate that HH patients have reduced numbers of iNKT cells and that these are influenced by iron overload.

Involvement of hepcidin in iron metabolism dysregulation in Gaucher disease.

PubMed

Lefebvre, Thibaud; Reihani, Niloofar; Daher, Raed; de Villemeur, Thierry Billette; Belmatoug, Nadia; Rose, Christian; Colin-Aronovicz, Yves; Puy, Hervé; Le Van Kim, Caroline; Franco, Mélanie; Karim, Zoubida

2018-04-01

Gaucher disease (GD) is an inherited deficiency of glucocerebrosidase leading to accumulation of glucosylceramide in tissues such as the spleen, liver, and bone marrow. The resulting lipid-laden macrophages lead to the appearance of "Gaucher cells". Anemia associated with an unexplained hyperferritinemia is a frequent finding in GD, but whether this pathogenesis is related to an iron metabolism disorder has remained unclear. To investigate this issue, we explored the iron status of a large cohort of 90 type I GD patients, including 66 patients treated with enzyme replacement therapy. Ten of the patients treated with enzyme replacement were followed up before and during treatment. Serum levels of hepcidin, the iron regulatory peptide, remained within the physiological range, while the transferrin saturation was slightly decreased in children. Inflammation-independent hyperferritinemia was found in 65% of the patients, and Perl's staining of the spleen and marrow smear revealed iron accumulation in Gaucher cells. Treated patients exhibited reduced hyperferritinemia, increased transferrin saturation and transiently increased systemic hepcidin. In addition, the hepcidin and ferritin correlation was markedly improved, and, in most patients, the hemoglobin level was normalized. To further explore eventual iron sequestration in macrophages, we produce a Gaucher cells model by treating the J774 macrophage cell line with a glucocerebrosidase inhibitor and showed induced local hepcidin and membrane retrieval of the iron exporter, ferroportin. These data reveal the involvement of Gaucher cells in abnormal iron sequestration, which may explain the mechanism of hyperferritinemia in GD patients. Local hepcidin-ferroportin interaction was involved in this pathogenesis. Copyright© 2018 Ferrata Storti Foundation.

Deferoxamine inhibition of malaria is independent of host iron status

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hershko, C.; Peto, T.E.

The mechanism whereby deferoxamine (DF) inhibits the growth of malaria parasites was studied in rats infected with Plasmodium berghei. Peak parasitemia was 32.6% (day 14) in untreated controls and 0.15% (day 7) in rats receiving 0.33 mg/g in 8 hourly DF injections, subcutaneously. DF inhibition of parasite growth was achieved without any reduction in transferrin saturation or hemoglobin synthesis and with only a partial (56%) depletion of hepatic iron stores. Dietary iron depletion resulted in anemia (hematocrit 25 vs. 46%), microcytosis (MCV 54 vs. 60 fl), and reduced transferrin saturation (17 vs. 96%) without any effect on infection (peak parasitemiamore » 30 vs. 36%). Similarly, parenteral iron loading with ferric citrate over 10 d (75 mg iron/kg) failed to aggravate infection. In a search for evidence of direct interaction between DF and parasitized erythrocytes, gel filtration and ultrafiltration was performed on hemolysates obtained from in vivo /sup 59/Fe-labeled parasitized erythrocytes. This showed that 1.1-1.9% of the intracellular radioiron was located in a chelatable, labile iron pool. Incubation of intact cells with 0-500 microM DF resulted in a proportional increase in intracellular iron chelation, and the chelation of all available labile intracellular iron was completed within 6 h. These observations indicate that the severity of P. berghei infection in rats and its in vivo suppression by DF are independent of host iron status and suggest that DF inhibition of malaria involves intracellular chelation of a labile iron pool in parasitized erythrocytes.« less

Relationship Between Dietary Factors and Bodily Iron Status Among Japanese Collegiate Elite Female Rhythmic Gymnasts.

PubMed

Kokubo, Yuki; Yokoyama, Yuri; Kisara, Kumiko; Ohira, Yoshiko; Sunami, Ayaka; Yoshizaki, Takahiro; Tada, Yuki; Ishizaki, Sakuko; Hida, Azumi; Kawano, Yukari

2016-04-01

This cross-sectional study explored the prevalence of iron deficiency (ID) and associations between dietary factors and incidence of ID in female rhythmic gymnasts during preseason periods. Participants were 60 elite collegiate rhythmic gymnasts (18.1 ± 0.3 years [M ± SD]) who were recruited every August over the course of 8 years. Participants were divided into 2 groups according to the presence or absence of ID. Presence of ID was defined either by ferritin less than 12 μg/L or percentage of transferrin saturation less than 16%. Anthropometric and hematologic data, as well as dietary intake, which was estimated via a semiquantitative food frequency questionnaire, were compared. ID was noted in 48.3% of participants. No significant group-dependent differences were observed in physical characteristics, red blood cell counts, hemoglobin, hematocrit, haptoglobin, or erythropoietin concentrations. The ID group had a significantly lower total iron-binding capacity; serum-free iron; percentage of transferrin saturation; ferritin; and intake of protein, fat, zinc, vitamin B2, vitamin B6, beans, and eggs but not iron or vitamin C. The recommended dietary allowance for intake of protein, iron, zinc, and various vitamins was not met by 30%, 90%, 70%, and 22%-87% of all participants, respectively. Multiple logistic analysis showed that protein intake was significantly associated with the incidence of ID (odds ratio = 0.814, 95% confidence interval [0.669, 0.990], p = .039). Participants in the preseason's weight-loss periods showed a tendency toward insufficient nutrient intake and were at a high risk for ID, particularly because of lower protein intake.

Systemic and lung protein changes in sarcoidosis. Lymphocyte counts, gallium uptake values, and serum angiotensin-converting enzyme levels may reflect different aspects of disease activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Check, I.J.; Kidd, M.R.; Staton, G.W. Jr.

1986-01-01

BAL lymphocyte percentages, quantitated gallium-67 lung uptake, and SACE levels have all been proposed as measures of disease activity in sarcoidosis. We analyzed 32 paired sera and BAL fluids from sarcoidosis patients by high-resolution agarose electrophoresis to look for protein changes characteristic of systemic or local inflammation and compared the results with those from the above tests. Nine patients (group 1) had serum inflammatory protein changes and increased total protein, albumin, beta 1-globulin (transferrin), and gamma-globulin levels in fluid recovered by BAL. Thirteen patients (group 2) had normal protein levels in sera but abnormal protein levels in BAL specimens. Tenmore » patients (group 3) had normal protein levels in sera and in BAL specimens. Patients in groups 1 and 2 had a disproportionate increase in beta 1-globulin (transferrin) and gamma-globulin levels in their BAL specimens. The BAL lymphocyte percentage changes paralleled the BAL protein level changes, suggesting relationships among the immunoregulatory role of these cells, increased local immunoglobulin synthesis, and the pathogenesis of altered alveolar permeability. Gallium-67 uptake was highest in patients with serum inflammatory protein changes. Thus, systemic inflammation may facilitate pulmonary gallium-67 uptake, possibly by changes in BAL fluid or serum transferrin saturation and/or kinetics. SACE levels showed no relationship to changes in the levels of serum or BAL proteins. These data suggest that the various proposed measures of disease activity reflect different aspects of inflammation in sarcoidosis.« less

A Novel Rat Model of Hereditary Hemochromatosis Due to a Mutation in Transferrin Receptor 2

PubMed Central

Bartnikas, Thomas B; Wildt, Sheryl J; Wineinger, Amy E; Schmitz-Abe, Klaus; Markianos, Kyriacos; Cooper, Dale M; Fleming, Mark D

2013-01-01

Sporadic iron overload in rats has been reported, but whether it is due to genetic or environmental causes is unknown. In the current study, phenotypic analysis of Hsd:HHCL Wistar rats revealed a low incidence of histologically detected liver iron overload. Here we characterized the pathophysiology of the iron overload and showed that the phenotype is heritable and due to a mutation in a single gene. We identified a single male rat among the 132 screened animals that exhibited predominantly periportal, hepatocellular iron accumulation. This rat expressed low RNA levels of the iron regulatory hormone hepcidin and low protein levels of transferrin receptor 2 (Tfr2), a membrane protein essential for hepcidin expression in humans and mice and mutated in forms of hereditary hemochromatosis. Sequencing of Tfr2 in the iron-overloaded rat revealed a novel Ala679Gly polymorphism in a highly conserved residue. Quantitative trait locus mapping indicated that this polymorphism correlated strongly with serum iron and transferrin saturations in male rats. Expression of the Gly679 variant in tissue culture cell lines revealed decreased steady-state levels of Tfr2. Characterization of iron metabolism in the progeny of polymorphic rats suggested that homozygosity for the Ala679Gly allele leads to a hemochromatosis phenotype. However, we currently cannot exclude the possibility that a polymorphism or mutation in the noncoding region of Tfr2 contributes to the iron-overload phenotype. Hsd:HHCL rats are the first genetic rat model of hereditary hemochromatosis and may prove useful for understanding the molecular mechanisms underlying the regulation of iron metabolism. PMID:23582421

Blood and hair lead in children with different extents of iron deficiency in Karachi

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ataur Rahman, Muhammad; Rahman, Bushra; Saeed Ahmad, Muhammad

Childhood iron deficiency has a high incidence in Pakistan. Some but not all studies have shown that dietary iron deficiency may cause increased absorption of lead as both compete for the same transporters in the small intestine. Therefore, children in Pakistan, residing in heavily polluted cities like Karachi may be prone to lead poisoning. This hypothesis was tested by investigating blood and hair lead concentrations in children from Karachi who were divided into four groups of iron status; normal, borderline iron deficiency, iron deficiency and iron deficiency anaemia. A prospective observational study was conducted where 269 children were categorized intomore » four groups of iron status using the World Health Organization criteria and one based on soluble transferrin receptor measurements. Blood iron status was determined using a full blood count, serum iron, ferritin, transferrin saturation and soluble transferrin receptor measurements. Blood lead was determined by graphite atomic absorption spectroscopy, whereas hair lead was assessed using an inductively coupled plasma atomic emission spectroscopy technique. Blood lead concentrations were significantly higher in children with iron deficiency anaemia (mean [95% confidence intervals] were 24.9 [22.6-27.2] {mu}g/dL) compared to those with normal iron status (19.1 [16.8-21.4] {mu}g/dL) using WHO criteria. In contrast, hair lead content was not significantly different in children of different iron status. Our findings reinforce the importance of not only reducing environmental lead pollution but also the development of national health strategies to reduce childhood iron deficiency in Pakistan.« less

The structural basis of transferrin sequestration by transferrin-binding protein B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calmettes, Charles; Alcantara, Joenel; Yu, Rong-Hua

2012-03-28

Neisseria meningitidis, the causative agent of bacterial meningitis, acquires the essential element iron from the host glycoprotein transferrin during infection through a surface transferrin receptor system composed of proteins TbpA and TbpB. Here we present the crystal structures of TbpB from N. meningitidis in its apo form and in complex with human transferrin. The structure reveals how TbpB sequesters and initiates iron release from human transferrin.

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

[Biological diagnosis of iron deficiency in children].

PubMed

Thuret, I

2017-05-01

Measurement of serum ferritin (SF) is currently the laboratory test recommended for diagnosing iron deficiency. In the absence of an associated disease, a low SF value is an early and highly specific indicator of iron deficiency. The WHO criteria proposed to define depleted storage iron are 12μg/L for children under 5 years and 15μg/L for those over 5 years. A higher threshold of 30μg/L is used in the presence of infection or inflammation. Iron deficiency anemia, with typical low mean corpuscular volume and mean corpuscular hemoglobin, is only present at the end stage of iron deficiency. Other diagnostic tests for iron deficiency including iron parameters (low serum iron, increased total iron-binding capacity, low transferrin saturation) and erythrocyte traits (low mean corpuscular volume, increased zinc protoporphyrin) provide little additional diagnostic value over SF. In children, serum soluble transferrin receptor (sTfR) has been reported to be a sensitive indicator of iron deficiency and is relatively unaffected by inflammation. On the other hand, sTfR is directly related to extent of erythroid activity and not commonly used in clinical practice. In population surveys, approaches based on combinations of markers have been explored to improve the specificity and sensitivity of diagnostic. In addition to Hb value determination, a combination of parameters (among transferrin saturation, zinc protoporphyrin, mean corpuscular volume or serum ferritin) was generally used to assess iron deficiency. More recently sTfR/ ferritin index were evaluated, sTfR in conjunction with SF allowing to better distinguishing iron deficiency from inflammatory anemia. Also, hepcidin measurements appeared an interesting marker for diagnosing iron deficiency and identifying individuals in need of iron supplementation in populations where inflammatory or infectious diseases are frequently encountered. Reticulocyte Hb content (CHr) determination is an early parameter of iron deficiency erythropoiesis. CHr can be measured with several automated hematology analyzers and so, used for individual's iron status assessment. In addition to Hb concentration determination, individual's iron status is commonly assessed in the pediatric clinical practice by the SF measurement accompanied by the determination of C-reactive protein for detection of a simultaneous acute infection and/or inflammation. © 2017 Elsevier Masson SAS. Tous droits réservés.

Analysis of Familial Tendencies in Transferrin Saturation in a Korean Population.

PubMed

Oh, Sung-Hee; Jeong, Tae-Dong; Lee, Woochang; Chun, Sail; Min, Won-Ki

2015-10-01

Despite the high transferrin saturation (TS) level in Koreans, the p.Cys282Tyr and p.His63Asp mutations are markedly less frequent than in Caucasians. We aimed to determine TS levels and their familial tendencies in a Korean population using nationwide data from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1 2010). A total of 4904 subjects without a history of hepatitis B and C virus infection, or liver cirrhosis, and who were negative for anemia and hepatitis B antigen were enrolled. A familial tendency analysis was performed in 260 families. Parents were grouped into four quartiles based on their TS levels. Offspring were categorized according to the mean parental TS four quartile scores (1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0). A familial tendency was evaluated by comparing the mean TS of offspring in seven parental groups. The mean TS was 39.3 ± 15.6% for Korean males and 33.2 ± 12.9% for Korean females, and both were significantly higher than those of Caucasians reported in the HEIRS study (30.6 ± 11.0% for male, 25.6 ± 10.6% for female, P < 0.001). The 260 families showed statistically significant familial tendencies of TS values (P < 0.001). The mean TS of offspring in parental group 1.0, 1.5, 2.0, and 2.5 showed a lower value than that in higher group 3.0, 3.5, and 4.0. In contrast, there were no significant differences in age, daily dietary iron intake, and AST or ALT value among seven groups. These findings suggest unidentified genetic variations on high TS in Koreans beyond the p.Cys282Tyr and p.His63Asp mutations commonly identified in Caucasians.

Associations of Serum Ferritin and Transferrin % Saturation With All-cause, Cancer, and Cardiovascular Disease Mortality: Third National Health and Nutrition Examination Survey Follow-up Study

PubMed Central

Kim, Ki-Su; Son, Hye-Gyeong; Hong, Nam-Soo

2012-01-01

Objectives Even though experimental studies have suggested that iron can be involved in generating oxidative stress, epidemiologic studies on the association of markers of body iron stores with cardiovascular disease or cancer remain controversial. This study was performed to examine the association of serum ferritin and transferrin saturation (%TS) with all-cause, cancer, and cardiovascular mortality. Methods The study subjects were men aged 50 years or older and postmenopausal women of the Third National Health and Nutrition Examination Survey 1988-1994. Participants were followed-up for mortality through December 31, 2006. Results Serum ferritin was not associated with all-cause, cancer, or cardiovascular mortality for either men or postmenopausal women. However, all-cause, cancer, and cardiovascular mortality were inversely associated with %TS in men. Compared with men in the lowest quintile, adjusted hazard ratios for all-cause, cancer, and cardiovascular mortality were 0.85, 0.86, 0.76, and 0.74 (p for trend < 0.01), 0.82, 0.73, 0.75, and 0.63 (p for trend < 0.01), and 0.86, 0.81, 0.72, and 0.76 (p for trend < 0.01), respectively. For postmenopausal women, inverse associations were also observed for all-cause and cardiovascular mortality, but cancer mortality showed the significantly lower mortality only in the 2nd quintile of %TS compared with that of the 1st quintile. Conclusions Unlike speculation on the role of iron from experimental studies, %TS was inversely associated with all-cause, cancer and cardiovascular mortality in men and postmenopausal women. On the other hand, serum ferritin was not associated with all-cause, cancer, or cardiovascular mortality. PMID:22712047

Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment.

PubMed

Porter, John B; El-Alfy, Mohsen; Viprakasit, Vip; Giraudier, Stephane; Chan, Lee Lee; Lai, Yongrong; El-Ali, Ali; Han, Jackie; Cappellini, Maria D

2016-01-01

Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade(®) ) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), predose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n = 1114), myelodysplastic syndromes (MDS, n = 336), and sickle-cell disease (SCD, n = 80). Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in patients with SCD, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised in TM and MDS, but not in patients with SCD, decreasing at EOS in both patient groups. After 1 year of chelation therapy, there was a significant trend for greater LPI reduction in patients with TM achieving LIC <7 mg Fe/g dw (P = 0.0137). Despite limitations, SF showed the clearest relationship, of the plasma markers evaluated, to LIC before and after 1 year of deferasirox in patients with TM, MDS, and SCD. In patients with TM, changes in LPI with chelation show a significant relationship to EOS LIC and may provide an additional indicator of chelation response (clinicaltrials.gov identifier: NCT00171821). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The comparative short-term effectiveness of iron dosing and formulations in US hemodialysis patients.

PubMed

Kshirsagar, Abhijit V; Freburger, Janet K; Ellis, Alan R; Wang, Lily; Winkelmayer, Wolfgang C; Brookhart, M Alan

2013-06-01

Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type. We conducted a retrospective cohort study using data from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the US Renal Data System to compare the effects of intravenous iron use on anemia management. Dosing comparisons were bolus (consecutive doses ≥100 mg exceeding 600 mg during 1 month) versus maintenance (all other iron doses during the month); and high (>200 mg over 1 month) versus low dose (≤200 mg over 1 month). Formulation comparison was administration of ferric gluconate versus iron sucrose over 1 month. Outcomes were hemoglobin, epoetin dose, transferrin saturation, and serum ferritin during 6 weeks of follow-up. We identified 117,050 patients for the dosing comparison, and 66,207 patients for the formulation comparison. Bolus dosing was associated with higher average adjusted hemoglobin (+0.23 g/dL; 95% confidence interval [CI], 0.21-0.26), transferrin saturation (+3.31%; 95% CI, 2.99-3.63), serum ferritin (+151 μg/L; 95% CI, 134.9-168.7), and lower average epoetin dose (-464 units; 95% CI, -583 to -343) compared with maintenance. Similar trends were observed with high-dose iron versus low-dose. Iron sucrose was associated with higher adjusted average hemoglobin (+0.16 g/dL; 95% CI, 0.12-0.19) versus ferric gluconate. Strategies favoring large doses of intravenous iron or iron sucrose lead to improved measures of anemia management. These potential benefits should be weighed against risks, which currently remain incompletely characterized. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparative response to single or divided doses of parenteral iron for functional iron deficiency in hemodialysis patients receiving erythropoietin (EPO).

PubMed

Saltissi, D; Sauvage, D; Westhuyzen, J

1998-01-01

EPO treatment rapidly corrects anemia in patients with end-stage renal failure treated with hemodialysis, as long as sufficient iron is available. Absolute and relative (to demand) iron deficiency blunts the erythropoietic response and parenteral iron is frequently required during the course of therapy to restore EPO efficacy. Since the optimum time course of iron administration to restore EPO response in the short term is unknown, we compared three protocols of i.v. iron dextran administration in apparent functionally iron-deficient HD patients on oral iron therapy (hemoglobin < 10.0 g/dl plus ferritin < 100 micrograms/l and/or transferrin saturation < 20%). Intravenous iron (Imferon; Fisons Pty Ltd.) was given either as a single 600 mg dose (n = 15, Group I) or in divided doses of 100 mg administered on 6 successive dialyses (n = 14, Group II) or weekly for 6 weeks (n = 14, Group III). Response was monitored for 8 weeks. No adverse effects were observed. Collectively, mean hemoglobin increased (p < 0.01) by 0.4-0.5 g/dl plateauing at 4 weeks (between group comparison, p = 0.92). Mean ferritin concentrations changed with time (p < 0.01), peaking at 2 weeks in Groups I and II and at 4 weeks in Group III. Mean transferrin saturation levels also increased during the study (p < 0.001). The between group comparisons for the trends in iron indices were significant (p < 0.01 and 0.05 respectively). As there were no clinically significant differences in hemoglobin response at 4 weeks, single dose iron infusion would seem to be the most expedient in the short term, however frequent small doses are similarly effective.

Trends in anemia management among US hemodialysis patients.

PubMed

Coladonato, Joseph A; Frankenfield, Diane L; Reddan, Donal N; Klassen, Preston S; Szczech, Lynda A; Johnson, Curtis A; Owen, William F

2002-05-01

This study was undertaken to describe the relationship between hematocrit (Hct) and changes in the prescribed dose of erythropoietin (EPO) as well as selected patient and process care measures across annual national samples of hemodialysis patients from 1994 to 1998. This study uses the cohorts identified in the ESRD Core Indicators Project, random samples of 6181, 6241, 6364, 6634, and 7660 patients, stratified by ESRD Networks drawn for each year from 1994 to 1998. Patient demographic and clinical information was collected from October to December for each year. Surrogates of iron stores and patterns of iron and EPO administration were profiled from 1996 to 1998. Multivariable stepwise linear regression analyses were performed to adjust for potential confounding variables and to identify independent variables associated with Hct and EPO dose. Mean Hct and EPO dose increased each year from 31.1 +/- 5.2% to 34.1 +/- 3.7% and from 58.2 +/- 41.8 U/kg to 68.2 +/- 55.0 U/kg, respectively (P = 0.0001). Increasing Hct was positively associated with male gender, more years on dialysis, older age, higher urea reduction ratio and transferrin saturation, prescription of intravenous iron, and lower ferritin and EPO dose in multivariable models (all P = 0.0001). Male gender, older age, diabetes, higher Hct, and increasing weight, urea reduction ration, and transferrin saturation were associated with lower EPO doses (all P < 0.01). Conversely, intravenous EPO and iron were associated with higher prescribed EPO doses (all P = 0.0001). Although increasing Hct is associated with decreasing EPO dose at the patient level, the increase in Hct seen across years among the cohorts of hemodialysis patients in the United States has been associated with increasing doses of EPO at the population level.

Prolonged red cell storage before transfusion increases extravascular hemolysis

PubMed Central

Rapido, Francesca; Brittenham, Gary M.; Bandyopadhyay, Sheila; La Carpia, Francesca; L’Acqua, Camilla; McMahon, Donald J.; Rebbaa, Abdelhadi; Wojczyk, Boguslaw S.; Netterwald, Jane; Wang, Hangli; Schwartz, Joseph; Eisenberger, Andrew; Soffing, Mark; Yeh, Randy; Divgi, Chaitanya; Ginzburg, Yelena Z.; Shaz, Beth H.; Sheth, Sujit; Francis, Richard O.; Spitalnik, Steven L.; Hod, Eldad A.

2016-01-01

BACKGROUND. Some countries have limited the maximum allowable storage duration for red cells to 5 weeks before transfusion. In the US, red blood cells can be stored for up to 6 weeks, but randomized trials have not assessed the effects of this final week of storage on clinical outcomes. METHODS. Sixty healthy adult volunteers were randomized to a single standard, autologous, leukoreduced, packed red cell transfusion after 1, 2, 3, 4, 5, or 6 weeks of storage (n = 10 per group). 51-Chromium posttransfusion red cell recovery studies were performed and laboratory parameters measured before and at defined times after transfusion. RESULTS. Extravascular hemolysis after transfusion progressively increased with increasing storage time (P < 0.001 for linear trend in the AUC of serum indirect bilirubin and iron levels). Longer storage duration was associated with decreasing posttransfusion red cell recovery (P = 0.002), decreasing elevations in hematocrit (P = 0.02), and increasing serum ferritin (P < 0.0001). After 6 weeks of refrigerated storage, transfusion was followed by increases in AUC for serum iron (P < 0.01), transferrin saturation (P < 0.001), and nontransferrin-bound iron (P < 0.001) as compared with transfusion after 1 to 5 weeks of storage. CONCLUSIONS. After 6 weeks of refrigerated storage, transfusion of autologous red cells to healthy human volunteers increased extravascular hemolysis, saturated serum transferrin, and produced circulating nontransferrin-bound iron. These outcomes, associated with increased risks of harm, provide evidence that the maximal allowable red cell storage duration should be reduced to the minimum sustainable by the blood supply, with 35 days as an attainable goal. REGISTRATION. ClinicalTrials.gov NCT02087514. FUNDING. NIH grant HL115557 and UL1 TR000040. PMID:27941245

HFE gene mutations and iron status of Brazilian blood donors.

PubMed

Santos, P C J L; Cançado, R D; Terada, C T; Rostelato, S; Gonzales, I; Hirata, R D C; Hirata, M H; Chiattone, C S; Guerra-Shinohara, E M

2010-01-01

Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542) were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC) than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018) and a 83.65% decrease (P = 0.007) in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001) and the HFE 63HD plus DD genotype (55.84%, P = 0.021). In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.

Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population

PubMed Central

Gordeuk, Victor R.; Reboussin, David M.; McLaren, Christine E.; Barton, James C.; Acton, Ronald T.; McLaren, Gordon D.; Harris, Emily L.; Reiss, Jacob A.; Adams, Paul C.; Speechley, Mark; Phatak, Pradyumna D.; Sholinsky, Phyliss; Eckfeldt, John H.; Chen, Wen-Pin; Passmore, Leah; Dawkins, Fitzroy W.

2013-01-01

How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores. PMID:18429050

Transferrin saturation phenotype and HFE genotype screening for hemochromatosis and primary iron overload: predictions from a model based on national, racial, and ethnic group composition in central Alabama.

PubMed

Barton, J C; Acton, R T

2000-01-01

There is interest in general population screening for hemochromatosis and other primary iron overload disorders, although not all persons are at equal risk. We developed a model to estimate the numbers of persons in national, racial, or ethnic population subgroups in Jefferson County, Alabama, who would be detected using transferrin saturation (phenotype) or HFE mutation analysis (genotype) screening. Approximately 62% are Caucasians, 37% are African Americans, and the remainder are Hispanics, Asians, or Native Americans. The predicted phenotype frequencies are greatest in a Caucasian subgroup, ethnicity unspecified, which consists predominantly of persons of Scotch and Irish descent (0.0065 men, 0.0046 women), and in African Americans (0.0089 men, 0.0085 women). Frequencies of the HFE genotype C282Y/C282Y > or = 0.0001 are predicted to occur only among Caucasians; the greatest frequency (0.0080) was predicted to occur in the ethnicity-unspecified Caucasian population. C282Y/C282Y frequency estimates were lower in Italian, Greek, and Jewish subgroups. There is excellent agreement in the numbers of the ethnicity-unspecified Caucasians who would be detected using phenotype and genotype criteria. Our model also indicates that phenotyping would identify more persons with primary iron overload than would genotyping in our Italian Caucasian, Hispanic, and African American subgroups. This is consistent with previous observations that indicate that primary iron overload disorders in persons of southern Italian descent and African Americans are largely attributable to non-HFE alleles. Because the proportions of population subgroups and their genetic constitution may differ significantly in other geographic regions, we suggest that models similar to the present one be constructed to predict optimal screening strategies for primary iron overload disorders.

Clinical expression of haemochromatosis in Irish C282Y homozygotes identified through family screening.

PubMed

Gleeson, F; Ryan, E; Barrett, S; Crowe, J

2004-09-01

In Ireland, the homozygote frequency of the C282Y mutation in the HFE gene is 1/83. The biochemical expression of this mutation is high in haemochromatosis (HH) individuals identified through family screening, but the clinical expression of the mutation in Irish HH subjects to date has not been investigated fully. To determine the clinical, biochemical and histological penetrance of the C282Y mutation in Irish C282Y homozygotes identified through family screening. Two hundred and nine C282Y homozygous individuals comprising of 172 first-degree relatives, 31 second-degree relatives and four unrelated individuals were identified following HFE mutation analysis of 167 families. The following variables were analysed: age at identification, gender, fasting transferrin saturation, fasting serum ferritin, liver enzymes, clinical symptomatology, liver histopathology and histochemical iron staining. An elevated transferrin saturation in combination with an elevated ferritin was present in 43.4% of males and 23.3% of females. Abnormal liver enzymes were found in 32.3% of males. Diabetes, a haemochromatosis-specific association, was noted in 2.8% of males. Of those individuals requiring liver histopathology evaluation, 38% had moderate-to-severe iron staining, and 42% had fibrosis; 2.8% of the biopsied cohort had cirrhosis. Thus, HH cirrhotics were identified in less than 1% of the screened population. Although the homozygote frequency in Ireland is very high, the prevalence of advanced liver disease was less than 1% of the family members screened. Nevertheless, 42% of biopsied patients had histological evidence of iron overload-related architectural change and 2.8% had cirrhosis. This cohort of young people had previously unrecognized biochemical iron overload and histopathological change. This emphasizes the importance and value of both genetic and biochemical screening in first-degree relatives of identified homozygotes.

White blood cells and subtypes in HFE p.C282Y and wild-type homozygotes in the Hemochromatosis and Iron Overload Screening Study.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T

2017-03-01

The major histocompatibility complex is linked to white blood cell (WBC) and lymphocyte counts in subjects unselected for HFE genotypes. We compared age, sex, body mass index, total WBC and subtypes (neutrophils, lymphocytes, monocytes, eosinophils, basophils) (Beckman Coulter® Gen-S), transferrin saturation, and serum ferritin of HFE p.C282Y and wild-type (p.C282Y, p.H63D negative) homozygotes without acquired conditions that influence WBC counts. We performed regressions on WBC and subtypes. There were 161 p.C282Y homozygotes (45.3% men) and 221 wild-type homozygotes (40.3% men). Mean WBC of men and women and between HFE genotypes were similar. Mean lymphocytes were higher in male p.C282Y homozygotes: 1.6×10 9 /L [95% confidence interval: 1.5,1.7] vs. 1.4 [1.3,1.5], p=0.0002. Mean lymphocytes and basophils were higher in female p.C282Y homozygotes: 1.6 [1.5,1.7] vs. 1.4 [1.3,1.5], p=0.0002; and 0.065 [0.059,0.071] vs. 0.052 [0.051,0.054], p=0.0001, respectively. Transferrin saturation was associated with neutrophils (negative; p=0.0163). Age was associated with lymphocytes (negative; p=0.0003) and monocytes (positive; p<0.0001). Regressions on lymphocytes and basophils revealed positive associations with p.C282Y homozygosity (p=0.0043 and 0.0003, respectively). There were significant positive associations of neutrophils, lymphocytes, monocytes, and eosinophils. We conclude that HFE p.C282Y homozygosity is significantly associated with lymphocyte and basophil counts. Copyright © 2016 Elsevier Inc. All rights reserved.

Iron deficiency anaemia among apparently healthy pre-school children in Lagos, Nigeria.

PubMed

Akodu, Olufemi S; Disu, Elizabeth A; Njokanma, Olisamedua F; Kehinde, Omolara A

2016-03-01

Iron deficiency, and specifically iron deficiency anaemia, remains one of the most severe and important nutritional deficiencies in the world today. To estimate the prevalence and associated factors for iron deficiency anaemia among pre-school children in Lagos. The study was conducted from December 2009 to February 2010 at the outpatient clinics of Lagos State University Teaching Hospital, Lagos. Serum iron, total iron binding capacity, transferrin saturation and serum ferritin were assayed in subjects. The primary outcome measured was iron deficiency anaemia established based on the following criteria: hemoglobin <11.0 g/dl1 plus 2 or more of the following: MCV <70fl, transferrin saturation <10% or serum ferritin <15ng/dL. Statistical analysis included Pearson Chi square analysis and logistic regression analysis. A total of 87 apparently healthy subjects were recruited. Only one subject had iron depletion and this child belonged to the ≤ 2 years age category. None of the recruited subjects had iron deficiency without anaemia. Nine of the study subjects (10.11%) had iron deficiency anaemia. The prevalence of iron deficiency anaemia was significantly higher among younger age group than in the older age group (19.1% Vs 2.1%, p = 0.022). The prevalence of iron deficiency anaemia was significantly higher among subjects with weight-for-age, and weight-for-height Z scores below two standard scores (83.3% and 75.0% respectively, p = <0.001 and 0.001 respectively). The overall prevalence of iron deficiency anaemia among study subjects was 10.11%. Iron deficiency anaemia was more common in children aged two years and below. Weight-for-age and weight-for-height Z scores below minus two standard scores were strongly associated with iron deficiency anaemia.

The effects of the glycation of transferrin on chromium binding and the transport and distribution of chromium in vivo.

PubMed

Deng, Ge; Dyroff, Samantha L; Lockart, Molly; Bowman, Michael K; Vincent, John B

2016-11-01

Chromium (III) has been shown to act as a pharmacological agent improving insulin sensitivity in rodent models of obesity, insulin resistance, and diabetes. To act in beneficial fashion, chromium must reach insulin-sensitive tissues. Chromium is transported from the bloodstream to the tissues by the iron-transport protein transferrin. When blood concentrations of glucose are high (as in a diabetic subject), transferrin can be glycated, modifying its ability to bind and transport iron. However, the effects of glycation of transferrin on its ability to bind and transport Cr have not been examined previously. Storage of transferrin at 37°C in the presence and absence of glucose has significant effects on the binding of Cr. Transferrin stored in the absence of glucose only binds one equivalent of Cr tightly, compared to the normal binding of two equivalents of Cr by transferrin. Glycated transferrin (stored in the presence of glucose) binds two equivalents of Cr but the changes in its extinction coefficient at 245nm that accompany binding suggest that the Cr-bound transferrin possesses a conformation that deviates appreciably from untreated transferrin. These changes have dramatic effects, greatly reducing the ability of transferrin to transport Cr in vivo in rats. The results suggest that glycation of transferrin in subjects with high blood glucose concentrations should reduce the ability of Cr from pharmacological agents to enter tissues. Copyright © 2016 Elsevier Inc. All rights reserved.

Risk of iron overload is decreased in beating heart coronary artery surgery compared to conventional bypass.

PubMed

Mumby, S; Koh, T W; Pepper, J R; Gutteridge, J M

2001-11-29

Conventional cardiopulmonary bypass surgery (CCPB) increases the iron loading of plasma transferrin often to a state of plasma iron overload, with the presence of low molecular mass iron. Such iron is a potential risk factor for oxidative stress and microbial virulence. Here we assess 'off-pump' coronary artery surgery on the beating heart for changes in plasma iron chemistry. Seventeen patients undergoing cardiac surgery using the 'Octopus' myocardial wall stabilisation device were monitored at five time points for changes in plasma iron chemistry. This group was further divided into those (n=9) who had one- or two- (n=8) vessel grafts, and compared with eight patients undergoing conventional coronary artery surgery. Patients undergoing beating heart surgery had significantly lower levels of total plasma non-haem iron, and a decreased percentage saturation of their transferrin at all time points compared to conventional bypass patients. Plasma iron overload occurred in only one patient undergoing CCPB. Beating heart surgery appears to decrease red blood cell haemolysis, and tissue damage during the operative procedures and thereby significantly decreases the risk of plasma iron overload associated with conventional bypass.

Competitive advantage of diferric transferrin in delivering iron to reticulocytes.

PubMed Central

Huebers, H A; Csiba, E; Huebers, E; Finch, C A

1983-01-01

Radioiron- and radioiodine-labeled forms of human diferric and monoferric transferrin and apotransferrin, isolated by preparative isoelectric focusing, were used to define transferrin-iron uptake by human reticulocytes. In mixtures of human diferric and monoferric transferrin, the diferric molecule had a constant 7-fold advantage in delivering iron to reticulocytes, as compared with the 2-fold advantage when single solutions of mono- and diferric transferrins were compared. This was shown to be due to competitive interaction in iron delivery, probably at a common membrane-receptor binding site for transferrin. Apotransferrin did not interfere with the iron-donating process and its limited cellular uptake was inhibited in noncompetitive fashion by diferric transferrin. PMID:6572005

Kinetics of Transferrin and Transferrin-Receptor during Iron Transport through Blood Brain Barrier

NASA Astrophysics Data System (ADS)

Khan, Aminul; Liu, Jin; Dutta, Prashanta

2017-11-01

Transferrin and its receptors play an important role during the uptake and transcytosis of iron by blood brain barrier (BBB) endothelial cells to maintain iron homeostasis in BBB endothelium and brain. In the blood side of BBB, ferric iron binds with the apo-transferrin to form holo-transferrin which enters the endothelial cell via transferrin receptor mediated endocytosis. Depending on the initial concentration of iron inside the cell endocytosed holo-transferrin can either be acidified in the endosome or exocytosed through the basolateral membrane. Acidification of holo-transferrin in the endosome releases ferrous irons which may either be stored and used by the cell or transported into brain side. Exocytosis of the holo-transferrin through basolateral membrane leads to transport of iron bound to transferrin into brain side. In this work, kinetics of internalization, recycling and exocytosis of transferrin and its receptors are modeled by laws of mass action during iron transport in BBB endothelial cell. Kinetic parameters for the model are determined by least square analysis. Our results suggest that the cell's initial iron content determines the extent of the two possible iron transport pathways, which will be presented in this talk Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM122081.

Using Biomolecules to Separate Plutonium

NASA Astrophysics Data System (ADS)

Gogolski, Jarrod

Used nuclear fuel has traditionally been treated through chemical separations of the radionuclides for recycle or disposal. This research considers a biological approach to such separations based on a series of complex and interdependent interactions that occur naturally in the human body with plutonium. These biological interactions are mediated by the proteins serum transferrin and the transferrin receptor. Transferrin to plutonium in vivo and can deposit plutonium into cells after interacting with the transferrin receptor protein at the cell surface. Using cerium as a non-radioactive surrogate for plutonium, it was found that cerium(IV) required multiple synergistic anions to bind in the N-lobe of the bilobal transferrin protein, creating a conformation of the cerium-loaded protein that would be unable to interact with the transferrin receptor protein to achieve a separation. The behavior of cerium binding to transferrin has contributed to understanding how plutonium(IV)-transferrin interacts in vivo and in biological separations.

Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1: the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer.

PubMed

Shigeta, S; Toyoshima, M; Kitatani, K; Ishibashi, M; Usui, T; Yaegashi, N

2016-07-07

Fallopian tubal epithelium is a candidate for the origin of high-grade serous ovarian cancer. Transferrin-containing follicular fluid and/or retrograde menstrual blood are possible risk factors for carcinogenesis. Accumulation of DNA double-strand breaks (DNA-DSBs) in the fallopian tubal epithelium is considered to play an important role in the development of cancer. However, the mechanisms by which DNA-DSBs accumulate have not yet been fully elucidated. The hydroxyl radical, which is produced in a Fenton reaction catalyzed by an iron ion, serves as a potent DNA-DSB-inducing molecule, raising the potential of an iron ion transporter of transferrin in the formation of DNA-DSBs. We studied the potential involvement of transferrin in DNA damage and the development of ovarian cancer. Treatment with transferrin facilitated the formation of histone 2AX phosphorylated at Serine 139 (γH2AX), which is known as a DNA-DSB marker, in human fallopian tube secretory epithelial cells and A2780 ovarian cancer cells. Knockdown of transferrin receptor 1 (TfR1), but not transferrin receptor 2, suppressed the transferrin uptake and consequent formation of γH2AX. As hydroxyl radicals in reactive oxygen species (ROS) are involved in DNA-DSBs, the formation of ROS was determined. Treatment with TfR1-specific small interference RNAs significantly diminished transferrin-induced formation of ROS. Moreover, TfR1-dependent uptake of transferrin was revealed to augment the formation of DNA-DSBs in the presence of hydrogen peroxide, which served as a substrate for the Fenton reaction. An ex vivo study with murine fallopian tubes further demonstrated that transferrin treatment introduced DNA-DSBs in the fallopian tubal epithelium. Collectively, these data suggested that the transferrin-TfR1 axis accounts for the induction of DNA-DSBs that potentially lead to DNA damage/genome instability. These findings also suggested that exposure to transferrin initiates and promotes the development of ovarian cancer by aiding the accumulation of DNA-DSBs in the fallopian tubal epithelium.

Host-derived transferrin is maintained and transferred from midgut to ovary in Haemaphysalis longicornis ticks.

PubMed

Mori, Hiroyuki; Galay, Remil Linggatong; Maeda, Hiroki; Matsuo, Tomohide; Umemiya-Shirafuji, Rika; Mochizuki, Masami; Fujisaki, Kozo; Tanaka, Tetsuya

2014-03-01

Transferrin is known to be an iron transporter in vertebrates and several arthropods. Iron from host blood is essential for ovarian development in blood-sucking arthropods. However, tick transferrin has been identified in only a few species, and its function has yet to be elucidated, resulting in incomplete understanding of iron metabolism in ticks. Here, we investigated the transfer of host-derived transferrin in the hard tick Haemaphysalis longicornis using immunological methods. Western blot showed that host-derived transferrin was maintained in all developmental stages of ticks up to 28 days after engorgement and was detected in the midgut and the ovary of adult females following blood feeding. However, no host-derived transferrin was detected in eggs after laying or in larvae after hatching, indicating that host-derived transferrin is not transferred to offspring transovarially. Indirect immunofluorescent antibody testing showed the localization of host-derived transferrin in digestive cells of the midgut and oocytes of the ovary from engorged adult females. These results suggest that host-derived transferrin is transferred to the ovary through the midgut and the hemolymph, and raise the possibility of the function of host-derived transferrin as an iron source in the ovary, providing additional insight on iron metabolism in ticks. Copyright © 2013 Elsevier GmbH. All rights reserved.

A comparison of the suppression of human transferrin synthesis by lead and lipopolysaccharide.

PubMed

Barnum-Huckins, K M; Martinez, A O; Rivera, E V; Adrian, E K; Herbert, D C; Weaker, F J; Walter, C A; Adrian, G S

1997-03-14

Transferrin, as the major iron-transport protein in serum and other body fluids, has a central role in managing iron the body receives. Liver is a major site of transferrin synthesis, and in this study we present evidence that liver synthesis of human transferrin is suppressed by both the toxic metal lead and bacterial lipopolysaccharide, an inducer of the hepatic acute phase response. The responses of intact endogenous transferrin in the human hepatoma cell line HepG2 and chimeric human transferrin-chloramphenicol acetyltransferase genes in transgenic mice were examined. In HepG2 cells, 35S-transferrin protein synthesis and mRNA levels were suppressed by 100 microM and 10 microM lead acetate as early as 24 h after the initial treatment. Yet, synthesis of two proteins known to respond in the hepatic acute phase reaction, complement C3 and albumin, was not altered by the lead treatment. In transgenic mouse liver, lead suppressed expression of chimeric human transferrin genes at both the protein and mRNA levels, but LPS only suppressed at the protein level. The study indicates that lead suppresses human transferrin synthesis by a mechanism that differs from the hepatic acute phase response and that lead may also affect iron metabolism in humans by interfering with transferrin levels.

Calcium-dependent transferrin receptor recycling in bovine chromaffin cells.

PubMed

Knight, Derek E

2002-04-01

The release of regulated secretory granules is known to be calcium dependent. To examine the Ca2+-dependence of other exocytic fusion events, transferrin recycling in bovine chromaffin cells was examined. Internalised 125I-transferrin was released constitutively from cells with a half-time of about 7 min. Secretagogues that triggered catecholamine secretion doubled the rate of 125I-transferrin release, the time courses of the two triggered secretory responses being similar. The triggered 125I-transferrin release came from recycling endosomes rather than from sorting endosomes or a triggered secretory vesicle pool. Triggered 125I-transferrin release, like catecholamine secretion from the same cells, was calcium dependent but the affinities for calcium were very different. The extracellular calcium concentrations that gave rise to half-maximal evoked secretion were 0.1 mm for 125I-transferrin and 1.0 mm for catecholamine, and the intracellular concentrations were 0.1 microm and 1 microm, respectively. There was significant 125I-transferrin recycling in the virtual absence of intracellular Ca2+, but the rate increased when Ca2+ was raised above 1 nm, and peaked at 1 microm when the rate had doubled. Botulinum toxin type D blocked both transferrin recycling and catecholamine secretion. These results indicate that a major component of the vesicular transport required for the constitutive recycling of transferrin in quiescent cells is calcium dependent and thus under physiological control, and also that some of the molecular machinery involved in transferrin recycling/fusion processes is shared with that for triggered neurosecretion.

Pentoxifylline for Anemia in Chronic Kidney Disease: A Systematic Review and Meta-Analysis

PubMed Central

Bolignano, Davide; D’Arrigo, Graziella; Pisano, Anna; Coppolino, Giuseppe

2015-01-01

Background Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this agent may be helpful for anemia management also in CKD patients is still object of debate. Study Design Systematic review and meta-analysis. Population Adults with CKD (any KDOQI stage, including ESKD patients on regular dialysis) and anemia (Hb<13 g/dL in men or < 12 g/dL in women). Search Strategy and Sources Cochrane CENTRAL, EMBASE, Ovid-MEDLINE and PubMed were searched for studies providing data on the effects of PTX on anemia parameters in CKD patients without design or follow-up restriction. Intervention PTX derivatives at any dose regimen. Outcomes Hemoglobin, hematocrit, ESAs dosage and resistance (ERI), iron indexes (ferritin, serum iron, TIBC, transferrin and serum hepcidin) and adverse events. Results We retrieved 11 studies (377 patients) including seven randomized controlled trials (all comparing PTX to placebo or standard therapy) one retrospective case-control study and three prospective uncontrolled studies. Overall, PTX increased hemoglobin in three uncontrolled studies but such improvement was not confirmed in a meta-analysis of seven studies (299 patients) (MD 0.12 g/dL, 95% CI -0.22 to 0.47). Similarly, there were no conclusive effects of PTX on hematocrit, ESAs dose, ferritin and TSAT in pooled analyses. Data on serum iron, ERI, TIBC and hepcidin were based on single studies. No evidence of increased rate of adverse events was also noticed. Limitations Small sample size and limited number of studies. High heterogeneity among studies with respect to CKD and anemia severity, duration of intervention and responsiveness/current therapy with iron or ESAs. Conclusions There is currently no conclusive evidence supporting the utility of pentoxifylline for improving anemia control in CKD patients. Future trials designed on hard, patient-centered outcomes with larger sample size and longer follow-up are advocated. PMID:26237421

The effect of glycosylation on the transferrin structure: A molecular dynamic simulation analysis.

PubMed

Ghanbari, Z; Housaindokht, M R; Bozorgmehr, M R; Izadyar, M

2016-09-07

Transferrins have been defined by the highly cooperative binding of iron and a carbonate anion to form a Fe-CO3-Tf ternary complex. As such, the layout of the binding site residues affects transferrin function significantly; In contrast to N-lobe, C-lobe binding site of the transferrin structure has been less characterized and little research which surveyed the interaction of carbonate with transferrin in the C-lobe binding site has been found. In the present work, molecular dynamic simulation was employed to gain access into the molecular level understanding of carbonate binding site and their interactions in each lobe. Residues responsible for carbonate binding of transferrin structure were pointed out. In addition, native human transferrin is a glycoprotein that two N-linked complex glycan chains located in the C-lobe. Usually, in the molecular dynamic simulation for simplifying, glycan is removed from the protein structure. Here, we explore the effect of glycosylation on the transferrin structure. Glycosylation appears to have an effect on the layout of the binding site residue and transferrin structure. On the other hand, sometimes the entire transferrin formed by separated lobes that it allows the results to be interpreted in a straightforward manner rather than more parameters required for full length protein. But, it should be noted that there are differences between the separated lobe and full length transferrin, hence, a comparative analysis by the molecular dynamic simulation was performed to investigate such structural variations. Results revealed that separation in C-lobe caused a significant structural variation in comparison to N-lobe. Consequently, the separated lobes and the full length one are different, showing the importance of the interlobe communication and the impact of the lobes on each other in the transferrin structure. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of endocytic pathways in cellular uptake of plasma non-transferrin iron

PubMed Central

Sohn, Yang-Sung; Ghoti, Hussam; Breuer, William; Rachmilewitz, Eliezer; Attar, Samah; Weiss, Guenter; Cabantchik, Z. Ioav

2012-01-01

Background In transfusional siderosis, the iron binding capacity of plasma transferrin is often surpassed, with concomitant generation of non-transferrin-bound iron. Although implicated in tissue siderosis, non-transferrin-bound iron modes of cell ingress remain undefined, largely because of its variable composition and association with macromolecules. Using fluorescent tracing of labile iron in endosomal vesicles and cytosol, we examined the hypothesis that non-transferrin-bound iron fractions detected in iron overloaded patients enter cells via bulk endocytosis. Design and Methods Fluorescence microscopy and flow cytometry served as analytical tools for tracing non-transferrin-bound iron entry into endosomes with the redox-reactive macromolecular probe Oxyburst-Green and into the cytosol with cell-laden calcein green and calcein blue. Non-transferrin-bound iron-containing media were from sera of polytransfused thalassemia major patients and model iron substances detected in thalassemia major sera; cell models were cultured macrophages, and cardiac myoblasts and myocytes. Results Exposure of cells to ferric citrate together with albumin, or to non-transferrin-bound iron-containing sera from thalassemia major patients caused an increase in labile iron content of endosomes and cytosol in macrophages and cardiac cells. This increase was more striking in macrophages, but in both cell types was largely reduced by co-exposure to non-transferrin-bound iron-containing media with non-penetrating iron chelators or apo-transferrin, or by treatment with inhibitors of endocytosis. Endosomal iron accumulation traced with calcein-green was proportional to input non-transferrin-bound iron levels (r2=0.61) and also preventable by pre-chelation. Conclusions Our studies indicate that macromolecule-associated non-transferrin-bound iron can initially gain access into various cells via endocytic pathways, followed by iron translocation to the cytosol. Endocytic uptake of plasma non-transferrin-bound iron is a possible mechanism that can contribute to iron loading of cell types engaged in bulk/adsorptive endocytosis, highlighting the importance of its prevention by iron chelation. PMID:22180428

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems § 866.5880 Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Transferrin immunological test system. 866.5880...

Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization.

PubMed

Santi, Melissa; Maccari, Giuseppe; Mereghetti, Paolo; Voliani, Valerio; Rocchiccioli, Silvia; Ucciferri, Nadia; Luin, Stefano; Signore, Giovanni

2017-02-15

The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chemically derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quantitative structure-activity and relationship (QSAR) analysis and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.

A facile drug delivery system preparation through the interaction between drug and iron ion of transferrin

NASA Astrophysics Data System (ADS)

Zhou, Lin; Liu, Jihua; Wei, Shaohua; Ge, Xuefeng; Zhou, Jiahong; Yu, Boyang; Shen, Jian

2013-09-01

Many anticancer drugs have the capability to form stable complex with metal ions. Based on such property, a simple method to combine these drugs with transferrin, through the interaction between drug and Fe ion of transferrin, to improve their anticancer activity, is proposed. To demonstrate this technique, the complex of photosensitive anticancer drug hypocrellin A and transferrin was prepared by such facile method. The results indicated that the complex of hypocrellin A and transferrin can stabilize in aqueous solution. In vitro studies have demonstrated the superior cancer cell uptake ability of hypocrellin A-transferrin complex to the free hypocrellin A. Significant damage to such drug-impregnated tumor cells was observed upon irradiation and the cancer cells killing ability of hypocrellin A-transferrin was stronger than the free hypocrellin A within a certain range of concentrations. The above results demonstrated the validity and potential of our proposed strategy to prepare the drug delivery system of this type of anti-cancer drugs and transferrin.

Erythroblast transferrin receptors and transferrin kinetics in iron deficiency and various anemias

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muta, K.; Nishimura, J.; Ideguchi, H.

1987-06-01

To clarify the role of transferrin receptors in cases of altered iron metabolism in clinical pathological conditions, we studied: number of binding sites; affinity; and recycling kinetics of transferrin receptors on human erythroblasts. Since transferrin receptors are mainly present on erythroblasts, the number of surface transferrin receptors was determined by assay of binding of /sup 125/I-transferrin and the percentage of erythroblasts in bone marrow mononuclear cells. The number of binding sites on erythroblasts from patients with an iron deficiency anemia was significantly greater than in normal subjects. Among those with an aplastic anemia, hemolytic anemia, myelodysplastic syndrome, and polycythemia veramore » compared to normal subjects, there were no considerable differences in the numbers of binding sites. The dissociation constants (Kd) were measured using Scatchard analysis. The apparent Kd was unchanged (about 10 nmol/L) in patients and normal subjects. The kinetics of endocytosis and exocytosis of /sup 125/I-transferrin, examined by acid treatment, revealed no variations in recycling kinetics among the patients and normal subjects. These data suggest that iron uptake is regulated by modulation of the number of surface transferrin receptors, thereby reflecting the iron demand of the erythroblast.« less

Contributions of transferrin to acute inflammation in the goldfish, C. auratus.

PubMed

Trites, M J; Barreda, D R

2017-02-01

Transferrin is an evolutionary conserved protein that in addition to having a critical role in iron transport also has been shown to have a crucial role in host defence, by depriving iron from invading pathogens. Recently cleaved transferrin products was shown to activate macrophages in vitro. We now use an in vivo model of self-resolving peritonitis in goldfish, coupled with gene expression and protein analysis to evaluate the contributions of cleaved transferrin to acute inflammation. We show, for the first time, that cleaved transferrin products are produced in vivo early during an acute inflammatory response. These cleaved transferrin fragments were produced during pathogen-induced, but not sterile, inflammation. Both macrophages and neutrophils were able to contribute to transferrin cleavage. However, only macrophages contributed to this innate process through inducible expression of transferrin. The appearance of transferrin cleavage products in vivo correlated with the influx of leukocytes but did not necessarily correlate the induction of robust respiratory burst and nitric oxide responses. Overall, this study adds to a growing body of work highlighting the role of transferrin as an immune regulator during acute inflammation. Given the significant conservation of this and related molecules, these findings have potentially broad implications for host defences and inflammation control across evolution. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of calcium on hepatocyte iron uptake from transferrin, iron-pyrophosphate and iron-ascorbate.

PubMed

Nilsen, T

1991-10-16

Calcium stimulates hepatocyte iron uptake from transferrin, ferric-iron-pyrophosphate and ferrous-iron-ascorbate. Maximal stimulation of iron uptake is observed at 1-1.5 mM of extra-cellular calcium and the effect is reversible and immediate. Neither the receptor affinity for transferrin, nor the total amounts of transferrin associated with the cells or the rate of transferrin endocytosis are significantly affected by calcium. In the presence of calcium the rate of iron uptake of non-transferrin bound iron increases abruptly at approximate 17 degrees C and 27 degrees C and as assessed by Arrhenius plots, the activation energy is reduced in a calcium dependent manner at approx. 27 degrees C. At a similar temperature, i.e., between 25 degrees C and 28 degrees C, calcium increases the rates of cellular iron uptake from transferrin in a way that is not reflected in the rate of transferrin endocytosis. By the results of this study it is concluded that calcium increases iron transport across the plasma membrane by a mechanism dependent on membrane fluidity.

Comparison of transferrin isoform analysis by capillary electrophoresis and HPLC for screening congenital disorders of glycosylation.

PubMed

Dave, Mihika B; Dherai, Alpa J; Udani, Vrajesh P; Hegde, Anaita U; Desai, Neelu A; Ashavaid, Tester F

2018-01-01

Transferrin, a major glycoprotein has different isoforms depending on the number of sialic acid residues present on its oligosaccharide chain. Genetic variants of transferrin as well as the primary (CDG) & secondary glycosylation defects lead to an altered transferrin pattern. Isoform analysis methods are based on charge/mass variations. We aimed to compare the performance of commercially available capillary electrophoresis CDT kit for diagnosing congenital disorders of glycosylation with our in-house optimized HPLC method for transferrin isoform analysis. The isoform pattern of 30 healthy controls & 50 CDG-suspected patients was determined by CE using a Carbohydrate-Deficient Transferrin kit. The results were compared with in-house HPLC-based assay for transferrin isoforms. Transferrin isoform pattern for healthy individuals showed a predominant tetrasialo transferrin fraction followed by pentasialo, trisialo, and disialotransferrin. Two of 50 CDG-suspected patients showed the presence of asialylated isoforms. The results were comparable with isoform pattern obtained by HPLC. The commercial controls showed a <20% CV for each isoform. Bland Altman plot showed the difference plot to be within +1.96 with no systemic bias in the test results by HPLC & CE. The CE method is rapid, reproducible and comparable with HPLC and can be used for screening Glycosylation defects. © 2017 Wiley Periodicals, Inc.

Quantification of polarized trafficking of transferrin and comparison with bulk membrane transport in hepatic cells

PubMed Central

Wüstner, Daniel

2006-01-01

Transport of the recycling marker transferrin was analysed in polarized hepatic HepG2 cells using quantitative fluorescence microscopy and mathematical modelling. A detailed map and kinetic model for transport of transferrin in hepatic cells was developed. Fluorescent transferrin was found to be transported sequentially through basolateral SE (sorting endosomes) to a SAC/ARC (subapical compartment/apical recycling compartment). DiI (di-indocarbocyanine) lipid probes of different acyl chain length (DiIC12 and DiIC16) co-localized with transferrin in basolateral SE and in the SAC/ARC. By kinetic comparison of hepatic transport of transferrin and labelled HDL (high-density lipoprotein), it is shown that transport of transferrin from SE to the SAC/ARC follows a default pathway together with HDL. Kinetic modelling of fluorescence data provides an identical half-time for SE-to-SAC/ARC transport of transferrin and fluorescent HDL (t½=4.2 min). Fluorescent transferrin was found to recycle with a half-time of t½=12.9 min from the SAC/ARC to the basolateral cell surface of HepG2 cells. In contrast with HDL, targeting of labelled transferrin from the SAC/ARC to the apical biliary canaliculus was negligible. The results indicate that transport from basolateral hepatic SE to the SAC/ARC represents a bulk flow process and that polarized sorting occurs mainly at the level of the SAC/ARC. PMID:16879100

The impact of highly hydrophobic material on the structure of transferrin and its ability to bind iron.

PubMed

Drug, E; Fadeev, L; Gozin, M

2011-05-30

Transferrin is a blood-plasma glycoprotein, which is responsible for ferric-ion delivery and which functions as the most important ferric pool in the body. The reversible complexation process of Fe(3+) ions is associated with conformational changes of the three-dimensional structure of the transferrin. This conformational dynamics is attributed to a partial unfolding of the N-lobe of the protein and could be described as a transition between the holo to the apo forms of the transferrin. The aim of the present work is to demonstrate the unprecedented ability of the transferrin to solubilize various polycyclic aromatic hydrocarbons in physiological solution and to explore the impact of these materials on the structure and functionality of the transferrin. The synthesis and characterization of novel materials, consisting of complexes between human transferrin and hydrophobic high-carbon-content compounds, is reported here for the first time. Furthermore, it is shown that the preparation of these complexes from holo-transferrin leads to an irreversible loss of the ferric ions from the protein. Analytical studies of these novel complexes may shed a light on the mechanism by which transferrin could lose its ability to bind and thus to transport and store iron. These findings clearly demonstrate a possible damaging impact of various hydrophobic pollutants, which can enter an organism by inhalation or ingestion, on the functionality of the transferrin. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The characteristics of transferrin variants by carbohydrate-deficient transferrin tests using capillary zone electrophoresis.

PubMed

Yoo, Gilsung; Kim, Juwon; Yoon, Kap Joon; Lee, Jong-Han

2018-04-17

Transferrin is the major plasma transport protein for iron. We aimed to investigate the characteristics of transferrin variant by carbohydrate-deficient transferrin (CDT) test using capillary zone electrophoresis. We retrospectively analyzed the CDT tests of 2449 patients from March 2009 to May 2017 at a tertiary hospital in Korea. CDT was quantified using a Capillarys 2 system (Sebia, Lisses, France) by capillary zone electrophoresis. The characteristics of variant transferrin patterns using electropherogram of CDT tests were analyzed. Seventy-seven (3.1%) patients were classified as variant transferrin. Mean age of these patients was 51.8 years, and the male-to-female ratio was 3.5:1. The most common variants were the BC variants (n = 37), followed by the CD variants (n = 27), unclear patterns (n = 7), BD variants (n = 3), CC variants (n = 2), misclassification (n = 1). In the variant Tf group, the most common disease was alcoholic liver cirrhosis (n = 22, 28.6%), followed by the toxic effects of substances (n = 17, 22.1%), and mental and behavioral disorders attributable to alcohol (n = 11, 14.3%). Nonvariant group showed a predominance of the toxic substance effects (n = 880, 37.1%), a personal history of suicide attempts (n = 634, 26.7%), and mental and behavioral disorders due to alcohol (n = 336, 14.2%). We analyzed the basic characteristics of variant transferrin by CDT tests using capillary zone electrophoresis. The prevalence of variant transferrin was 3.1% of the study subjects. Male patients, alcohol abusers, and liver cirrhosis patients predominated in the variant transferrin population. Further prospective studies are warranted to elucidate variant transferrin in clinical practice. © 2018 Wiley Periodicals, Inc.

Fibroblast growth factor 23, iron and inflammation - are they related in early stages of chronic kidney disease?

PubMed

Lukaszyk, Ewelina; Lukaszyk, Mateusz; Koc-Zorawska, Ewa; Bodzenta-Lukaszyk, Anna; Malyszko, Jolanta

2017-06-01

Fibroblast growth factor 23 (FGF-23) levels are elevated in impaired renal function. Inflammation and iron are potential regulators of FGF-23. The aim of the study was to evaluate the association between FGF-23 concentration, novel iron status biomarkers and inflammatory parameters among patients with early stages of chronic kidney disease (CKD). The study population included 84 patients with CKD in the early stage. Serum hemoglobin, fibrinogen, creatinine, iron, transferrin saturation and ferritin levels were measured using standard laboratory methods. Commercially available kits were used to measure: intact FGF-23, hepcidin, soluble transferrin receptor (sTfR), interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP). In patients with CKD no differences in FGF-23 concentration according to iron status were observed. Lower iron concentration was associated with higher concentrations of hsCRP, IL-6 and fibrinogen. In univariate and multivariate analysis FGF-23 correlated with fibrinogen ( r = -0.23, p < 0.05) and eGFR ( r = -0.36, p < 0.05). FGF-23 is affected by kidney function and fibrinogen but not iron status parameters in the early stages of CKD. Our data are paving the way for further studies on the role of FGF-23 in iron metabolism, especially in early stages of CKD.

Receptor-mediated internalization of [3H]-neurotensin in synaptosomal preparations from rat neostriatum.

PubMed

Nguyen, Ha Minh Ky; Cahill, Catherine M; McPherson, Peter S; Beaudet, Alain

2002-06-01

Following its binding to somatodendritic receptors, the neuropeptide neurotensin (NT) internalizes via a clathrin-mediated process. In the present study, we investigated whether NT also internalizes presynaptically using synaptosomes from rat neostriatum, a region in which NT1 receptors are virtually all presynaptic. Binding of [(3)H]-NT to striatal synaptosomes in the presence of levocabastine to block NT2 receptors is specific, saturable, and has NT1 binding properties. A significant fraction of the bound radioactivity is resistant to hypertonic acid wash indicating that it is internalized. Internalization of [(3)H]-NT, like that of [(125)I]-transferrin, is blocked by sucrose and low temperature, consistent with endocytosis occurring via a clathrin-dependent pathway. However, contrary to what was reported at the somatodendritic level, neither [(3)H]-NT nor [(125)I]-transferrin internalization in synaptosomes is sensitive to the endocytosis inhibitor phenylarsine oxide. Moreover, treatment of synaptosomes with monensin, which prevents internalized receptors from recycling to the plasma membrane, reduces [(3)H]-NT binding and internalization, suggesting that presynaptic NT1 receptors, in contrast to somatodendritic ones, are recycled back to the plasma membrane. Taken together, these results suggest that NT internalizes in nerve terminals via an endocytic pathway that is related to, but is mechanistically distinct from that responsible for NT internalization in nerve cell bodies.

Pressure sores and blood and serum dysmetabolism in spinal cord injury patients.

PubMed

Scivoletto, G; Fuoco, U; Morganti, B; Cosentino, E; Molinari, M

2004-08-01

Spinal cord injury (SCI) patients with pressure sores were studied before and after surgical intervention for ulcer healing and compared with matched SCI patients without sores and with patients with pressure sores and other diseases. To analyse the relationship between pressure sores and anaemia and serum protein alteration in SCI patients. To study the pathogenesis of these alterations and suggest appropriate therapy. Spinal cord unit in Rome, Italy. A total of 13 SCI patients with pressure sores, 13 comparable patients without pressure sores and four patients with other diseases and pressure sores. Haematochemical parameters. Patients with pressure sore showed significant decreased red cells, decreased haemoglobin and haematocrit, increased white cells and ferritin and decreased transferrin and transferrin saturation; total hypoproteinemia and hypoalbuminemia with increased Alfa-1 and gamma globulins increased erythrocyte sedimentation rate and C-reactive protein were also present. The alterations returned to normal after surgical intervention for pressure sore healing. Patients with pressure sores suffer from anaemia and serum protein alteration that fells within the range of metabolic alteration of chronic disorders and neoplastic diseases. The alterations depend on a decreased utilisation of iron stores in the reticuloendothelial system and on inhibition of the hepatic synthesis of albumin. With regard to treatment, iron treatment should be avoided because of the risk of haemochromatosis.

Serum hepcidin levels and muscle iron proteins in humans injected with low- or high-dose erythropoietin.

PubMed

Robach, Paul; Recalcati, Stefania; Girelli, Domenico; Campostrini, Natascia; Kempf, Tibor; Wollert, Kai C; Corbella, Michela; Santambrogio, Paolo; Perbellini, Luigi; Brasse-Lagnel, Carole; Christensen, Britt; Moutereau, Stéphane; Lundby, Carsten; Cairo, Gaetano

2013-07-01

Inhibition of hepcidin expression by erythropoietic signals is of great physiological importance; however, the inhibitory pathways remain poorly understood. To investigate (i) the direct effect of erythropoietin (Epo) and (ii) the contribution of putative mediators on hepcidin repression, healthy volunteers were injected with a single dose of Epo, either low (63 IU/kg, n = 8) or high (400 IU/kg, n = 6). Low-dose Epo provoked hepcidin down-modulation within 24 h; the effect was not immediate as hepcidin circadian variations were still present following injection. High-dose Epo induced no additional effect on the hepcidin response, that is hepcidin diurnal fluctuations were not abolished in spite of extremely high Epo levels. We did not find significant changes in putative mediators of hepcidin repression, such as transferrin saturation, soluble transferrin receptor, or growth differentiation factor 15. Furthermore, the potential hepcidin inhibitor, soluble hemojuvelin, was found unaltered by Epo stimulation. This finding was consistent with the absence of signs of iron deficiency observed at the level of skeletal muscle tissue. Our data suggest that hepcidin repression by erythropoietic signals in humans may not be controlled directly by Epo, but mediated by a still undefined factor. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Oral Zinc Supplementation Decreases the Serum Iron Concentration in Healthy Schoolchildren: A Pilot Study

PubMed Central

de Brito, Naira Josele Neves; de Medeiros Rocha, Érika Dantas; de Araújo Silva, Alfredo; Costa, João Batista Sousa; França, Mardone Cavalcante; das Graças Almeida, Maria; Brandão-Neto, José

2014-01-01

The recognized antagonistic actions between zinc and iron prompted us to study this subject in children. A convenience sample was used. Thirty healthy children between 8 and 9 years of age were studied with the aim of establishing the effect of a 3-mo oral zinc supplementation on iron status. Fifteen individuals were given a placebo (control group), and 15 were given 10 mg Zn/day (experimental group). Blood samples were collected at 0, 60, 120, 180 and 210 min after a 12-h overnight fast, before and after placebo or zinc supplementation. This supplementation was associated with significant improvements in energy, protein, fat, carbohydrate, fiber, calcium, iron, and zinc intake in accordance with the recommendations for age and sex. The basal serum zinc concentration significantly increased after oral zinc supplementation (p < 0.001). However, basal serum iron concentrations and area under the iron curves significantly decreased in the experimental group (p < 0.0001) and remained at the same level throughout the 210-min study. The values obtained for hemoglobin, mean corpuscular volume, ferritin, transferrin, transferrin saturation, ceruloplasmin and total protein were within normal reference ranges. In conclusion, the decrease in serum iron was likely due to the effects of chronic zinc administration, and the decrease in serum iron was not sufficient to cause anemia. PMID:25192026

Mechanism and developmental changes in iron transport across the blood-brain barrier.

PubMed

Morgan, Evan H; Moos, Torben

2002-01-01

Transferrin and iron uptake by the brain were measured using [(59)Fe-(125)I]transferrin injected intravenously in rats aged from 15 days to 22 weeks. The values for both decreased with age. In rats aged 18 and 70 days the uptake was measured at short time intervals after the injection. When expressed as the volume of distribution (Vd), which represents the volume of plasma from which the transferrin and iron were derived, the results for iron were greater than those of transferrin as early as 7 min after injection and the difference increased rapidly with time, especially in the younger animals. A very similar time course was found for uptake by bone marrow (femurs) where iron uptake involves receptor-mediated endocytosis of Fe-transferrin, release of iron in the cell and recycling of apo-transferrin to the blood. It is concluded that, during transport of transferrin-bound plasma iron into the brain, a similar process occurs in brain capillary endothelial cells (BCECs) and that transcytosis of transferrin into the brain interstitium is only a minor pathway. Also, the high rate of iron transport into the brain in young animals, when iron requirements are high due to rapid growth of the brain, is a consequence of the level of expression and rate of recycling of transferrin receptors on BCECs. As the animal and brain mature both decrease. Copyright 2002 S. Karger AG, Basel

Inducing cell death in vitro in cancer cells by targeted delivery of cytochrome c via a transferrin conjugate

PubMed Central

Delgado, Yamixa; Sharma, Rohit Kumar; Sharma, Shweta; Guzmán, Solimar Liz Ponce De León; Tinoco, Arthur D.; Griebenow, Kai

2018-01-01

One of the major drawbacks of many of the currently used cancer drugs are off-target effects. Targeted delivery is one method to minimize such unwanted and detrimental events. To actively target lung cancer cells, we have developed a conjugate of the apoptosis inducing protein cytochrome c with transferrin because the transferrin receptor is overexpressed by many rapidly dividing cancer cells. Cytochrome c and transferrin were cross-linked with a redox sensitive disulfide bond for the intra-cellular release of the protein upon endocytosis by the transferrin receptor. Confocal results demonstrated the cellular uptake of the cytochrome c-transferrin conjugate by transferrin receptor overexpressing A549 lung cancer cells. Localization studies further validated that this conjugate escaped the endosome. Additionally, an in vitro assay showed that the conjugate could induce apoptosis by activating caspase-3. The neo-conjugate not only maintained an IC50 value similar to the well known drug cisplatin (50 μM) in A549 cancer cells but also was nontoxic to the normal lung (MRC5) cells. Our neo-conjugate holds promise for future development to target cancers with enhanced transferrin receptor expression. PMID:29649293

Binding of trivalent chromium to serum transferrin is sufficiently rapid to be physiologically relevant.

PubMed

Deng, Ge; Wu, Kristi; Cruce, Alex A; Bowman, Michael K; Vincent, John B

2015-02-01

Transferrin, the major iron transport protein in the blood, also transports trivalent chromium in vivo. Recent in vitro studies have, however, suggested that the binding of chromic ions to apotransferrin is too slow to be biologically relevant. Nevertheless, the in vitro studies have generally failed to adequately take physiological bicarbonate concentrations into account. In aqueous buffer (with ambient (bi)carbonate concentrations), the binding of chromium to transferrin is too slow to be physiologically relevant, taking days to reach equilibrium with the protein's associated conformational changes. However, in the presence of 25mM (bi)carbonate, the concentration in human blood, chromic ions bind rapidly and tightly to transferrin. Details of the kinetics of chromium binding to human serum transferrin and conalbumin (egg white transferrin) in the presence of bicarbonate and other major potential chromium ligands are described and are consistent with transferrin being the major chromic ion transporter from the blood to tissues. Copyright © 2014 Elsevier Inc. All rights reserved.

Cross sectional, comparative study of serum erythropoietin, transferrin receptor, ferritin levels and other hematological indices in normal pregnancies and iron deficiency anemia during pregnancy.

PubMed

Sharma, Jai B; Bumma, Sirisha D; Saxena, Renu; Kumar, Sunesh; Roy, Kallol K; Singh, Neeta; Vanamail, P

2016-08-01

To test the correlation of the serum erythropoietin levels, serum transferrrin receptor levels and serum ferritin levels along with other hematological parameters in normal pregnant and anemic pregnant patients. In a prospective study, 120 pregnant women were recruited between 18 and 36 weeks of gestation; 53 normal pregnant patients, 67 anemic pregnant patients, in which, 17 had mild, 30 had moderate anemia, 20 had severe anemia. A blood sample was taken. The various hematological parameters, hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), total iron binding capacity (TIBC), serum ferritin, percentage saturation of iron, serum erythropoietin (SEPO) levels, serum transferrin receptors (STfRS) were performed. For statistics, Student's 't' test, Pearson's Chi test, Mann Whitney test and Bartlett test were used as per data. MCV was significantly reduced in anemic pregnancies as compared to non-anemic pregnancies (80.2±9.6 vs 94.12±9.8fl, p=0.001), MCHC was also reduced in them (30.2±3.38% vs 34.2±2.33%, p=0.176), TIBC was significantly increased in anemic pregnancies (343.31±28.54% vs 322.88±23.84%, p=0.001), serum ferritin was significantly reduced (24.9±10.48μg/L vs 31.03±9.98μg/L, p=0.001), percentage saturation of iron was also reduced (53.85±13.21% vs 62.04±15.79%, p=0.0024), serum erythropoietin levels were significantly higher in anemic women (26.24±26.61mU/ml vs 18.12±19.08mU/ml, p=0.064). The levels were significantly higher in severe anemia (46.5±46.8mU/ml than in moderate anemia 27.4±28.1mU/ml and mild anemia 22.8±22.8mU/ml. Serum transferrin receptors were significantly higher in anemic pregnancies than in non-anemic pregnancies (1.40±0.0802μg/ml vs 1.08±0.641μg/ml, p=0.019) with rise being higher in severe anemia (2.28±0.986μg/ml) than in moderate (1.4±0.816μg/ml) and mild anemia (1.16±0.702μg/ml). Various hematological parameters especially sTfR, serum erythropoietin, serum ferritin and sTfR/log ferritin levels correlate with the severity of anemia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The effect of monoclonal antibodies to the human transferrin receptor on transferrin and iron uptake by rat and rabbit reticulocytes.

PubMed

McArdle, H J; Morgan, E H

1984-02-10

The effect of monoclonal antibodies to the human transferrin receptor on transferrin and iron uptake by rat and rabbit reticulocytes has been examined. The antibodies used were as follows: T58/1.4, B3/25.4, 42/6.3, T56/14.3.1, and 43/31. The effects were the same, irrespective of the antibody. Transferrin and iron uptake were stimulated in both rat and rabbit reticulocytes. The stimulation was not due to an increase in the number or affinity of the receptors, but rather to an increase in the rate of turnover of the receptors. Electron microscopy suggested that the antibody acted by facilitating the formation of coated pits containing the transferrin-receptor complex.

Intravenous iron-dextran: studies on unsaturated iron-binding capacity

PubMed Central

Cox, J. S. G.; Moss, G. F.; Bremner, I.; Reason, Janet

1968-01-01

A method is described for measuring the plasma unsaturated iron-binding capacity in the presence of very high concentrations of iron as iron-dextran. The procedure utilizes 59Fe to label the apotransferrin with subsequent separation of ionic iron from transferrin-bound iron on an ion exchange or Sephadex G.25 column. The unsaturated iron-binding capacity has been measured in rabbits and dogs after intravenous injection of iron-dextran and in human subjects after total dose infusion of iron-dextran. No evidence of saturation of the unsaturated iron-binding capacity was found even when the plasma iron values were greater than 40,000 μg Fe/100 ml. PMID:5697365

Sorting of endocytosed transferrin and asialoglycoprotein occurs immediately after internalization in HepG2 cells

PubMed Central

1987-01-01

After receptor-mediated uptake, asialoglycoproteins are routed to lysosomes, while transferrin is returned to the medium as apotransferrin. This sorting process was analyzed using 3,3'- diaminobenzidine (DAB) cytochemistry, followed by Percoll density gradient cell fractionation. A conjugate of asialoorosomucoid (ASOR) and horseradish peroxidase (HRP) was used as a ligand for the asialoglycoprotein receptor. Cells were incubated at 0 degree C in the presence of both 131I-transferrin and 125I-ASOR/HRP. Endocytosis of prebound 125I-ASOR/HRP and 131I-transferrin was monitored by cell fractionation on Percoll density gradients. Incubation of the cell homogenate in the presence of DAB and H2O2 before cell fractionation gave rise to a density shift of 125I-ASOR/HRP-containing vesicles due to HRP-catalyzed DAB polymerization. An identical change in density for 125I-transferrin and 125I-ASOR/HRP, induced by DAB cytochemistry, is taken as evidence for the concomitant presence of both ligands in the same compartment. At 37 degrees C, sorting of the two ligands occurred with a half-time of approximately 2 min, and was nearly completed within 10 min. The 125I-ASOR/HRP-induced shift of 131I-transferrin was completely dependent on the receptor-mediated uptake of 125I-ASOR/HRP in the same compartment. In the presence of a weak base (0.3 mM primaquine), the recycling of transferrin receptors was blocked. The cell surface transferrin receptor population was decreased within 6 min to 15% of its original size. DAB cytochemistry showed that sorting between endocytosed 131I-transferrin and 125I-ASOR/HRP was also blocked in the presence of primaquine. These results indicate that transferrin and asialoglycoprotein are taken up via the same compartments and that segregation of the transferrin-receptor complex and asialoglycoprotein occurs very efficiently soon after uptake. PMID:3032986

Polymorphism, selection and tandem duplication of transferrin genes in Atlantic cod (Gadus morhua) - Conserved synteny between fish monolobal and tetrapod bilobal transferrin loci

PubMed Central

2011-01-01

Background The two homologous iron-binding lobes of transferrins are thought to have evolved by gene duplication of an ancestral monolobal form, but any conserved synteny between bilobal and monolobal transferrin loci remains unexplored. The important role played by transferrin in the resistance to invading pathogens makes this polymorphic gene a highly valuable candidate for studying adaptive divergence among local populations. Results The Atlantic cod genome was shown to harbour two tandem duplicated serum transferrin genes (Tf1, Tf2), a melanotransferrin gene (MTf), and a monolobal transferrin gene (Omp). Whereas Tf1 and Tf2 were differentially expressed in liver and brain, the Omp transcript was restricted to the otoliths. Fish, chicken and mammals showed highly conserved syntenic regions in which monolobal and bilobal transferrins reside, but contrasting with tetrapods, the fish transferrin genes are positioned on three different linkage groups. Sequence alignment of cod Tf1 cDNAs from Northeast (NE) and Northwest (NW) Atlantic populations revealed 22 single nucleotide polymorphisms (SNP) causing the replacement of 16 amino acids, including eight surface residues revealed by the modelled 3D-structures, that might influence the binding of pathogens for removal of iron. SNP analysis of a total of 375 individuals from 14 trans-Atlantic populations showed that the Tf1-NE variant was almost fixed in the Baltic cod and predominated in the other NE Atlantic populations, whereas the NW Atlantic populations were more heterozygous and showed high frequencies of the Tf-NW SNP alleles. Conclusions The highly conserved synteny between fish and tetrapod transferrin loci infers that the fusion of tandem duplicated Omp-like genes gave rise to the modern transferrins. The multiple nonsynonymous substitutions in cod Tf1 with putative structural effects, together with highly divergent allele frequencies among different cod populations, strongly suggest evidence for positive selection and local adaptation in trans-Atlantic cod populations. PMID:21612617

Polymorphism, selection and tandem duplication of transferrin genes in Atlantic cod (Gadus morhua)--conserved synteny between fish monolobal and tetrapod bilobal transferrin loci.

PubMed

Andersen, Øivind; De Rosa, Maria Cristina; Pirolli, Davide; Tooming-Klunderud, Ave; Petersen, Petra E; André, Carl

2011-05-25

The two homologous iron-binding lobes of transferrins are thought to have evolved by gene duplication of an ancestral monolobal form, but any conserved synteny between bilobal and monolobal transferrin loci remains unexplored. The important role played by transferrin in the resistance to invading pathogens makes this polymorphic gene a highly valuable candidate for studying adaptive divergence among local populations. The Atlantic cod genome was shown to harbour two tandem duplicated serum transferrin genes (Tf1, Tf2), a melanotransferrin gene (MTf), and a monolobal transferrin gene (Omp). Whereas Tf1 and Tf2 were differentially expressed in liver and brain, the Omp transcript was restricted to the otoliths. Fish, chicken and mammals showed highly conserved syntenic regions in which monolobal and bilobal transferrins reside, but contrasting with tetrapods, the fish transferrin genes are positioned on three different linkage groups. Sequence alignment of cod Tf1 cDNAs from Northeast (NE) and Northwest (NW) Atlantic populations revealed 22 single nucleotide polymorphisms (SNP) causing the replacement of 16 amino acids, including eight surface residues revealed by the modelled 3D-structures, that might influence the binding of pathogens for removal of iron. SNP analysis of a total of 375 individuals from 14 trans-Atlantic populations showed that the Tf1-NE variant was almost fixed in the Baltic cod and predominated in the other NE Atlantic populations, whereas the NW Atlantic populations were more heterozygous and showed high frequencies of the Tf-NW SNP alleles. The highly conserved synteny between fish and tetrapod transferrin loci infers that the fusion of tandem duplicated Omp-like genes gave rise to the modern transferrins. The multiple nonsynonymous substitutions in cod Tf1 with putative structural effects, together with highly divergent allele frequencies among different cod populations, strongly suggest evidence for positive selection and local adaptation in trans-Atlantic cod populations.

Effect of non-surgical periodontal treatment on transferrin serum levels in patients with chronic periodontitis

PubMed Central

Shirmohamadi, Adileh; Chitsazi, Mohamad Taghi; Faramarzi, Masoumeh; Salari, Ashkan; Naser Alavi, Fereshteh; Pashazadeh, Nazila

2016-01-01

Background. Transferrin is a negative acute phase protein, which decreases during inflammation and infection. The aim of the present investigation was to evaluate changes in the transferrin serum levels subsequent to non-surgical treatment of chronic periodontal disease. Methods. Twenty patients with chronic periodontitis and 20 systemically healthy subjects without periodontal disease, who had referred to Tabriz Faculty of Dentistry, were selected. Transferrin serum levels and clinical periodontal parameters (pocket depth, clinical attachment level, gingival index, bleeding index and plaque index) were measured at baseline and 3 months after non-surgical periodontal treatment. Data were analyzed with descriptive statistical methods (means ± standard deviations). Independent samples t-test was used to compare transferrin serum levels and clinical variables between the test and control groups. Paired samples t-test was used in the test group for comparisons before and after treatment. Statistical significance was set at P < 0.05. Results. The mean transferrin serum level in patients with chronic periodontitis (213.1 ± 9.2 mg/dL) was significantly less than that in periodontally healthy subjects (307.8 ± 11.7 mg/dL). Three months after periodontal treatment, the transferrin serum level increased significantly (298.3 ± 7.6 mg/dL) and approached the levels in periodontally healthy subjects (P < 0.05). Conclusion. The decrease and increase in transferrin serum levels with periodontal disease and periodontal treatment, respectively, indicated an inverse relationship between transferrin serum levels and chronic periodontitis. PMID:27651883

Cloning and characterization of transferrin cDNA and rapid detection of transferrin gene polymorphism in rainbow trout (Oncorhynchus mykiss).

PubMed

Tange, N; Jong-Young, L; Mikawa, N; Hirono, I; Aoki, T

1997-12-01

A cDNA clone of rainbow trout (Oncorhynchus mykiss) transferrin was obtained from a liver cDNA library. The 2537-bp cDNA sequence contained an open reading frame encoding 691 amino acids and the 5' and 3' noncoding regions. The amino acid sequences at the iron-binding sites and the two N-linked glycosylation sites, and the cysteine residues were consistent with known, conserved vertebrate transferrin cDNA sequences. Single N-linked glycosylation sites existed on the N- and C-lobe. The deduced amino acid sequence of the rainbow trout transferrin cDNA had 92.9% identities with transferrin of coho salmon (Oncorhynchus kisutch); 85%, Atlantic salmon (Salmo salar); 67.3%, medaka (Oryzias latipes); 61.3% Atlantic cod (Gadus morhua); and 59.7%, Japanese flounder (Paralichthys olivaceus). The long and accurate polymerase chain reaction (LA-PCR) was used to amplify approximately 6.5 kb of the transferrin gene from rainbow trout genomic DNA. Restriction fragment length polymorphisms (RFLPs) of the LA-PCR products revealed three digestion patterns in 22 samples.

Alterations in sympathetic nerve traffic in genetic haemochromatosis before and after iron depletion therapy: a microneurographic study.

PubMed

Seravalle, Gino; Piperno, Alberto; Mariani, Raffaella; Pelloni, Irene; Facchetti, Rita; Dell'Oro, Raffaella; Cuspidi, Cesare; Mancia, Giuseppe; Grassi, Guido

2016-03-21

Haemochromatosis (HH) displays a number of circulatory alterations concurring at increase cardiovascular risk. Whether these include sympathetic abnormalities in unknown. In 18 males with primary HH (age: 42.3 ± 10.4 years, mean ± SD), clinic and beat-to-beat blood pressure (BP, Finapres), heart rate (HR, EKG), and muscle sympathetic nerve activity (MSNA, microneurography) traffic were measured in the iron overload state and after iron depletion therapy. Haemochromatosis patients displayed elevated serum iron indices while other haemodynamic and metabolic variables were superimposable to ones seen in 12 healthy subjects (C). Muscle sympathetic nerve activity was significantly greater in HH than C (64.8 ± 13.3 vs. 37.8 ± 6.7 bs/100 hb, P < 0.01). Iron depletion caused a significant reduction in serum ferritin, transferrin saturation, and MSNA (from 64.8 ± 13.3 to 39.2 ± 9.2 bs/100 hb, P < 0.01) and a significant improvement in baroreflex-MSNA modulation. This was paralleled by a significant increase in the high-frequency HR variability and by a significant reduction in the low-frequency systolic BP variability components. Before after iron depletion therapy, MSNA was significantly and directly related to transferrin saturation, liver iron concentration, and iron removed, while the MSNA reductions observed after the procedure were significantly and inversely related to the baroreflex-MSNA increases detected after iron depletion. In C, all variables remained unchanged following 1 month observation. These data provide the first evidence that in HH iron overload is associated with an hyperadrenergic state and a baroreflex alteration, which are reversed by iron depletion. These findings underline the importance of iron overload in modulating sympathetic activation, possibly participating at the elevated cardiovascular risk reported in HH. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Cognitive function, iron status, and hemoglobin concentration in obese dieting women.

PubMed

Kretsch, M J; Fong, A K; Green, M W; Johnson, H L

1998-07-01

To determine the relationships between cognitive function and iron status in dieting obese women. Longitudinal weight loss study (repeated measures within-subject design) with 3 weeks of baseline, 15 weeks of 50% caloric restriction, and 3 weeks of weight stabilization. Dietary iron was fed at twice the US Recommended Dietary Allowance with half of the iron from food sources and half from an oral supplement. This was a free-living study with the exception that subjects came to the research center for one meal per day and were provided all other meals and snacks to take home. Healthy, premenopausal, obese women (mean BMI=31.5) were recruited through local newspaper, poster and radio advertising. Twenty-four women volunteers were recruited and 14 completed the study. Cognitive function, iron and hematological status, height, body weights and body composition were measured at baseline; at weeks 5, 10, and 15 of the energy restriction period; and at the end of weight stabilization. Computerized cognitive tests included: Bakan vigilance task, two finger tapping, simple reaction time, immediate word recall, and a focused attention task. Iron status and hematological measures included: serum iron, total iron binding capacity (TIBC), transferrin saturation, serum ferritin, hemoglobin (Hb), hematocrit, red cell count, MCV, MCH, MCHC, and RDW. A significant reduction in Hb, hematocrit, and red blood cell count occurred across the study. Hb at the end of the study was positively correlated (r=0.72, P < 0.01) with mean performance on a measure of sustained attention. Transferrin saturation also correlated positively to sustained attention task performance for those subjects whose Hb declined across the study (r=0.86, P < 0.01). These findings suggest that dieting diminishes iron status in obese women, even when sufficient dietary iron is available, and that the inability to sustain attention may be an early sign of developing iron deficiency in dieting women.

Management of early renal anaemia: diagnostic work-up, iron therapy, epoetin therapy.

PubMed

Van Wyck, D B

2000-01-01

Effective management of early anaemia in the course of chronic renal insufficiency requires the following: (i) implementing an efficient diagnostic strategy to exclude common contributing factors; (ii) initiating epoetin therapy for the majority of patients; for and (iii) ensuring adequate iron supply erythropoiesis. Diagnostic inquiry is warranted whenever the haemoglobin concentration is below the normal range adjusted for age and gender. The most efficient diagnostic approach is to assume erythropoietin deficiency, exclude iron deficiency, and pursue further diagnostic tests only when red-cell indices are abnormal or when leukopenia or thrombocytopenia are also present. Macrocytosis should prompt an inquiry into alcoholism, B12 deficiency, or folate deficiency. Microcytosis suggests iron deficiency or thalassaemia. Associated cytopenias raise the possibility of alcohol toxicity, pernicious anaemia, malignancy, or myelodysplastic syndrome. Epoetin therapy is warranted whenever the haemoglobin concentration has fallen below 10.0 g/dl. To initiate therapy prior to dialysis, epoetin should be administered at an average dose of 100 IU/kg/week (80-120 IU/kg/week, 50-150 IU/kg/ week) by subcutaneous injection. Haemoglobin concentration should be monitored every 2 weeks and the epoetin dose adjusted by increments or decrements of 25% to maintain a rate of rise of haemoglobin concentration of 0.2-0.6 g/dl (0.3 0.6 g/dl/week, 0.2-0.5 g/dl/week). When the target range is achieved, the dose of epoetin should be continually adjusted to maintain a stable haemoglobin concentration. Transferrin saturation and ferritin concentration should be monitored monthly, and sufficient iron provided to maintain transferrin saturation above 20%. The lower the haemoglobin concentration, the greater the likelihood that future intravenous iron will be required. Oral iron supplements should be avoided, since they are costly, ineffective, and troublesome to patients. Finally, a blunted therapeutic response to epoetin therapy provides important diagnostic information and gnostic inquiry.

Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer.

PubMed

Keeler, B D; Simpson, J A; Ng, O; Padmanabhan, H; Brookes, M J; Acheson, A G

2017-02-01

Treatment of preoperative anaemia is recommended as part of patient blood management, aiming to minimize perioperative allogeneic red blood cell transfusion. No clear evidence exists outlining which treatment modality should be used in patients with colorectal cancer. The study aimed to compare the efficacy of preoperative intravenous and oral iron in reducing blood transfusion use in anaemic patients undergoing elective colorectal cancer surgery. Anaemic patients with non-metastatic colorectal adenocarcinoma were recruited at least 2 weeks before surgery and randomized to receive oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. Perioperative changes in haemoglobin, ferritin, transferrin saturation and blood transfusion use were recorded until postoperative outpatient review. Some 116 patients were included in the study. There was no difference in blood transfusion use from recruitment to trial completion in terms of either volume of blood administered (P = 0·841) or number of patients transfused (P = 0·470). Despite this, increases in haemoglobin after treatment were higher with intravenous iron (median 1·55 (i.q.r. 0·93-2·58) versus 0·50 (-0·13 to 1·33) g/dl; P < 0·001), which was associated with fewer anaemic patients at the time of surgery (75 versus 90 per cent; P = 0·048). Haemoglobin levels were thus higher at surgery after treatment with intravenous than with oral iron (mean 11·9 (95 per cent c.i. 11·5 to 12·3) versus 11·0 (10·6 to 11·4) g/dl respectively; P = 0·002), as were ferritin (P < 0·001) and transferrin saturation (P < 0·001) levels. Intravenous iron did not reduce the blood transfusion requirement but was more effective than oral iron at treating preoperative anaemia and iron deficiency in patients undergoing colorectal cancer surgery. © 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

PubMed Central

Gallego, Carlos J.; Burt, Amber; Sundaresan, Agnes S.; Ye, Zi; Shaw, Christopher; Crosslin, David R.; Crane, Paul K.; Fullerton, S. Malia; Hansen, Kris; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; de Andrade, Mariza; McCarty, Catherine A.; Kitchner, Terrie E.; Ragon, Brittany K.; Stallings, Sarah C.; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E.; Aufox, Sharon A.; Pacheco, Jennifer A.; Patel, Vaibhav; Friesema, Elisha M.; Erwin, Angelika Ludtke; Gottesman, Omri; Gerhard, Glenn S.; Ritchie, Marylyn; Motulsky, Arno G.; Kullo, Iftikhar J.; Larson, Eric B.; Tromp, Gerard; Brilliant, Murray H.; Bottinger, Erwin; Denny, Joshua C.; Roden, Dan M.; Williams, Marc S.; Jarvik, Gail P.

2015-01-01

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data. PMID:26365338

Relationship between high serum ferritin level and glaucoma in a South Korean population: the Kangbuk Samsung health study.

PubMed

Gye, Hyo Jung; Kim, Joon Mo; Yoo, Chungkwon; Shim, Seong Hee; Won, Yu Sam; Sung, Ki Chul; Lee, Mi Yeon; Park, Ki Ho

2016-12-01

To investigate the association between serum ferritin levels and glaucoma in a South Korean population. This retrospective cross-sectional study included 164 029 subjects who underwent screening at Kangbuk Samsung Hospital Health Screening Center between August 2012 and July 2013. All subjects underwent a physical examination, answered sociodemographic and behavioural questions, and provided samples for laboratory analyses. A digital fundus photograph of both eyes was taken, and all photographs were reviewed by ophthalmologists. The ophthalmologists determined if an eye had glaucoma based on criteria set forth by the International Society of Geographical and Epidemiological Ophthalmology and the appearance of the retinal nerve fibre layer and optic disc. The mean serum ferritin level was 56.98 ng/mL in women and 223.82 ng/mL in men. After adjusting for age, serum iron, total iron-binding capacity (TIBC), transferrin saturation, white blood cell (WBC) count, high-sensitivity C-reactive protein (HsCRP) and total vitamin D level, males in the highest quartile for serum ferritin level had a higher OR for glaucoma than males in the lowest quartile (OR=1.176, 95% CI 1.030 to 1.342, p=0.016); we did not observe this relationship among women. Other markers of iron metabolism, such as iron level, transferrin saturation and TIBC, and inflammation measures, including WBC, HsCRP and total vitamin D, were not associated with glaucoma. High serum ferritin level was associated with a high risk of glaucoma in men, but not in women. Because serum ferritin is related to oxidative stress and inflammation, it might play a role in glaucoma development. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Comparative haematological parameters of HbAA and HbAS genotype children infected with Plasmodium falciparum malaria in Yemen.

PubMed

Albiti, Anisa H; Nsiah, Kwabena

2014-04-01

Sickle haemoglobin (HbS) is known to offer considerable protection against falciparum malaria. However, the mechanism of protection is not yet completely understood. In this study, we investigate how the presence of the sickle cell trait affects the haematological profile of AS persons with malaria, in comparison with similarly infected persons with HbAA. This study is based on the hypothesis that the sickle cell trait plays a protective role against malaria. Children from an endemic malaria transmission area in Yemen were enrolled in this study. Hematological parameters were estimated using manual methods, the percentage of parasite density on stained thin smear was calculated, haemoglobin genotypes were determined on paper electrophoresis, ferritin was measured using enzyme-linked immunosorbent assay, serum iron and TIBC were assayed using spectrophotometer, transferrin saturation index was calculated by dividing serum iron by TIBC and expressing the result as a percentage. Haematological parameters were compared in HbAA- and HbAS-infected children. Falciparum malaria parasitaemia was confirmed in the blood smears of 62 children, 44 (55.7%) of AA and 18 (37.5%) AS, so there was higher prevalence in HbAA children (P = 0.047). Parasite density was lower in HbAS- than HbAA-infected children (P = 0.003). Anaemia was prominent in malaria-infected children, with high proportions of moderate and severe forms in HbAA (P = 0.001). The mean levels of haemoglobin, packed cell volume, reticulocyte count, platelets count, lymphocytes, eosinophils, and serum iron were significantly lower while total leukocytes, immature granulocytes, monocytes, erythrocyte sedimentation rate, transferrin saturation, and serum ferritin were significantly higher in HbAA-infected children than HbAS-infected children. Infection with Plasmodium falciparum malaria caused more significant haematological alterations of HbAA children than HbAS. This study supports the observation that sickle cell trait seems to be a beneficial genetic factor that resists malaria, since inheriting it protects against significant haematological consequences of malaria.

Iron Deficiency in Patients with Nonalcoholic Fatty Liver Disease is Associated with Obesity, Female Sex, and Low Serum Hepcidin

PubMed Central

Siddique, Asma; Nelson, James E.; Aouizerat, Bradley; Yeh, Matthew M.; Kowdley, Kris V.

2014-01-01

Background & Aims Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines IL6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin and IL6 and IL1β, and other risk factors in patients with non-alcoholic fatty liver disease (NAFLD) with iron deficiency. Methods We collected data on 675 adult subjects (>18 y old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation <20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, as well as serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency. Results One third of patients (231/675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P<.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61±45 vs 81±51 ng/mL; P<.0001). Iron deficiency was significantly associated with female sex, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, Black or American Indian/Alaska Native race (P≤.018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal; P≤.0001 and 0.45 vs 0.32 for iron normal; P≤.005). Conclusion Iron deficiency is prevalent in patients with NAFLD and associated with female sex, increased body mass index, and non-white race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiological response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD. PMID:24269922

Breast carcinoma and the role of iron metabolism. A cytochemical, tissue culture, and ultrastructural study.

PubMed

Elliott, R L; Elliott, M C; Wang, F; Head, J F

1993-11-30

Transferrin receptors on proliferating and malignant cells are well documented. Iron is an essential micronutrient for cell growth that plays an important role in energy metabolism and DNA synthesis. Malignant cells requiring more iron modulate a transferrin receptor. Iron-bound transferrin interacts with this receptor, facilitating the transport of iron across the cell membrane. Transferrin is a glycoprotein and is the chief iron transport protein in mammalian blood. The more aggressive the tumor, the higher the transferrin receptor levels and the greater the proliferative index. We have found by cytochemical and ultrastructural studies that ferritin, an iron storage protein, is increased in breast cancer tissue. Anaplastic tumors have higher tissue ferritin levels. Tissue ferritin concentration may be an indirect method of measuring transferrin receptors and thus might be an index of proliferation and a prognostic indicator. Transferrin may be used as a carrier to target toxic therapy selectively to tumor tissue. A platinum transferrin complex (MPTC-63) has been developed and shown to be cytostatic in tissue culture, animal, and human studies. It also sensitizes tissue to agents that produce free radicals, such as adriamycin, and thus is synergistic with other drugs and radiation. Other transferrin complexes and conjugates of gallium, indium, and daunorubicin have also shown growth inhibition in tissue culture and animals. Human studies are in progress. By studying iron metabolism in breast cancer, we may be able to selectively inhibit tumor growth without toxic effects, and with other tumor biologic data be better able to select the stage I patient for adjuvant therapy.

Nerves and Tissue Repair.

DTIC Science & Technology

1994-07-01

axolotl limbs are transected the concentration of transferrin in the distal limb tissue declines rapidly and limb regeneration stops. These results...transferrin binding and expression of the transferrin gene in cells of axolotl peripheral nerve indicate that both uptake and synthesis of this factor occur

Dietary iron intervention using a staple food product for improvement of iron status in female runners.

PubMed

Alaunyte, Ieva; Stojceska, Valentina; Plunkett, Andrew; Derbyshire, Emma

2014-01-01

Adequate nutrient intake is critically important for achieving optimal sports performance. Like all athletes, female runners require a nutritionally balanced diet to maintain daily activities and a successful training regime. This study investigates the effects of cereal product based dietary iron intervention on iron status of recreational female runners (n = 11; 32 ± 7yr; 239 ± 153 minutes exercise/week, of which 161 ± 150 minutes running activity/week; VO2max 38 ± 4 ml/kg/min). Participants completed a 6-week dietary intervention study. They were asked to replace their usual bread with iron-rich Teff bread as part of their daily diet. During this period, their dietary habits were assessed by multiple pass 24-hr recalls; iron status was determined by venous blood analysis for serum transferrin, serum transferrin receptor, serum ferritin, total iron-binding capacity and transferrin receptor/ferritin log index. Pre-intervention a cohort of 11 female runners reported inadequate daily dietary iron intake of 10.7 ± 2.7 mg/day, which was associated with overall compromised iron status. Over a third of all participants showed depleted bodily iron stores (serum ferritin <12 μg/L). Pre-intervention macronutrient assessment revealed adequate energy, protein and fibre intakes, whilst total fat and saturated fat intake was above the recommendations at the expense of carbohydrate intake. A 6-week dietary intervention resulted in significantly higher total iron intakes (18.5 mg/day, P < 0.05) and improved iron tissue supply but not enlarged iron stores. Improvements in heamatological indices were associated with compromised baseline iron status, prolonged intervention period and increase in dietary iron intake. Dietary iron interventions using a staple cereal product offer an alternative way of improving dietary iron intake and favourable affecting overall iron status in physically active females.

Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges.

PubMed

Pfeiffer, Christine M; Looker, Anne C

2017-12-01

Biochemical assessment of iron status relies on serum-based indicators, such as serum ferritin (SF), transferrin saturation, and soluble transferrin receptor (sTfR), as well as erythrocyte protoporphyrin. These indicators present challenges for clinical practice and national nutrition surveys, and often iron status interpretation is based on the combination of several indicators. The diagnosis of iron deficiency (ID) through SF concentration, the most commonly used indicator, is complicated by concomitant inflammation. sTfR concentration is an indicator of functional ID that is not an acute-phase reactant, but challenges in its interpretation arise because of the lack of assay standardization, common reference ranges, and common cutoffs. It is unclear which indicators are best suited to assess excess iron status. The value of hepcidin, non-transferrin-bound iron, and reticulocyte indexes is being explored in research settings. Serum-based indicators are generally measured on fully automated clinical analyzers available in most hospitals. Although international reference materials have been available for years, the standardization of immunoassays is complicated by the heterogeneity of antibodies used and the absence of physicochemical reference methods to establish "true" concentrations. From 1988 to 2006, the assessment of iron status in NHANES was based on the multi-indicator ferritin model. However, the model did not indicate the severity of ID and produced categorical estimates. More recently, iron status assessment in NHANES has used the total body iron stores (TBI) model, in which the log ratio of sTfR to SF is assessed. Together, sTfR and SF concentrations cover the full range of iron status. The TBI model better predicts the absence of bone marrow iron than SF concentration alone, and TBI can be analyzed as a continuous variable. Additional consideration of methodologies, interpretation of indicators, and analytic standardization is important for further improvements in iron status assessment. © 2017 American Society for Nutrition.

Iron Status in Chronic Heart Failure: Impact on Symptoms, Functional Class and Submaximal Exercise Capacity.

PubMed

Enjuanes, Cristina; Bruguera, Jordi; Grau, María; Cladellas, Mercé; Gonzalez, Gina; Meroño, Oona; Moliner-Borja, Pedro; Verdú, José M; Farré, Nuria; Comín-Colet, Josep

2016-03-01

To evaluate the effect of iron deficiency and anemia on submaximal exercise capacity in patients with chronic heart failure. We undertook a single-center cross-sectional study in a group of stable patients with chronic heart failure. At recruitment, patients provided baseline information and completed a 6-minute walk test to evaluate submaximal exercise capacity and exercise-induced symptoms. At the same time, blood samples were taken for serological evaluation. Iron deficiency was defined as ferritin < 100 ng/mL or transferrin saturation < 20% when ferritin is < 800 ng/mL. Additional markers of iron status were also measured. A total of 538 heart failure patients were eligible for inclusion, with an average age of 71 years and 33% were in New York Heart Association class III/IV. The mean distance walked in the test was 285 ± 101 meters among those with impaired iron status, vs 322 ± 113 meters (P=.002). Symptoms during the test were more frequent in iron deficiency patients (35% vs 27%; P=.028) and the most common symptom reported was fatigue. Multivariate logistic regression analyses showed that increased levels of soluble transferrin receptor indicating abnormal iron status were independently associated with advanced New York Heart Association class (P < .05). Multivariable analysis using generalized additive models, soluble transferrin receptor and ferritin index, both biomarkers measuring iron status, showed a significant, independent and linear association with submaximal exercise capacity (P=.03 for both). In contrast, hemoglobin levels were not significantly associated with 6-minute walk test distance in the multivariable analysis. In patients with chronic heart failure, iron deficiency but not anemia was associated with impaired submaximal exercise capacity and symptomatic functional limitation. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

The fate of a designed protein corona on nanoparticles in vitro and in vivo.

PubMed

Bargheer, Denise; Nielsen, Julius; Gébel, Gabriella; Heine, Markus; Salmen, Sunhild C; Stauber, Roland; Weller, Horst; Heeren, Joerg; Nielsen, Peter

2015-01-01

A variety of monodisperse superparamagnetic iron oxide particles (SPIOs) was designed in which the surface was modified by PEGylation with mono- or bifunctional poly(ethylene oxide)amines (PEG). Using (125)I-labeled test proteins (transferrin, albumin), the binding and exchange of corona proteins was studied first in vitro. Incubation with (125)I-transferrin showed that with increasing grade of PEGylation the binding was substantially diminished without a difference between simply adsorbed and covalently bound protein. However, after incubation with excess albumin and subsequently whole plasma, transferrin from the preformed transferrin corona was more and more lost from SPIOs in the case of adsorbed proteins. If non-labeled transferrin was used as preformed corona and excess (125)I-labeled albumin was added to the reaction mixtures with different SPIOs, a substantial amount of label was bound to the particles with initially adsorbed transferrin but little or even zero with covalently bound transferrin. These in vitro experiments show a clear difference in the stability of a preformed hard corona with adsorbed or covalently bound protein. This difference seems, however, to be of minor importance in vivo when polymer-coated (59)Fe-SPIOs with adsorbed or covalently bound (125)I-labeled mouse transferrin were injected intravenously in mice. With both protein coronae the (59)Fe/(125)I-labelled particles were cleared from the blood stream within 30 min and appeared in the liver and spleen to a large extent (>90%). In addition, after 2 h already half of the (125)I-labeled transferrin from both nanodevices was recycled back into the plasma and into tissue. This study confirms that adsorbed transferrin from a preformed protein corona is efficiently taken up by cells. It is also highlighted that a radiolabelling technique described in this study may be of value to investigate the role of protein corona formation in vivo for the respective nanoparticle uptake.

Targeted Delivery of Amoxicillin to C. trachomatis by the Transferrin Iron Acquisition Pathway

PubMed Central

Hai, Jun; Serradji, Nawal; Mouton, Ludovic; Redeker, Virginie; Cornu, David; El Hage Chahine, Jean-Michel

2016-01-01

Weak intracellular penetration of antibiotics makes some infections difficult to treat. The Trojan horse strategy for targeted drug delivery is among the interesting routes being explored to overcome this therapeutic difficulty. Chlamydia trachomatis, as an obligate intracellular human pathogen, is responsible for both trachoma and sexually transmitted diseases. Chlamydia develops in a vacuole and is therefore protected by four membranes (plasma membrane, bacterial inclusion membrane, and bacterial membranes). In this work, the iron-transport protein, human serum-transferrin, was used as a Trojan horse for antibiotic delivery into the bacterial vacuole. Amoxicillin was grafted onto transferrin. The transferrin-amoxicillin construct was characterized by mass spectrometry and absorption spectroscopy. Its affinity for transferrin receptor 1, determined by fluorescence emission titration [KaffTf-amox = (1.3 ± 1.0) x 108], is very close to that of transferrin [4.3 x 108]. Transmission electron and confocal microscopies showed a co-localization of transferrin with the bacteria in the vacuole and were also used to evaluate the antibiotic capability of the construct. It is significantly more effective than amoxicillin alone. These promising results demonstrate targeted delivery of amoxicillin to suppress Chlamydia and are of interest for Chlamydiaceae and maybe other intracellular bacteria therapies. PMID:26919720

Targeted Delivery of Amoxicillin to C. trachomatis by the Transferrin Iron Acquisition Pathway.

PubMed

Hai, Jun; Serradji, Nawal; Mouton, Ludovic; Redeker, Virginie; Cornu, David; El Hage Chahine, Jean-Michel; Verbeke, Philippe; Hémadi, Miryana

2016-01-01

Weak intracellular penetration of antibiotics makes some infections difficult to treat. The Trojan horse strategy for targeted drug delivery is among the interesting routes being explored to overcome this therapeutic difficulty. Chlamydia trachomatis, as an obligate intracellular human pathogen, is responsible for both trachoma and sexually transmitted diseases. Chlamydia develops in a vacuole and is therefore protected by four membranes (plasma membrane, bacterial inclusion membrane, and bacterial membranes). In this work, the iron-transport protein, human serum-transferrin, was used as a Trojan horse for antibiotic delivery into the bacterial vacuole. Amoxicillin was grafted onto transferrin. The transferrin-amoxicillin construct was characterized by mass spectrometry and absorption spectroscopy. Its affinity for transferrin receptor 1, determined by fluorescence emission titration [KaffTf-amox = (1.3 ± 1.0) x 108], is very close to that of transferrin [4.3 x 108]. Transmission electron and confocal microscopies showed a co-localization of transferrin with the bacteria in the vacuole and were also used to evaluate the antibiotic capability of the construct. It is significantly more effective than amoxicillin alone. These promising results demonstrate targeted delivery of amoxicillin to suppress Chlamydia and are of interest for Chlamydiaceae and maybe other intracellular bacteria therapies.

Liquid Film Cooling in Rocket Engines

DTIC Science & Technology

1991-03-01

calculated below for the case: L = 5 cm and U = 1.5 m/s , at a pressure of 100 psia (data Reference 31): Fuel Tsat A P~ Pv o~ Qbo (°K) (10SJ/kg) (kg...burnou t heat flux limit is calculated as: Qbo = 0 -0164~p~ ° * S s 4 p v ° ’ I s s ( U l i q ° / x l i q ) ° ’ s s s This is compared with the

Iron acquisition in Pasteurella haemolytica: expression and identification of a bovine-specific transferrin receptor.

PubMed Central

Ogunnariwo, J A; Schryvers, A B

1990-01-01

Seven type 1 field isolates of Pasteurella haemolytica were screened for their ability to use different transferrins as a source of iron for growth. All seven strains were capable of using bovine but not human, porcine, avian, or equine transferrin. A screening assay failed to detect siderophore production in any of the strains tested. Iron-deficient cells from these strains expressed a binding activity, specific for bovine transferrin, that was regulated by the level of iron in the medium. Inhibition of expression by translation and transcription inhibitors suggested that iron regulation was occurring at the gene level. Affinity isolation of receptor proteins from all seven strains with biotinylated bovine transferrin identified a 100-kilodalton iron-regulated outer membrane protein as the bovine transferrin receptor. Iron-regulated outer membrane proteins of 71 and 77 kilodaltons were isolated along with the 100-kilodalton protein when less stringent washing procedures were employed in the affinity isolation procedure. Images PMID:2365453

Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects

PubMed Central

Boyce, M; Warrington, S; Cortezi, B; Zöllner, S; Vauléon, S; Swinkels, D W; Summo, L; Schwoebel, F

2016-01-01

Background and Purpose Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l‐oligoribonucleotide, binds and inactivates hepcidin. Experimental Approach We conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1. Key Results After treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration. Conclusions and Implications Lexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease. PMID:26773325

Early signs of maternal iron deficiency do not influence the iron status of the newborn, but are associated with higher infant birthweight.

PubMed

Ervasti, Mari; Sankilampi, Ulla; Heinonen, Seppo; Punnonen, Kari

2009-01-01

To investigate the associations between maternal iron status, pregnancy outcome and newborn iron status using sensitive and specific red blood cell indices reflecting iron-deficient erythropoiesis. Cross-sectional study in Kuopio University Hospital, Finland. One hundred and ninety-two pregnant women and their full-term newborns (cord blood). Quartile analysis and Spearman correlations were used to investigate the associations of the iron status of pregnant women with that of their newborns, and with pregnancy outcome. Maternal and cord blood analysis including indices reflecting the hemoglobin (Hb) content of red blood cells as well as serum iron, transferrin saturation, transferrin receptor and ferritin. Gestational age, birthweight and placental weight. The highest quartile of the maternal percentage of hypochromic red blood cells (%HYPOm) indicating the lowest iron status was associated with a high birthweight and a long duration of pregnancy. The newborns in this group did not show any signs of iron deficiency even though the maternal %HYPOm was elevated. In a well-nourished maternal population, lower maternal iron status did not affect the iron accumulation on the fetal side. However, longer duration of pregnancy and growth of the fetus appeared to be associated with a lower amount of iron for Hb synthesis in maternal red blood cells, as reflected by the increased maternal %HYPOm, birthweight and length of gestation.

Lymphocyte ceruloplasmin and Behçet's disease.

PubMed

Oliveira, Rita; Banha, João; Martins, Fátima; Paixão, Eleonora; Pereira, Dina; Barcelos, Filipe; Teixeira, Ana; Patto, José Vaz; Costa, Luciana

2006-01-01

Behçet's disease (BD) is a rare chronic inflammatory disorder of unknown aetiology. However, it has been postulated that a dysregulation of the prooxidant/antioxidant balance may be important to its pathogenesis. Ceruloplasmin (CP) is an acute phase protein expressed at the surface of peripheral blood lymphocytes (PBL) with antioxidant properties and with a relevant role in iron (Fe) metabolism. To study CP expression at the surface of PBL (PBLCP) in patients with BD. We measured serum CP and PBLCP obtained from BD patients (n=10) and respective controls (n=10) using nephelometry and flow cytometry techniques, respectively. Additionally, haematological parameters, biochemical Fe metabolism markers [serum Fe, serum ferritin, serum transferrin, total Fe binding capacity (TIBC), transferrin saturation] and non-specific markers of inflammation [serum C reactive protein (CRP), beta2-microglobulin] were measured in all individuals. Despite the absence of significant differences between the two study groups when comparing serum CP, a significant difference in PBLCP was found in BD patients mainly due to a significant decrease of CP expression at the surface of CD3-CD56+ lymphocytes. Also, a significant decrease of PBLCP was observed in patients treated with azathioprine compared to patients that were not being treated with this drug. According to this study, we suggest that the significant decrease of PBLCP observed in BD patients might be due to azathioprine treatment and not directly related to the pathophysiology of BD.

The acute phase response and exercise: court and field sports

PubMed Central

Fallon, K; Fallon, S; Boston, T

2001-01-01

Objective—To determine the presence or absence of an acute phase response after training for court and field sports. Participants—All members of the Australian women's soccer team (n = 18) and all members of the Australian Institute of Sport netball team (n = 14). Methods—Twelve acute phase reactants (white blood cell count, neutrophil count, platelet count, serum iron, ferritin, and transferrin, percentage transferrin saturation, α1 antitrypsin, caeruloplasmin, α2 acid glycoprotein, C reactive protein, and erythrocyte sedimentation rate) were measured during a rest period and after moderate and heavy training weeks in members of elite netball and women's soccer teams. Results—Responses consistent with an acute phase response were found in five of 24 tests in the soccer players, and in three of 24 tests in the netball players. Responses in the opposite direction were found in seven of 24 tests in the soccer players and two of 24 tests in the netballers. The most sensitive reactant measured, C reactive protein, did not respond in a manner typical of an acute phase response. Conclusion—An acute phase response does not seem to occur as a consequence of the levels of training typical of elite female netball and soccer teams. This has implications for the interpretation of biochemical variables in these groups. Key Words: acute phase response; iron; plasma proteins; inflammation PMID:11375875

A new sample treatment for asialo-Tf determination with capillary electrophoresis: an added value to the analysis of CDT.

PubMed

Porpiglia, Nadia Maria; De Palo, Elio Franco; Savchuk, Sergey Alexandrovich; Appolonova, Svetlana Alexandrovna; Bortolotti, Federica; Tagliaro, Franco

2018-05-10

The non-glycosylated glycoform of transferrin (Tf), known as asialo-Tf, was not selected (in favor of disialo-Tf) as the measurand for the standardization of carbohydrate deficient transferrin (CDT) determination because of a lower diagnostic sensitivity provided with the currently available analytical procedures for sera. However, asialo-Tf could provide an additional value to disialo-Tf in the CDT analysis employed in forensic toxicology contexts. The present work aimed at developing an easy sample preparation based on PEG precipitation in order to improve the detectability of asialo-Tf in capillary electrophoresis (CE). Equal volumes (35 μL) of serum and of 30% PEG-8000 were mixed and briefly vortexed. After centrifugation, the supernatant was iron saturated with a ferric solution (1:1, v/v). The mixture was analyzed in CE for asialo-Tf and disialo-Tf determination. PEG-8000 precipitation allowed the improvement of the baseline in the electropherograms in terms of interferences reduction particularly in the asialo-Tf migration region. The detection of asialo-Tf was possible in 89% of samples with disialo-Tf above the cut-off limit, whereas only 16% of them showed asialo-Tf by employing the traditional sample preteatment. Asialo-Tf represents an additional value to disialo-Tf as a biomarker of alcohol abuse in forensic toxicology. Copyright © 2018. Published by Elsevier B.V.

Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis

PubMed Central

Santos, Paulo C. J. L.; Krieger, Jose E.; Pereira, Alexandre C.

2012-01-01

Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment. PMID:22408404

Engineering an Anti-Transferrin Receptor ScFv for pH-Sensitive Binding Leads to Increased Intracellular Accumulation.

PubMed

Tillotson, Benjamin J; Goulatis, Loukas I; Parenti, Isabelle; Duxbury, Elizabeth; Shusta, Eric V

2015-01-01

The equilibrium binding affinity of receptor-ligand or antibody-antigen pairs may be modulated by protonation of histidine side-chains, and such pH-dependent mechanisms play important roles in biological systems, affecting molecular uptake and trafficking. Here, we aimed to manipulate cellular transport of single-chain antibodies (scFvs) against the transferrin receptor (TfR) by engineering pH-dependent antigen binding. An anti-TfR scFv was subjected to histidine saturation mutagenesis of a single CDR. By employing yeast surface display with a pH-dependent screening pressure, scFvs having markedly increased dissociation from TfR at pH 5.5 were identified. The pH-sensitivity generally resulted from a central cluster of histidine residues in CDRH1. When soluble, pH-sensitive, scFv clone M16 was dosed onto live cells, the internalized fraction was 2.6-fold greater than scFvs that lacked pH-sensitive binding and the increase was dependent on endosomal acidification. Differences in the intracellular distribution of M16 were also observed consistent with an intracellular decoupling of the scFv M16-TfR complex. Engineered pH-sensitive TfR binding could prove important for increasing the effectiveness of TfR-targeted antibodies seeking to exploit endocytosis or transcytosis for drug delivery purposes.

Engineering an Anti-Transferrin Receptor ScFv for pH-Sensitive Binding Leads to Increased Intracellular Accumulation

PubMed Central

Tillotson, Benjamin J.; Goulatis, Loukas I.; Parenti, Isabelle; Duxbury, Elizabeth; Shusta, Eric V.

2015-01-01

The equilibrium binding affinity of receptor-ligand or antibody-antigen pairs may be modulated by protonation of histidine side-chains, and such pH-dependent mechanisms play important roles in biological systems, affecting molecular uptake and trafficking. Here, we aimed to manipulate cellular transport of single-chain antibodies (scFvs) against the transferrin receptor (TfR) by engineering pH-dependent antigen binding. An anti-TfR scFv was subjected to histidine saturation mutagenesis of a single CDR. By employing yeast surface display with a pH-dependent screening pressure, scFvs having markedly increased dissociation from TfR at pH 5.5 were identified. The pH-sensitivity generally resulted from a central cluster of histidine residues in CDRH1. When soluble, pH-sensitive, scFv clone M16 was dosed onto live cells, the internalized fraction was 2.6-fold greater than scFvs that lacked pH-sensitive binding and the increase was dependent on endosomal acidification. Differences in the intracellular distribution of M16 were also observed consistent with an intracellular decoupling of the scFv M16-TfR complex. Engineered pH-sensitive TfR binding could prove important for increasing the effectiveness of TfR-targeted antibodies seeking to exploit endocytosis or transcytosis for drug delivery purposes. PMID:26713870

Inhibitory effect of a toxic peptide isolated from a waterbloom of Microcystis sp. (Cyanobacteria) on iron uptake by rabbit reticulocytes.

PubMed

Rojas, M; Nuñez, M T; Zambrano, F

1990-01-01

The effect of a soluble toxin purified from the algae bloom of a eutrophic lake dominated by Microcystis on the receptor-mediated endocytosis of ferro-transferrin in rabbit reticulocytes was studied. The toxin was a very effective inhibitor of cell iron uptake. Kinetic studies using 125I, 59Fe-labeled transferrin indicated that the step of ferrotransferrin internalization was selectively inhibited by the toxin while the surface receptor-binding capacity, the externalization of previously internalized transferrin, and the cellular ATP levels were not affected. These findings indicate that the reduction of iron uptake caused by the toxin is due to inhibition of the internalization of surface-located transferrin-transferrin receptor complexes, perhaps due to a disruption of cytoskeleton integrity.

Transferrin Impacts Bacillus thuringiensis Biofilm Levels

PubMed Central

Brown, Elrica; Taplin, Martha; Garcia, Angel; Williams-Mapp, Baracka

2016-01-01

The present study examined the impact of transferrin on Bacillus thuringiensis biofilms. Three commercial strains, an environmental strain (33679), the type strain (10792), and an isolate from a diseased insect (700872), were cultured in iron restricted minimal medium. All strains produced biofilm when grown in vinyl plates at 30°C. B. thuringiensis 33679 had a biofilm biomass more than twice the concentration exhibited by the other strains. The addition of transferrin resulted in slightly increased growth yields for 2 of the 3 strains tested, including 33679. In contrast, the addition of 50 μg/mL of transferrin resulted in an 80% decrease in biofilm levels for strain 33679. When the growth temperature was increased to 37°C, the addition of 50 μg/mL of transferrin increased culture turbidity for only strain 33679. Biofilm levels were again decreased in strain 33679 at 37°C. Growth of B. thuringiensis cultures in polystyrene resulted in a decrease in overall growth yields at 30°C, with biofilm levels significantly decreased for 33679 in the presence of transferrin. These findings demonstrate that transferrin impacts biofilm formation in select strains of B. thuringiensis. Identification of these differences in biofilm regulation may be beneficial in elucidating potential virulence mechanisms among the differing strains. PMID:28025643

Electron Spin Relaxation Rates for High-Spin Fe(III) in Iron Transferrin Carbonate and Iron Transferrin Oxalate

PubMed Central

Gaffney, Betty Jean; Eaton, Gareth R.; Eaton*, Sandra S.

2005-01-01

To optimize simulations of CW EPR spectra for high-spin Fe(III) with zero-field splitting comparable to the EPR quantum, information is needed on the factors that contribute to the line shapes and line widths. Continuous wave electron paramagnetic resonance (EPR) spectra obtained for iron transferrin carbonate from 4 to 150 K and for iron transferrin oxalate from 4 to 100 K did not exhibit significant temperature dependence of the line shape, which suggested that the line shapes were not relaxation determined. To obtain direct information concerning the electron spin relaxation rates, electron spin echo and inversion recovery EPR were used to measure T1 and Tm for the high-spin Fe(III) in iron transferrin carbonate and iron transferrin oxalate between 5 and 20–30 K. For comparison with the data for the transferrin complexes, relaxation times were obtained for tris(oxalato)ferrate(III). The relaxation rates are similar for the three complexes and do not exhibit a strong dependence on position in the spectrum. Extrapolation of the observed temperature dependence of the relaxation rates to higher temperatures gives values consistent with the conclusion that the CW line shapes are not relaxation determined up to 150 K. PMID:16429607

The significance of transferrin receptors in oncology: the development of functional nano-based drug delivery systems.

PubMed

Tortorella, Stephanie; Karagiannis, Tom C

2014-01-01

Anticancer therapeutic research aims to improve clinical management of the disease through the development of strategies that involve currently-relevant treatment options and targeted delivery. Tumour-specific and -targeted delivery of compounds to the site of malignancy allows for enhanced cellular uptake, increased therapeutic benefit with high intratumoural drug concentrations, and decreased systemic exposure. Due to the upregulation of transferrin receptor expression in a wide variety of cancers, its function and its highly efficient recycling pathway, strategies involving the selective targeting of the receptor are well documented. Direct conjugation and immunotoxin studies using the transferrin peptide or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake, cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. Limitations in direct conjugation, including the difficulty in linking an adequate amount of therapeutic compound to the ligand or antibody have identified the requirement to develop novel delivery methods. The application of nanoparticulate theory in the development of functional drug delivery systems has proven to be most promising, with the ability to selectively modify size-dependent properties and surface chemistry. The transferrin modification on a range of nanoparticle formulations enhances selective cellular uptake through transferrin-mediated processes, and increases therapeutic benefit through the ability to encapsulate high concentrations of relevant drug to the tumour site. Although ineffective in crossing the blood brain barrier in its free form, chemotherapeutic compounds including doxorubicin, may be loaded into transferrin-conjugated nanocarriers and impart cytotoxic effects in glioma cells in vitro and in vivo. Additionally, transferrin-targeted nanoparticles may be used in selective diagnostic applications with enhanced selectivity and sensitivity. Four transferrin-modified nano-based drug delivery systems are currently in early phases of human clinical trials. Despite the collective promise, inconsistencies in some studies have exposed some limitations in current formulations and the difficulty in translating preliminary studies into clinically-relevant therapeutic options. The main objective of this review is to investigate the development of transferrin targeted nano-based drug delivery systems in order to establish the use of transferrin as a cancer-targeted moiety, and to ultimately evaluate the progression of cancer therapeutic strategies for future research.

Reptilian transferrins: evolution of disulphide bridges and conservation of iron-binding center.

PubMed

Ciuraszkiewicz, Justyna; Biczycki, Marian; Maluta, Aleksandra; Martin, Samuel; Watorek, Wiesław; Olczak, Mariusz

2007-07-01

Transferrins, found in invertebrates and vertebrates, form a physiologically important family of proteins playing a major role in iron acquisition and transport, defense against microbial pathogens, growth and differentiation. These proteins are bilobal in structure and each lobe is composed of two domains divided by a cleft harboring an iron atom. Vertebrate transferrins comprise of serotransferrins, lactoferrins and ovotransferrins. In mammals serotransferrins transport iron in physiological fluids and deliver it to cells, while lactoferrins scavenge iron, limiting its availability to invading microbes. In oviparous vertebrates there is only one transferrin gene, expressed either in the liver to be delivered to physiological fluids as serotransferrin, or in the oviduct with a final localization in egg white as ovotransferrin. Being products of one gene sero- and ovotransferrin are identical at the amino-acid sequence level but with different, cell specific glycosylation patterns. Our knowledge of the mechanisms of transferrin iron binding and release is based on sequence and structural data obtained for human serotransferrin and hen and duck ovotransferrins. No sequence information about other ovotransferrins was available until our recent publication of turkey, ostrich, and red-eared turtle (TtrF) ovotransferrin mRNA sequences [Ciuraszkiewicz, J., Olczak, M., Watorek, W., 2006. Isolation, cloning and sequencing of transferrins from red-eared turtle, African ostrich and turkey. Comp. Biochem. Physiol. 143 B, 301-310]. In the present paper, ten new reptilian mRNA transferrin sequences obtained from the Nile crocodile (NtrF), bearded dragon (BtrF), Cuban brown anole (AtrF), veiled and Mediterranean chameleons (VtrF and KtrF), sand lizard (StrF), leopard gecko (LtrF), Burmese python (PtrF), African house snake (HtrF), and grass snake (GtrF) are presented and analyzed. Nile crocodile and red-eared turtle transferrins have a disulphide bridge pattern identical to known bird homologues. A partially different disulphide bridge pattern was found in the Squamata (snakes and lizards). The possibility of a unique interdomain disulphide bridge was predicted for LtrF. Differences were found in iron-binding centers from those of previously known transferrins. Substitutions were found in the iron-chelating residues of StrF and TtrF and in the synergistic anion-binding residues of NtrF. In snakes, the transferrin (PtrF, HtrF and GtrF) N-lobe "dilysine trigger" occurring in all other known transferrins was not found, which indicates a different mechanism of iron release.

Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response

PubMed Central

Aydinok, Yesim; Evans, Patricia; Manz, Chantal Y.; Porter, John B.

2012-01-01

Background Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone. Design and Methods Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year. Results Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months. Conclusions The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number NCT00350662. PMID:22180427

Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool.

PubMed

Jamnongkan, Wassana; Thanan, Raynoo; Techasen, Anchalee; Namwat, Nisana; Loilome, Watcharin; Intarawichian, Piyapharom; Titapun, Attapol; Yongvanit, Puangrat

2017-07-01

Labile iron pool is a cellular source of ions available for Fenton reactions resulting in oxidative stress. Living organisms avoid an excess of free irons by a tight control of iron homeostasis. We investigated the altered expression of iron regulatory proteins and iron discrimination in the development of liver fluke-associated cholangiocarcinoma. Additionally, the levels of labile iron pool and the functions of transferrin receptor-1 on cholangiocarcinoma development were also identified. Iron deposition was determined using the Prussian blue staining method in human cholangiocarcinoma tissues. We investigated the alteration of iron regulatory proteins including transferrin, transferrin receptor-1, ferritin, ferroportin, hepcidin, and divalent metal transporter-1 in cholangiocarcinoma tissues using immunohistochemistry. The clinicopathological data of cholangiocarcinoma patients and the expressions of proteins were analyzed. Moreover, the level of intracellular labile iron pool in cholangiocarcinoma cell lines was identified by the RhoNox-1 staining method. We further demonstrated transferrin receptor-1 functions on cell proliferation and migration upon small interfering RNA for human transferrin receptor 1 transfection. Results show that Iron was strongly stained in tumor tissues, whereas negative staining was observed in normal bile ducts of healthy donors. Interestingly, high iron accumulation was significantly correlated with poor prognosis of cholangiocarcinoma patients. The expressions of iron regulatory proteins in human cholangiocarcinoma tissues and normal liver from cadaveric donors revealed that transferrin receptor-1 expression was increased in the cancer cells of cholangiocarcinoma tissues when compared with the adjacent normal bile ducts and was significantly correlated with cholangiocarcinoma metastasis. Labile iron pool level and transferrin receptor-1 expression were significantly increased in KKU-214 and KKU-213 when compared with cholangiocyte cells (MMNK1). Additionally, the suppression of transferrin receptor-1 expression significantly decreased intracellular labile iron pool, cholangiocarcinoma migration, and cell proliferation when compared with control media and control small interfering RNA. In Conclusion, high expression of transferrin receptor-1 resulting in iron uptake contributes to increase in the labile iron pool which plays roles in cholangiocarcinoma progression with aggressive clinical outcomes.

Iron and gallium increase iron uptake from transferrin by human melanoma cells: further examination of the ferric ammonium citrate-activated iron uptake process.

PubMed

Richardson, D R

2001-04-30

Previously we showed that preincubation of cells with ferric ammonium citrate (FAC) resulted in a marked increase in Fe uptake from both (59)Fe-transferrin (Tf) and (59)Fe-citrate (D.R. Richardson, E. Baker, J. Biol. Chem. 267 (1992) 13972-13979; D.R. Richardson, P. Ponka, Biochim. Biophys. Acta 1269 (1995) 105-114). This Fe uptake process was independent of the transferrin receptor and appeared to be activated by free radicals generated via the iron-catalysed Haber-Weiss reaction. To further understand this process, the present investigation was performed. In these experiments, cells were preincubated for 3 h at 37 degrees C with FAC or metal ion solutions and then labelled for 3 h at 37 degrees C with (59)Fe-Tf. Exposure of cells to FAC resulted in Fe uptake from (59)Fe-citrate that became saturated at an Fe concentration of 2.5 microM, while FAC-activated Fe uptake from Tf was not saturable up to 25 microM. In addition, the extent of FAC-activated Fe uptake from citrate was far greater than that from Tf. These results suggest a mechanism where FAC-activated Fe uptake from citrate may result from direct interaction with the transporter, while Fe uptake from Tf appears indirect and less efficient. Preincubation of cells with FAC at 4 degrees C instead of 37 degrees C prevented its effect at stimulating (59)Fe uptake from (59)Fe-Tf, suggesting that an active process was involved. Previous studies by others have shown that FAC can increase ferrireductase activity that may enhance (59)Fe uptake from (59)Fe-Tf. However, there was no difference in the ability of FAC-treated cells compared to controls to reduce ferricyanide to ferrocyanide, suggesting no change in oxidoreductase activity. To examine if activation of this Fe uptake mechanism could occur by incubation with a range of metal ions, cells were preincubated with either FAC, ferric chloride, ferrous sulphate, ferrous ammonium sulphate, gallium nitrate, copper chloride, zinc chloride, or cobalt chloride. Stimulation of (59)Fe uptake from Tf was shown (in order of potency) with ferric chloride, ferrous sulphate, ferrous ammonium sulphate, and gallium nitrate. The other metal ions examined decreased (59)Fe uptake from Tf. The fact that redox-active Cu(II) ion did not stimulate Fe uptake while redox-inactive Ga(III) did, suggests a mechanism of transporter activation not solely dependent on free radical generation. Indeed, the activation of Fe uptake appears dependent on the presence of the Fe atom itself or a metal ion with atomic similarities to Fe (e.g. Ga).

Uptake and release of metal ions by transferrin and interaction with receptor 1.

PubMed

El Hage Chahine, Jean-Michel; Hémadi, Miryana; Ha-Duong, Nguyêt-Thanh

2012-03-01

For a metal to follow the iron acquisition pathway, four conditions are required: 1-complex formation with transferrin; 2-interaction with receptor 1; 3-metal release in the endosome; and 4-metal transport to cytosol. This review deals with the mechanisms of aluminum(III), cobalt(III), uranium(VI), gallium(III) and bismuth(III) uptake by transferrin and interaction with receptor 1. The interaction of the metal-loaded transferrin with receptor 1 takes place in one or two steps: a very fast first step (μs to ms) between the C-lobe and the helical domain of the receptor, and a second slow step (2-6h) between the N-lobe and the protease-like domain. In transferrin loaded with metals other than iron, the dissociation constants for the interaction of the C-lobe with TFR are in a comparable range of magnitudes 10 to 0.5μM, whereas those of the interaction of the N-lobe are several orders of magnitudes lower or not detected. Endocytosis occurs in minutes, which implies a possible internalization of the metal-loaded transferrin with only the C-lobe interacting with the receptor. A competition with iron is possible and implies that metal internalization is more related to kinetics than thermodynamics. As for metal release in the endosome, it is faster than the recycling time of transferrin, which implies its possible liberation in the cell. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders. Copyright © 2011 Elsevier B.V. All rights reserved.

H-Ferritin Is Preferentially Incorporated by Human Erythroid Cells through Transferrin Receptor 1 in a Threshold-Dependent Manner

PubMed Central

Sakamoto, Soichiro; Kawabata, Hiroshi; Masuda, Taro; Uchiyama, Tatsuki; Mizumoto, Chisaki; Ohmori, Katsuyuki; Koeffler, H. Phillip; Kadowaki, Norimitsu; Takaori-Kondo, Akifumi

2015-01-01

Ferritin is an iron-storage protein composed of different ratios of 24 light (L) and heavy (H) subunits. The serum level of ferritin is a clinical marker of the body’s iron level. Transferrin receptor (TFR)1 is the receptor not only for transferrin but also for H-ferritin, but how it binds two different ligands and the blood cell types that preferentially incorporate H-ferritin remain unknown. To address these questions, we investigated hematopoietic cell-specific ferritin uptake by flow cytometry. Alexa Fluor 488-labeled H-ferritin was preferentially incorporated by erythroid cells among various hematopoietic cell lines examined, and was almost exclusively incorporated by bone marrow erythroblasts among human primary hematopoietic cells of various lineages. H-ferritin uptake by erythroid cells was strongly inhibited by unlabeled H-ferritin but was only partially inhibited by a large excess of holo-transferrin. On the other hand, internalization of labeled holo-transferrin by these cells was not inhibited by H-ferritin. Chinese hamster ovary cells lacking functional endogenous TFR1 but expressing human TFR1 with a mutated RGD sequence, which is required for transferrin binding, efficiently incorporated H-ferritin, indicating that TFR1 has distinct binding sites for H-ferritin and holo-transferrin. H-ferritin uptake by these cells required a threshold level of cell surface TFR1 expression, whereas there was no threshold for holo-transferrin uptake. The requirement for a threshold level of TFR1 expression can explain why among primary human hematopoietic cells, only erythroblasts efficiently take up H-ferritin. PMID:26441243

Transferrin-derived synthetic peptide induces highly conserved pro-inflammatory responses of macrophages.

PubMed

Haddad, George; Belosevic, Miodrag

2009-02-01

We examined the induction of macrophage pro-inflammatory responses by transferrin-derived synthetic peptide originally identified following digestion of transferrin from different species (murine, bovine, human N-lobe and goldfish) using elastase. The mass spectrometry analysis of elastase-digested murine transferrin identified a 31 amino acid peptide located in the N2 sub-domain of the transferrin N-lobe, that we named TMAP. TMAP was synthetically produced and shown to induce a number of pro-inflammatory genes by quantitative PCR. TMAP induced chemotaxis, a potent nitric oxide response, and TNF-alpha secretion in different macrophage populations; P338D1 macrophage-like cells, mouse peritoneal macrophages, mouse bone marrow-derived macrophages (BMDM) and goldfish macrophages. The treatment of BMDM cultures with TMAP stimulated the production of nine cytokines and chemokines (IL-6, MCP-5, MIP-1 alpha, MIP-1 gamma, MIP-2, GCSF, KC, VEGF, and RANTES) that was measured using cytokine antibody array and confirmed by Western blot. Our results indicate that transferrin-derived peptide, TMAP, is an immunomodulating molecule capable of inducing pro-inflammatory responses in lower and higher vertebrates.

Analysis of carbohydrate deficient transferrin by capillary zone electrophoresis.

PubMed

Prasad, R; Stout, R L; Coffin, D; Smith, J

1997-09-01

We report a capillary zone electrophoresis method to separate the various sialylated isoforms of transferrin. The separation is carried out under nondenaturing conditions and at basic pH. Under these conditions, transferrin exhibits two major and three minor peaks. Plasma samples from a population consuming varying amounts of alcohol at different intervals were studied. A cut-off value of 3% carbohydrate deficient transferrin (CDT: disialo, monosialo, and asialo transferrin), results in a clinical sensitivity of 88% in a population consuming at least 70 g/day alcohol for a minimum of two weeks. The sensitivity dropped significantly in a population consuming less than 70 g/day. This confirms previous reports of CDT as a specific marker for significant and chronic use of alcohol. Capillary electrophoresis offers an alternative method with respect to analysis time and throughput in the clinical laboratory.

Nutritional status changes in humans during a 14-day saturation dive: the NASA Extreme Environment Mission Operations V project

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Davis-Street, Janis E.; Fesperman, J. Vernell; Smith, Myra D.; Rice, Barbara L.; Zwart, Sara R.

2004-01-01

Ground-based analogs of spaceflight are an important means of studying physiologic and nutritional changes associated with space travel, and the NASA Extreme Environment Mission Operations V (NEEMO) is such an analog. To determine whether saturation diving has nutrition-related effects similar to those of spaceflight, we conducted a clinical nutritional assessment of the NEEMO crew (4 men, 2 women) before, during, and after their 14-d saturation dive. Blood and urine samples were collected before, during, and after the dive. The foods consumed by the crew were typical of the spaceflight food system. A number of physiologic changes were observed, during and after the dive, that are also commonly observed during spaceflight. Hemoglobin and hematocrit were lower (P < 0.05) after the dive. Transferrin receptors were significantly lower immediately after the dive. Serum ferritin increased significantly during the dive. There was also evidence indicating that oxidative damage and stress increased during the dive. Glutathione peroxidase and superoxide dismutase decreased during and after the dive (P < 0.05). Decreased leptin during the dive (P < 0.05) may have been related to the increased stress. Subjects had decreased energy intake and weight loss during the dive, similar to what is observed during spaceflight. Together, these similarities to spaceflight provide a model to use in further defining the physiologic effects of spaceflight and investigating potential countermeasures.

Identification of the membrane remnants of transferrin receptor with domain-specific antibodies.

PubMed

Baynes, R D; Shih, Y J; Hudson, B G; Cook, J D

1994-03-01

Tissue culture studies with K562 and HL60 cells have demonstrated the production of a soluble form of transferrin receptor identical to that identified in human serum. The present study was undertaken to search for membrane remnants of the truncated receptor with peptide antibodies specific for the extracellular and cytoplasmic domain of transferrin receptor. In cell membranes, a 105K remnant was identified that is consistent with truncation of one extracellular domain monomer of the transferrin receptor. In the exosomal fraction of the culture supernatant, a smaller 20K remnant consistent with truncation of both extracellular domains was also demonstrated. These findings provide evidence that soluble receptor is the product of proteolytic cleavage of intact membrane-bound transferrin receptor. Prior studies showing that the concentration of the extracellular domain in exosomes remained stable during incubation in culture supernatant suggest that this cleavage possibly occurs intracellularly.

Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation

PubMed Central

Atilla, Erden; Toprak, Selami K.; Demirer, Taner

2017-01-01

Iron overload is an adverse prognostic factor for patients undergoing hematopoietic stem cell transplantation (HSCT). In the HSCT setting, pretransplant and early posttransplant ferritin and transferrin saturation were found to be highly elevated due to high transfusion requirements. In addition to that, post-HSCT iron overload was shown to be related to infections, hepatic sinusoidal obstruction syndrome, mucositis, liver dysfunction, and acute graft-versus-host disease. Hyperferritinemia causes decreased survival rates in both pre- and posttransplant settings. Serum ferritin levels, magnetic resonance imaging, and liver biopsy are diagnostic tools for iron overload. Organ dysfunction due to iron overload may cause high mortality rates and therefore sufficient iron chelation therapy is recommended in this setting. In this review the management of iron overload in adult HSCT is discussed. PMID:27956374

Relative iron "overload" in offspring of patients with type 2 diabetes mellitus: a new component in the conundrum of insulin resistance syndrome?

PubMed

Psyrogiannis, Agathoklis; Kyriazopoulou, Venetsana; Symeonidis, Argiris; Leotsinidis, Michalis; Vagenakis, Apostolos G

2003-01-01

There are a few reports suggesting that subtle disturbances of iron metabolism are frequently found in patients with type 2 diabetes (DM2), but it is not known if these disturbances precede or accompany the diabetic state. We investigated the serum iron indices in 41 offspring of DM2 parents (group I) with normal glucose tolerance, and in 49 offspring whose parents had no history of DM2 and were matched for sex, age, body mass index (BMI), waist to hip ratio (WHR) and blood pressure (group II). Serum iron, ferritin, total iron binding capacity (TIBC), transferrin saturation, serum triglycerides, cholesterol, Apo-B, high density lipoprotein (HDL) and glucose and insulin values during an oral glucose tolerance test were measured. Insulin resistance was assessed using the homeostasis model assessment (HOMA - Insuline resistence index-IRI). In comparison to controls (group II), the offspring of DM2 subjects (group I) had higher fasting serum triglycerides (mean +/- SD 2.25+/-2.08 vs. 1.6+/-0.8 mmol/L, p<0,05), lower HDL cholesterol (0.96 +/- 0.2 vs. 1.1 +/- 0.2 mmol/L, p<0.001), higher total cholesterol (5.5 +/- 1.1 vs. 5.1 +/- 0.8 mmol/L, p < 0.05), higher apo-B-lipoprotein (133.2+/-34.3 vs. 125.5+/-30.5 mg/dl, p<0.05), higher LDL-C (3.7 +/- 0.8 vs. 3.2 +/- 0.6 mmol/L), higher gamma-GT (28+/-10 vs. 17+/-5.6 iu/L, p<0.01) higher insulin in the Area Under the Curve (204.7+/-140.8 v. 153.1 +/- 63.0 microU/ml, p<0.05) and higher HOMA-IRI (2.84+/-1.39 vs. 1.67+/-0.77, p<0.001), higher serum ferritin concentrations (98.3+/-57.7 vs. 62.0+/-41.1 ng/ml, p<0.01), higher serum iron concentration (20.2+/-6.0 micromol/L vs. 14.5+/-4.3, p<0.001) and higher transferrin saturation index (31.3+/-8.4 vs. 22.6+/-7.3, p<0.0001). By single linear analysis in the offspring of DM2 parents, there was a positive correlation of IRI with transferrin saturation (r=0.400, p<0.01), fibrinogen (r=0.377, p=0.025) and ferritin concentration (r=0.344, p=0.041), and a negative correlation with TIBC (r=-0.477, p < 0.0001), while stepwise multiple regression analysis, IRI showed a positive correlation with fibrinogen (b=0.64, t=3.746, p<0.001), triglycerides (b=0.37, t=2.619, p<0.01) and ferritin (b=0.20, t=1.827, p=0.05). No correlation of IRI, with any of the above parameters was seen in the offspring of normal parents. By logistic regression analysis the parameters characterizing the offspring of parents with DM2 were IRI (OR 14.9 CI 2.4-91.0) serum iron (OR 44.2 CI 6.9-281), TIBC (OR 6.1 CI 1.01-37.0 and gamma-GT (OR 29.6 CI 5.0-174). In conclusion, the data indicate that the iron load, is significantly increased in offspring of DM2 subjects with unaffected glucose tolerance. Furthermore, ferritin concentration is related to insulin resistance. Hence, the relative iron "overload" in offspring of type 2 diabetics is present along with insulin resistance and might worsen the hepatic insulin insensitivity already present in these patients.

Complex of transferrin with ruthenium for medical applications

DOEpatents

Richards, Powell; Srivastava, Suresh C.; Meinken, George E.

1984-05-15

A novel Ruthenium-transferrin complex, prepared by reacting iron-free human transferrin dissolved in a sodium acetate solution at pH 7 with ruthenium by heating at about 40.degree. C. for about 2 hours, and purifying said complex by means of gel chromotography with pH 7 sodium acetate as eluent. The mono- or di-metal complex produced can be used in nuclear medicine in the diagnosis and/or treatment of tumors and abscesses. Comparative results with Ga-67-citrate, which is the most widely used tumor-localizing agent in nuclear medicine, indicate increased sensitivity of detection and greater tumor uptake with the Ru-transferrin complex.

In search of transient subduction interfaces in the Dent Blanche-Sesia Tectonic System (W. Alps)

NASA Astrophysics Data System (ADS)

Angiboust, Samuel; Glodny, Johannes; Oncken, Onno; Chopin, Christian

2014-09-01

In this paper we study the Alpine metamorphic history of a major tectonic zone which formed during Alpine orogeny, the Dent Blanche Thrust (DBT). This contact, located in the Northern Western Alps, juxtaposes some ophiolitic metasediment-rich remnants of the Liguro-Piemontese ocean (Tsaté Complex) with a composite continental, km-sized complex (Dent Blanche Tectonic System, DBTS) of Adriatic affinity thrusted over the ophiolite. In order to better understand the geodynamic meaning of the DBT region and adjacent units, we have reconstructed the pressure-temperature-time-deformation (P-T-t-d) history of these two units using modern thermobarometric tools, Rb/Sr geochronology, and field relationships. We show that the Tsaté Complex is formed by a stack of km-thick calcschists-bearing tectonic slices having experienced variable maximum burial temperatures between 360 °C and 490 °C at depths of ca. 25-40 km. Associated deformation ages span a range between 37 Ma and 41 Ma. The Arolla gneissic mylonites at the base of the DBTS experienced high-pressure (12-14 kbar), top-to-NW deformation at ca. 450 °C between 43 and 48 Ma. A first age of ca. 58 Ma has been obtained for high-pressure ductile deformation in the Valpelline shear zone, atop Arolla gneisses. Some of the primary, peak metamorphic fabrics have been reworked and later backfolded during exhumation and collisional overprint (ca. 20 km depth, 37-40 Ma) leading to the regional greenschist-facies retrogression which is particularly prominent within Tsaté metasediments. We interpret the Dent Blanche Thrust, at the base of the Arolla unit, as a fossilized subduction interface active between 43 and 48 Ma. Our geochronological results on the shear zone lining the top of the Arolla unit, together with previous P-T-t estimates on equivalent blueschist-facies shear zones cutting the Sesia unit, indicate an older tectonic activity between 58 and 65 Ma. We demonstrate here that observed younger ages towards lowermost structural levels are witness of the transient, downwards migration of the Alpine early Cenozoic blueschist-facies subduction interface. This down-stepping is interpreted to reflect the progressive underplating acting between 30 and 40 km depth in the Alpine subduction zone between late Cretaceous and late Eocene. Underplating involved first continental material derived from the stretched Adriatic margin followed by underplating of ocean-derived rocks in the Eocene. These results shed light on subduction-zone accretion processes and therefore provide a new perspective for the understanding of geophysical results imaging the plate-interface region in active subduction zones.

Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain.

PubMed

Somani, Sukrut; Blatchford, David R; Millington, Owain; Stevenson, M Lynn; Dufès, Christine

2014-08-28

The possibility of using genes as medicines to treat brain diseases is currently limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier, thus resulting in a failure to reach the brain after intravenous administration. On the basis that iron can effectively reach the brain by using transferrin receptors for crossing the blood-brain barrier, we propose to investigate if a transferrin-bearing generation 3-polypropylenimine dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration. In vitro, the conjugation of transferrin to the polypropylenimine dendrimer increased the DNA uptake by bEnd.3 murine brain endothelioma cells overexpressing transferrin receptors, by about 1.4-fold and 2.3-fold compared to that observed with the non-targeted dendriplex and naked DNA. This DNA uptake appeared to be optimal following 2h incubation with the treatment. In vivo, the intravenous injection of transferrin-bearing dendriplex more than doubled the gene expression in the brain compared to the unmodified dendriplex, while decreasing the non-specific gene expression in the lung. Gene expression was at least 3-fold higher in the brain than in any tested peripheral organs and was at its highest 24h following the injection of the treatments. These results suggest that transferrin-bearing polypropylenimine dendrimer is a highly promising gene delivery system to the brain. Copyright © 2014 Elsevier B.V. All rights reserved.

Possible Mechanism for Denervation Effect on Wound Healing

DTIC Science & Technology

1989-05-17

under investigation is the regenerating limb of the axolotl , in which growth is strictly dependent on unknown factors from peripheral nerves. The...hypothesis that nerves contribute transferrin to cells of the regenerating tissues. Before experiments of this nature can be undertaken, axolotl transferrin...other tissues from axolotls . During the first year of this project, transferrin was purified from axolotls and antisera against it were generated in

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients.

PubMed

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-12-01

Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis.

Association of Increased Serum Ferritin With Impaired Muscle Strength/Quality in Hemodialysis Patients.

PubMed

Nakagawa, Chie; Inaba, Masaaki; Ishimura, Eiji; Yamakawa, Tomoyuki; Shoji, Shigeichi; Okuno, Senji

2016-07-01

We reported previously that muscle quality and muscle strength provide clinically relevant predictors for better survival in hemodialysis patients. Iron overload might impair muscle function by its accumulation in muscle in such patients. Serum ferritin, a marker for body iron store, was examined for its association with handgrip strength (HGS) and muscle quality which was defined as the ratio of HGS to arm lean mass measured with dual-energy X-ray absorptiometry. In 300 Japanese hemodialysis patients, age, hemodialysis duration, body mass index, and serum albumin were 58.0 ±12.0 (mean ± standard deviation) years, 4.2 (1.8-10.4) (median [25th-75th percentile]) years, 20.4 ± 2.8 kg/m(2), 4.0 ± 0.3 g/dL, respectively. Hemoglobin and hematocrit were 8.9 ± 1.2 g/dL, and 28.8 ± 3.9%, respectively, whereas transferrin saturation and serum ferritin were 29.8 ± 11.0% and 100 (54-172) ng/mL, respectively. Serum ferritin significantly correlated in a positive manner with the total dose of iron orally administered during the previous 6 months (r = 0.185, P = .0013). HGS and muscle quality were 23.1 ± 10.4 kg and 11.6 ± 3.8 kg/kg, respectively. In multivariate analysis to elucidate the factors associated with HGS and muscle quality in 300 hemodialysis patients, which included transferrin saturation and log serum ferritin, in addition to age, gender, hemodialysis duration, the presence/absence of diabetes, body mass index as independent variables, log serum ferritin emerged as a significant and independent factor which associated in a negative fashion with HGS (β = -0.091, P = .0395) and tendency toward negative association with muscle quality (β = -0.100, P = .0754). In summary, the present study demonstrated the significant association of serum ferritin with HGS and muscle quality in hemodialysis patients and thus suggested that we should be careful of iron overload to avoid its possible harmful effect on muscle in such patients. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

PubMed Central

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-01-01

Background Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. Design and Methods: In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis. PMID:22773607

Complex of transferrin with ruthenium for medical applications

DOEpatents

Richards, P.; Srivastava, S.C.; Meinken, G.E.

1984-05-15

A novel ruthenium-transferrin complex is disclosed which is prepared by reacting iron-free human transferrin dissolved in a sodium acetate solution at pH 7 with ruthenium by heating at about 40 C for about 2 hours. The complex is purified by means of gel chromotography with pH 7 sodium acetate as eluent. The mono- or di-metal complex produced can be used in nuclear medicine in the diagnosis and/or treatment of tumors and abscesses. Comparative results with Ga-67-citrate, which is the most widely used tumor-localizing agent in nuclear medicine, indicate increased sensitivity of detection and greater tumor uptake with the Ru-transferrin complex. No Drawings

Complex of transferrin with ruthenium for medical applications. [Ru 97, Ru 103

DOEpatents

Richards, P.; Srivastava, S.C.; Meinken, G.E.

1980-11-03

A novel Ruthenium-transferrin complex, prepared by reacting iron-free human transferrin dissolved in a sodium acetate solution at pH 7 with ruthenium by heating at about 40/sup 0/C for about 2 hours, and purifying said complex by means of gel chromatography with pH 7 sodium acetate as eluent. The mono- or di-metal complex produced can be used in nuclear medicine in the diagnosis and/or treatment of tumors and abscesses. Comparitive results with Ga-67-citrate, which is the most widely used tumor-localizing agent in nuclear medicine, indicate increased sensitivity of detection and greater tumor uptake with the Ru-transferrin complex.

Influence of endurance exercise (triathlon) on circulating transferrin receptors and other indicators of iron status in female athletes.

PubMed

Röcker, Lothar; Hinz, Katrin; Holland, Karsten; Gunga, Hanns-Christian; Vogelgesang, Jens; Kiesewetter, Holger

2002-01-01

Numerous reports have described a poor iron status in female endurance athletes. However, the traditionally applied indicators of iron status (hemoglobin, ferritin, transferrin) may not truly reflect the iron status. Therefore we studied the newly developed soluble transferrin receptor and other indicators of iron status in twelve female endurance athletes before and after a triathlon race. Resting values showed a poor iron status in the participants of the race. Serum TfR concentration increased slightly after the race. However, if the values are corrected for hemoconcentration no change could be found. Hemoglobin, serum ferritin and transferrin values were increased after the race.

Space Situational Awareness of Large Numbers of Payloads from a Single Deployment

DTIC Science & Technology

2014-09-01

challenges [12]. 3. CHIPSAT CLOUD DEPLOYMENT AND CATALOGING One of the six satellites deployed as part of the April 18, 2014, Falcon 9 launch to the ISS was...Cloud Modeling Techniques,” Journal of Spacecraft and Rockets , Vol. 33, No. 4, 550–555, 1996. 2. Swinerd, G.G., Barrows, S.P., and Crowther, R., “Short... Big Sky, Montana, 2013. 11. Voss, H.D., Dailey, J.F., Crowley, J.C., et al., “TSAT Globalstar ELaNa-5 Extremely Low-Earth Orbit (ELEO) Satellite,” 28th

Polymorphism of transferrin in carp (Cyprinus carpio L.): genetic determination, isolation, and partial characterization.

PubMed

Valenta, M; Stratil, A; Slechtová, V; Kálal, L; Slechta, V

1976-02-01

Seven transferrin variants (A,B,C,D,E,F, and G) have been found in carp sera (Cyprinus carpio L.). Genetic analysis involves five variants and agrees with the hypothesis of simple codominant autosomal inheritance at one transferrin (Tf) locus in spite of the fact that the carp is a tetraploid in relation to other species of the same family. Carp populations from three regions were studied which differed in gene frequencies. Individual populations were in Hardy-Weinberg equilibrium. The polymorphism of carp transferrins can be used for the identification of offspring of single parent pairs, stocked in one pond. Transferrins have been isolated and characterized. Homozygous phenotypes comprised four iron-binding components differing in electrophoretic mobility. This heterogeneity is not caused by sialic acid, which is absent. Amino acid composition, content of hexoses (1 mole/mole of protein) and hexosamines (1 mole/mole of protein), molecualr weight (70,000), and the isoelectric point (5.0) have been determined. No N-terminal amino acid could be detected.

Resistance of different stocks and transferrin genotypes of coho salmon, Oncorhynchus kisutch, and steelhead trout, Salmo gairdneri, to bacterial kidney disease and vibriosis

USGS Publications Warehouse

Winter , Gary W.; Schreck, Carl B.; McIntyre, John D.

1979-01-01

Juvenile coho salmon and steelhead trout ofdifferentstocks and three transferrin genotypes(AA, AC, and CCl, all reared in identical or similar environments, were experimentally infected with Corynebacterium sp., the causative agent ofbacterial kidney disease, or with Vibrio anguillarum, the causative agent of vibriosis. Mortality due to the pathogens was compared among stocks within a species and among transferrin genotypes within a stock to determine whetherthere was a geneticbasis for resistance to disease. Differences in resistance to bacterial kidney disease among coho salmon stocks had a genetic basis. Stock susceptibility to vibriosis was strongly influenced by environmental factors. Coho salmon orsteelhead trout of one stock may be resistant to one disease but susceptible to another. The importance of transferrin genotype of coho salmon in resistance to bacterial kidney disease was stock specific; in stocks that showed differential resistance of genotypes, the AA was the most susceptible. No differencesin resistance to vibriosis were observed among transferrin genotypes.

Fate of blood meal iron in mosquitos

PubMed Central

Zhou, Guoli; Kohlhepp, Pete; Geiser, Dawn; Frasquillo, Maria del Carmen; Vazquez-Moreno, Luz; Winzerling, Joy J.

2007-01-01

Iron is an essential element of living cells and organisms as a component of numerous metabolic pathways. Hemoglobin and ferric-transferrin in vertebrate host blood are the two major iron sources for female mosquitoes. We used inductively coupled plasma mass spectrometry (ICP-MS) and radioisotope-labeling to quantify the fate of iron supplied from hemoglobin or as transferrin in Aedes aegypti. At the end of the first gonotrophic cycloe, ~87% of the ingested total meal heme iron was excreted, while 7% was distributed into the eggs and 6% was stored in different tissues. In contrast, ~8% of the iron provided as transferrin was excreted and of that absorbed, 77% was allocated to the eggs and 15% distributed in the tissues. Further analyses indicate that of the iron supplied in a blood meal, ~7% appears in the eggs and of this iron 98% is from hemoglobin and 2% from ferric-transferrin. Whereas of iron from a blood meal retained in body of the female, ~97% is from heme and <1 % is from transferrin. Evaluation of iron-binding proteins in hemolymph and egg following intake of 59Fe-transferrin revealed that ferritin is iron loaded in these animals, and indicate that this protein plays a critical role in meal iron transport and iron storage in eggs in A. aegypti. PMID:17689557

Occurrence of occult CSF leaks during standard FESS procedures.

PubMed

Bucher, S; Kugler, A; Probst, E; Epprecht, L; Stadler, R S; Holzmann, D; Soyka, M B

2018-03-18

To determine the incidence of occult cerebrospinal fluid leaks (CSF) after functional endoscopic sinus surgery (FESS) and to evaluate the diagnostic performance of beta2-transferrin in blood-contaminated conditions. Prospective cohort study. An analysis of 57 intraoperative samples using hydrogel 6 beta2-transferrin assay after FESS was undertaken. In case of CSF positive samples and continuing rhinorrhea, reanalysis after more than 1 year was conducted. In-vivo analysis of a primary spontaneous CSF leak sample took place to verify difficulties in detecting beta2-transferrin in blood-contaminated settings. Own titrations were performed to evaluate detection limits of CSF by beta2-transferrin and beta-trace protein assays in these settings. An incidence of 13% for occult CSF leaks after FESS was found. In blood-contaminated conditions, routine beta2-transferrin assays showed low sensitivity. In over 1 year follow-up, all samples were negative for CSF and none of them developed clinical relevant CSF leaks or meningitis. Occult and clinically irrelevant CSF leaks do occur in a significant proportion of patients during and shortly after FESS. Intra- and postoperatively, routine beta2-transferrin assays show low sensitivity. They should not be used in these settings. The clinical course of patients with occult CSF leaks indicated possibility of an uneventful follow-up.

Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma.

PubMed

Johnsen, Kasper Bendix; Burkhart, Annette; Melander, Fredrik; Kempen, Paul Joseph; Vejlebo, Jonas Bruun; Siupka, Piotr; Nielsen, Morten Schallburg; Andresen, Thomas Lars; Moos, Torben

2017-09-04

Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain.

Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1

PubMed Central

Ba, Qian; Zhou, Naiyuan; Duan, Juan; Chen, Tao; Hao, Miao; Yang, Xinying; Li, Junyang; Yin, Jun; Chu, Ruiai; Wang, Hui

2012-01-01

Artemisinin and its main active metabolite dihydroartemisinin, clinically used antimalarial agents with low host toxicity, have recently shown potent anticancer activities in a variety of human cancer models. Although iron mediated oxidative damage is involved, the mechanisms underlying these activities remain unclear. In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners. It decreased iron uptake and disturbed iron homeostasis in cancer cells, which were independent of oxidative damage. Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane. The regulation of dihydroartemisinin to transferrin receptor-1 could be reversed by nystatin, a cholesterol-sequestering agent but not the inhibitor of clathrin-dependent endocytosis. Dihydroartemisinin also induced transferrin receptor-1 palmitoylation and colocalization with caveolin-1, suggesting a lipid rafts mediated internalization pathway was involved in the process. Also, nystatin reversed the influences of dihydroartemisinin on cell cycle and apoptosis related genes and the siRNA induced downregulation of transferrin receptor-1 decreased the sensitivity to dihydroartemisinin efficiently in the cells. These results indicate that dihydroartemisinin can counteract cancer through regulating cell-surface transferrin receptor-1 in a non-classical endocytic pathway, which may be a new action mechanism of DHA independently of oxidative damage. PMID:22900042

Fluorescent adduct formation with terbium: a novel strategy for transferrin glycoform identification in human body fluids and carbohydrate-deficient transferrin HPLC method validation.

PubMed

Sorio, Daniela; De Palo, Elio Franco; Bertaso, Anna; Bortolotti, Federica; Tagliaro, Franco

2017-02-01

This paper puts forward a new method for the transferrin (Tf) glycoform analysis in body fluids that involves the formation of a transferrin-terbium fluorescent adduct (TfFluo). The key idea is to validate the analytical procedure for carbohydrate-deficient transferrin (CDT), a traditional biochemical serum marker to identify chronic alcohol abuse. Terbium added to a human body-fluid sample produced TfFluo. Anion exchange HPLC technique, with fluorescence detection (λ exc 298 nm and λ em 550 nm), permitted clear separation and identification of Tf glycoform peaks without any interfering signals, allowing selective Tf sialoforms analysis in human serum and body fluids (cadaveric blood, cerebrospinal fluid, and dried blood spots) hampered for routine test. Serum samples (n = 78) were analyzed by both traditional absorbance (Abs) and fluorescence (Fl) HPLC methods and CDT% levels demonstrated a significant correlation (p < 0.001 Pearson). Intra- and inter-runs CV% was 3.1 and 4.6%, respectively. The cut-off of 1.9 CDT%, related to the HPLC Abs proposed as the reference method, by interpolation in the correlation curve with the present method demonstrated a 1.3 CDT% cut-off. Method comparison by Passing-Bablok and Bland-Altman tests demonstrated Fl versus Abs agreement. In conclusion, the novel method is a reliable test for CDT% analysis and provides a substantial analytical improvement offering important advantages in terms of types of body fluid analysis. Its sensitivity and absence of interferences extend clinical applications being reliable for CDT assay on body fluids usually not suitable for routine test. Graphical Abstract The formation of a transferrin-terbium fluorescent adduct can be used to analyze the transferrin glycoforms. The HPLC method for carbohydrate-deficient transferrin (CDT%) measurement was validated and employed to determine the levels in different body fluids.

Diagnosis of Iron-Deficiency Anemia in Chronic Kidney Disease.

PubMed

Bahrainwala, Jehan; Berns, Jeffrey S

2016-03-01

Anemia is a common and clinically important consequence of chronic kidney disease (CKD). It is most commonly a result of decreased erythropoietin production by the kidneys and/or iron deficiency. Deciding on the appropriate treatment for anemia associated with CKD with iron replacement and erythropoietic-stimulating agents requires an ability to accurately diagnose iron-deficiency anemia. However, the diagnosis of iron-deficiency anemia in CKD patients is complicated by the relatively poor predictive ability of easily obtained routine serum iron indices (eg, ferritin and transferrin saturation) and more invasive gold standard measures of iron deficiency (eg, bone marrow iron stores) or erythropoietic response to supplemental iron. In this review, we discuss the diagnostic utility of currently used serum iron indices and emerging alternative markers of iron stores. Copyright © 2016 Elsevier Inc. All rights reserved.

Diagnosis and management of transfusion iron overload: The role of imaging

PubMed Central

Wood, John C.

2010-01-01

The characterization of iron stores is important to prevent and treat iron overload. Serum markers such as ferritin, serum iron, iron binding capacity, transferrin saturation, and nontransferrin-bound iron can be used to follow trends in iron status; however, variability in these markers limits predictive power for any given individual. Liver iron represents the best single marker of total iron balance. Measures of liver iron include biopsy, superconducting quantum interference device, computer tomography, and magnetic resonance imaging (MRI). MRI is the most accurate and widely available noninvasive tool to assess liver iron. The main advantages of MRI include a low-rate of variability between measurements and the ability to assess iron loading in endocrine tissues, the heart and the liver. This manuscript describes the principles, validation, and clinical utility of MRI for tissue iron estimation. PMID:17963249

Conserved Regions of Gonococcal TbpB Are Critical for Surface Exposure and Transferrin Iron Utilization

PubMed Central

Ostberg, Karen L.; DeRocco, Amanda J.; Mistry, Shreni D.; Dickinson, Mary Kathryne

2013-01-01

The transferrin-binding proteins TbpA and TbpB enable Neisseria gonorrhoeae to obtain iron from human transferrin. The lipoprotein TbpB facilitates, but is not strictly required for, TbpA-mediated iron acquisition. The goal of the current study was to determine the contribution of two conserved regions within TbpB to the function of this protein. Using site-directed mutagenesis, the first mutation we constructed replaced the lipobox (LSAC) of TbpB with a signal I peptidase cleavage site (LAAA), while the second mutation deleted a conserved stretch of glycine residues immediately downstream of the lipobox. We then evaluated the resulting mutants for effects on TbpB expression, surface exposure, and transferrin iron utilization. Western blot analysis and palmitate labeling indicated that the lipobox, but not the glycine-rich motif, is required for lipidation of TbpB and tethering to the outer membrane. TbpB was released into the supernatant by the mutant that produces TbpB LSAC. Neither mutation disrupted the transport of TbpB across the bacterial cell envelope. When these mutant TbpB proteins were produced in a strain expressing a form of TbpA that requires TbpB for iron acquisition, growth on transferrin was either abrogated or dramatically diminished. We conclude that surface tethering of TbpB is required for optimal performance of the transferrin iron acquisition system, while the presence of the polyglycine stretch near the amino terminus of TbpB contributes significantly to transferrin iron transport function. Overall, these results provide important insights into the functional roles of two conserved motifs of TbpB, enhancing our understanding of this critical iron uptake system. PMID:23836816

Hypertension increases urinary excretion of immunoglobulin G, ceruloplasmin and transferrin in normoalbuminuric patients with type 2 diabetes mellitus.

PubMed

Ohara, Nobumasa; Hanyu, Osamu; Hirayama, Satoshi; Nakagawa, Osamu; Aizawa, Yoshifusa; Ito, Seiki; Sone, Hirohito

2014-02-01

Increased urinary excretion of certain plasma proteins, such as immunoglobulin G (IgG), ceruloplasmin and transferrin, with different molecular radii of 55 Å or less and different isoelectric points have been reported to precede development of microalbuminuria in patients who have diabetes mellitus with hypertension. We examined how hypertension affects these urinary proteins in a diabetic state. Excretion of IgG, ceruloplasmin, transferrin, albumin, α2-macroglobulin with a large molecular radius of 88 Å and N-acetylglucosaminidase in first-morning urine samples were measured in normoalbuminuric patients (urinary albumin-to-creatinine ratio < 15 mg/g) with hypertension and nondiabetes mellitus (group hypertension, n = 32), type 2 diabetes mellitus and normotension (group diabetes mellitus, n = 52) and type 2 diabetes mellitus and hypertension (group Both, n =45), and in age-matched controls (n = 72). Urinary IgG, ceruloplasmin, transferrin, albumin and N-acetylglucosaminidase and estimated glomerular filtration rate (eGFR) were significantly elevated in groups diabetes mellitus and Both compared with controls. Furthermore, urinary IgG, ceruloplasmin and transferrin in group Both were significantly higher than those in group diabetes mellitus. These exhibited a positive and relatively strong association with eGFR compared with controls. No significant difference in urinary albumin or N-acetylglucosaminidase was found between the two diabetic groups. In contrast, group hypertension had elevated urinary transferrin without any changes in the other compounds. Urinary α2-macroglobulin did not differ among the four groups. These findings suggest that normoalbuminuric diabetic patients without hypertension have both glomerular hemodynamic changes such as increased intraglomerular hydraulic pressure and altered proximal tubules, and that hypertension increases intraglomerular hydraulic pressure. Increased urinary IgG, ceruloplasmin and transferrin may reflect an increase in intraglomerular hydraulic pressure.

Involvement of multiple distinct Bordetella receptor proteins in the utilization of iron liberated from transferrin by host catecholamine stress hormones

PubMed Central

Armstrong, Sandra K.; Brickman, Timothy J.; Suhadolc, Ryan J.

2012-01-01

Summary Bordetella bronchiseptica is a pathogen that can acquire iron using its native alcaligin siderophore system, but can also use the catechol xenosiderophore enterobactin via the BfeA outer membrane receptor. Transcription of bfeA is positively controlled by a regulator that requires induction by enterobactin. Catecholamine hormones also induce bfeA transcription and B. bronchiseptica can use the catecholamine norepinephrine for growth on transferrin. In this study, B. bronchiseptica was shown to use catecholamines to obtain iron from both transferrin and lactoferrin in the absence of siderophore. In the presence of siderophore, norepinephrine augmented transferrin utilization by B. bronchiseptica, as well as siderophore function in vitro. Genetic analysis identified BfrA, BfrD and BfrE as TonB dependent outer membrane catecholamine receptors. The BfeA enterobactin receptor was found to not be involved directly in catecholamine utilization; however, the BfrA, BfrD and BfrE catecholamine receptors could serve as receptors for enterobactin and its degradation product 2,3-dihydroxybenzoic acid. Thus, there is a functional link between enterobactin-dependent and catecholamine-dependent transferrin utilization. This investigation characterizes a new B. bronchiseptica mechanism for iron uptake from transferrin that uses host stress hormones that not only deliver iron directly to catecholamine receptors, but also potentiate siderophore activity by acting as iron shuttles. PMID:22458330

Honey bee (Apis mellifera) transferrin-gene structure and the role of ecdysteroids in the developmental regulation of its expression.

PubMed

do Nascimento, Adriana Mendes; Cuvillier-Hot, Virginie; Barchuk, Angel Roberto; Simões, Zilá Luz Paulino; Hartfelder, Klaus

2004-05-01

Social life is prone to invasion by microorganisms, and binding of ferric ions by transferrin is an efficient strategy to restrict their access to iron. In this study, we isolated cDNA and genomic clones encoding an Apis mellifera transferrin (AmTRF) gene. It has an open reading frame (ORF) of 2136 bp spread over nine exons. The deduced protein sequence comprises 686 amino acid residues plus a 26 residues signal sequence, giving a predicted molecular mass of 76 kDa. Comparison of the deduced AmTRF amino acid sequence with known insect transferrins revealed significant similarity extending over the entire sequence. It clusters with monoferric transferrins, with which it shares putative iron-binding residues in the N-terminal lobe. In a functional analysis of AmTRF expression in honey bee development, we monitored its expression profile in the larval and pupal stages. The negative regulation of AmTRF by ecdysteroids deduced from the developmental expression profile was confirmed by experimental treatment of spinning-stage honey bee larvae with 20-hydroxyecdysone, and of fourth instar-larvae with juvenile hormone. A juvenile hormone application to spinning-stage larvae, in contrast, had only a minor effect on AmTRF transcript levels. This is the first study implicating ecdysteroids in the developmental regulation of transferrin expression in an insect species.

Genetic characteristic of swamp buffalo (Bubalus bubalis) from Pampangan, South Sumatra based on blood protein profile

NASA Astrophysics Data System (ADS)

Windusari, Yuanita; Hanum, Laila; Wahyudi, Rizki

2017-11-01

Swamp buffalo (Bubalus bubalis) is an endemic species and one of the genetic wealth of South Sumatra with a distribution area in the district of Pampangan (OganIlir and OganOganIlir). Suspected inbreeding causes decreased phenotypic properties. Inbreeding among various swamp buffalo is certainly not only lower the qualities but also genotypes and phenotypes. It is of interest to determine kinship variants swamp buffaloes from Pampangan through the analysis of a blood protein profile. Blood protein profile of four variants swamps buffalo was studied by using five electrophoresis system i.e. pre-albumin (Palb), albumin (Alb), ceruloplasmin (Cp), transferrin (Tf) and transferrin post (Ptf). In this paper, it is obtained that there was no significant differences among the four variants of the buffaloes were used as a sample. Prealbumin has two alleles (Palb1 and Palb2), albumin has three alleles (Alba, AlbB, AlbC), ceruloplasmin has one allele (BPA), post-transferrin has one allele (PTFA) with an allele frequency 1.0000 at any time transferrin has two alleles (TFA and TFB) with the allele frequency of 0.7500 and 1.0000. Characteristics prealbumin (Palb), albumin (Alb), ceruloplasmin (Cp), and post-transferrin (P-tf) is monomorphic, while transferrin is polymorphic average heterozygosity values all loci (H) 0.1286. Based on average heterozygosity, the swamp buffalo (Bubalusbubalis) from Pampangan has low genetic variation and closest genetic relationship.

Iodine-131-labeled, transferrin-capped polypyrrole nanoparticles for tumor-targeted synergistic photothermal-radioisotope therapy.

PubMed

Song, Xuejiao; Liang, Chao; Feng, Liangzhu; Yang, Kai; Liu, Zhuang

2017-08-22

Combining different therapeutic functions within single tumor-targeted nanoscale delivery systems is promising to overcome the limitations of conventional cancer therapies. Herein, transferrin that recognizes transferrin receptors up-regulated on tumor cells is pre-labeled with iodine-131 ( 131 I) and then utilized as the stabilizer in the fabrication of polypyrrole (PPy) nanoparticles. The obtained transferrin-capped PPy@Tf- 131 I nanoparticles could be used for tumor-targeted radioisotope therapy (RIT) and photothermal therapy (PTT), by employing beta-emission from 131 I and the intrinsic high near-infrared (NIR) absorbance of PPy, respectively. Owing to the transferrin-mediated tumor targeting, PPy@Tf- 131 I nanoparticles exhibit obviously enhanced in vitro cancer cell binding and in vivo tumor uptake compared to its non-targeting counterpart. The combined RIT and PTT based on PPy@Tf- 131 I nanoparticles is then conducted, achieving a remarkable synergistic therapeutic effect. This work thus demonstrates a rather simple one-step approach to fabricate tumor-targeting nanoparticles based on protein-capped conjugated polymers, promising for combination cancer therapy with great efficacy and high safety.

Transferrin Family Genes in the Brown Planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) in Response to Three Insecticides.

PubMed

Wu, Shun-Fan; Li, Jian; Zhang, Yong; Gao, Cong-Fen

2018-02-09

Transferrins are involved in iron metabolism, immunity, xenobiotics tolerance, and development in eukaryotic organisms including insects. However, little is known about the relationship between transferrins and insecticide toxicology and resistance. Three transferrin family genes, NlTsf1, NlTsf2, and NlTsf3, of the brown planthopper, Nilaparvata lugens (Stål) (Hemiptera: Delphacidae)a major insect pest of rice field in Asia, had been identified and characterized in this study. Quantitative polymerase chain reaction results demonstrated that NlTsf1 was significantly higher than the other two genes in different tissues. All of them were expressed at higher levels in abdomen and head than in antenna, leg, stylet, and thorax. Compared with the control, the expression of three N. lugens transferrin family genes decreased dramatically 24 h after treatment with buprofezin, pymetrozine and imidacloprid. Published by Oxford University Press on behalf of Entomological Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

The impact of H63D HFE gene carriage on hemoglobin and iron status in children.

PubMed

Barbara, Kaczorowska-Hac; Marcin, Luszczyk; Jedrzej, Antosiewicz; Wieslaw, Ziolkowski; Elzbieta, Adamkiewicz-Drozynska; Malgorzata, Mysliwiec; Ewa, Milosz; Jacek, Kaczor Jan

2016-12-01

The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. Hereditary hemochromatosis is a heterogenic metabolic syndrome which is due to unchecked transfer of iron into the bloodstream and its toxic effects on parenchymatous organs. It is caused by the mutation of genes that encode proteins that help hepcidin to monitor serum iron. These proteins include the human hemochromatosis protein -HFE, transferrin-receptor 2, hemojuvelin in rare instances, and ferroportin. HFE-related hemochromatosis is the most frequent form of the disease. Interestingly, the low penetrance of polymorphic HFE genes results in rare clinical presentation of the disease, predominantly in middle-aged males. Taking into account the wide dispersion of HFE mutation in our population and also its unknown role in heterozygotes, we analyzed the impact of H63D HFE carriage in the developmental age, with respect to gender, on the iron status and hemoglobin concentration of carriers in comparison to those of wild-type HFE gene (12.7 ± 3.07 years, 42 boys and 41 girls). H63D carriers presented higher blood iron, transferrin saturation, and ferritin concentration than wild-type probands (p < 0.05.) Interestingly, male H63D carriers showed higher hemoglobin concentration than the unburdened children. Moreover, in the H63D carrier group, a positive correlation between iron and hemoglobin was noted. In conclusion, this study demonstrates that changes in iron metabolism occur at a young age in HFE heterozygotes.

Iron Status and Inflammation in Early Stages of Chronic Kidney Disease.

PubMed

Łukaszyk, Ewelina; Łukaszyk, Mateusz; Koc-Żórawska, Ewa; Tobolczyk, Jolanta; Bodzenta-Łukaszyk, Anna; Małyszko, Jolanta

2015-01-01

One of the most common causes of anemia of chronic disease (ACD) is chronic kidney disease. The main pathomechanism responsible for ACD is subclinical inflammation. The key element involved in iron metabolism is hepcidin, however, studies on new indices of iron status are in progress.The aim of the study was to assess the iron status in patients in early stages of chronic kidney disease, iron correlation with inflammation parameters and novel biomarkers of iron metabolism. The study included 69 patients. Standard laboratory measurements were used to measure the iron status, complete blood count, fibrinogen, prothrombin index, C-reactive protein concentration (CRP), creatinine, urea, uric acid. Commercially available kits were used to measure high-sensitivity CRP, interleukin 6 (IL-6), hepcidin-25, hemojuvelin, soluble transferrin receptor (sTfR), growth differentiation factor-15 (GDF-15) and zonulin. Absolute iron deficiency was present in 17% of the patients, functional iron deficiency was present in 12% of the patients. Functional iron deficiency was associated with significantly higher serum levels of fibrinogen, ferritin, transferrin saturation, total iron binding capacity, hepcidin and older age relative to patients with absolute iron deficiency. In comparison with patients without iron deficiency, patients with functional iron deficiency were older, with lower prothrombin index, higher fibrinogen, CRP, hsCRP, sTfR, GDF-15, urea and lower eGFR. Hepcidin was predicted by markers of inflammation:ferritin, fibrinogen and IL-6. Inflammation is correlated with iron status. Novel biomarkers of iron metabolism might be useful to distinguish iron deficiency anemia connected with inflammation and absolute iron deficiency. © 2015 S. Karger AG, Basel.

TIBC, UIBC and Transferrin

MedlinePlus

... 28 weeks to delivery) Primary Aldosteronism (Conn Syndrome) Prostate Cancer Protein in Urine (Proteinuria) Reactive Arthritis Rheumatoid Arthritis ... Blood Count (CBC) Hemoglobin Hematocrit Reticulocytes Soluble Transferrin Receptor Conditions Anemia Hemochromatosis Elsewhere On The Web American ...

Transferrin-mediated targeting of hypericin embedded in sterically stabilized PEG-liposomes.

PubMed

Derycke, Annelies S L; De Witte, Peter A M

2002-01-01

Over the last few decades, photodynamic therapy evolved to a promising new treating modality for cancer. The photosensitizers used, induce light sensitivity to a normal light insensitive chemical or physical process. Third generation photosensitizers are derivatives of second generation photosensitizers introduced into or attached to chemical devices. This modification increases the biological specificity to deliver photosensitizers to a defined cell type. The aim of this study was to improve the specificity of hypericin for tumor cells using transferrin-conjugated PEG-liposomes. Transferrin was used as tumor-seeking molecule, since many tumor cells, among which HeLa cells, overexpress transferrin receptors on their surface. Hypericin, a potent second generation photosensitizer, was integrated in the lipid bilayers of the liposomes. The antiproliferative effect of the targeted PEG-liposomes was determined and compared with the results of non-targeted PEG-liposomes and free hypericin. Additionally, the intracellular accumulation assay was performed. All manipulations were done on HeLa cells. To interpret the results, the data were supplemented by findings concerning embedding stability. Targeting hypericin by transferrin-conjugated PEG-liposomes did not significantly favour the photocytotoxicity and the intracellular accumulation of hypericin, in comparison with non-targeted PEG-liposomes or free hypericin. Embedding stability experiments showed only limited stable embedding. Despite of their proven efficiency as a targeting carrier system, transferrin-conjugated PEG-liposomes seem less effective in targeting hypericin to tumor cells due to the amount of hypericin leaking out of the PEG-liposomes.

Studies on the erythron and the ferrokinetic responses in beagles adapted to hypergravity

NASA Technical Reports Server (NTRS)

Beckman, D. A.; Evans, J. W.; Oyama, J.

1978-01-01

Red cell survival, ferrokinetics, and hematologic parameters were investigated in beagle dogs exposed to chronic hypergravity (2.6 Gx). Ineffective erythropoiesis, red cell mass, plasma volume, and Cr-51-elution were significantly increased; maximum Fe-59 incorporation was decreased; and there was no change in the mean erythrocyte life span following autologous injection of Cr-51-labeled red cells and Fe-59-labeled transferrin. Red cell count, F(cells), total body hemoglobin (Hb), susceptability to osmotic lysis, and differential reticulocyte count were increased. White blood cell count, venous blood %Hb, mean cell volume, mean cell Hb, mean cell Hb concentration, and serum iron were decreased. No changes were observed for body mass, mg Fe per g Hb, iron binding capacity, percent saturation of iron carrying capacity, or the electrophoretic mobility of purified Hb. This study indicated that chronic exposure to hypergravity induced changes in red cell size, volume, total mass, and membrane permeability.

Analysis of lymphopoietic stem cells with a monoclonal antibody to the rat transferrin receptor.

PubMed Central

Jefferies, W A; Brandon, M R; Williams, A F; Hunt, S V

1985-01-01

A mouse monoclonal IgG2a antibody, designated MRC OX-26, is shown to be specific for the rat transferrin receptor, but does not block transferrin binding. The antibody labelled a myeloma, three leukaemia cell lines and normal dividing cells of various types, but also bound to a number of nondividing normal tissues. No labelling of lymphopoietic stem cells could be detected, even though approximately 25% of bone marrow and over 95% of fetal liver cells were clearly labelled. Images Figure 1 Figure 3 PMID:2981766

Serum transferrin receptor in polycythemia.

PubMed

Manteiga, R; Remacha, A F; Sardà, M P; Ubeda, J

1998-10-01

We measured serum transferrin receptor (sTfR) levels in 22 patients with polycythemia vera and in 26 cases of secondary polycythemia. In our study, raised sTfR levels in both polycythemia groups were related to iron deficiency.

Self-assembled Targeting of Cancer Cells by Iron(III)-doped, Silica Nanoparticles.

PubMed

Mitchell, K K Pohaku; Sandoval, S; Cortes-Mateos, M J; Alfaro, J G; Kummel, A C; Trogler, W C

2014-12-07

Iron(III)-doped silica nanoshells are shown to possess an in vitro cell-receptor mediated targeting functionality for endocytosis. Compared to plain silica nanoparticles, iron enriched ones are shown to be target-specific, a property that makes them potentially better vehicles for applications, such as drug delivery and tumor imaging, by making them more selective and thereby reducing the nanoparticle dose. Iron(III) in the nanoshells can interact with endogenous transferrin, a serum protein found in mammalian cell culture media, which subsequently promotes transport of the nanoshells into cells by the transferrin receptor-mediated endocytosis pathway. The enhanced uptake of the iron(III)-doped nanoshells relative to undoped silica nanoshells by a transferrin receptor-mediated pathway was established using fluorescence and confocal microscopy in an epithelial breast cancer cell line. This process was also confirmed using fluorescence activated cell sorting (FACS) measurements that show competitive blocking of nanoparticle uptake by added holo-transferrin.

Insect transferrin functions as an antioxidant protein in a beetle larva.

PubMed

Kim, Bo Yeon; Lee, Kwang Sik; Choo, Young Moo; Kim, Iksoo; Je, Yeon Ho; Woo, Soo Dong; Lee, Sang Mong; Park, Hyun Cheol; Sohn, Hung Dae; Jin, Byung Rae

2008-06-01

In insects transferrin is known as an iron transporter, an antibiotic agent, a vitellogenin, and a juvenile hormone regulated protein. Here, a novel functional role for insect transferrin as an antioxidant protein is demonstrated. Stressors, such as heat shock, fungal challenge, and H(2)O(2) exposure, cause upregulation of the white-spotted flower chafer Protaetia brevitarsis (Coleoptera: Scarabaeidae) transferrin (PbTf) mRNA in the fat body and increases PbTf protein levels in the hemolymph. RNA interference (RNAi) treated PbTf reduction causes increased iron and H(2)O(2) levels in the hemolymph and results in induction of apoptotic cell death in the fat body during exposure to stress. The observed effects of PbTf RNAi suggest that PbTf inhibits stress-induced apoptosis by diminishing the Fenton reaction via the binding of iron, thus supporting an antioxidant role for PbTf in stress responses.

Inflammation associated anemia and ferritin as disease markers in SLE

PubMed Central

2012-01-01

Introduction In a recent screening to detect biomarkers in systemic lupus erythematosus (SLE), expression of the iron storage protein, ferritin, was increased. Given that proteins that regulate the storage, transfer and release of iron play an important role in inflammation, this study aims to determine the serum and urine levels of ferritin and of the iron transfer protein, transferrin, in lupus patients and to correlate these levels with disease activity, inflammatory cytokine levels and markers of anemia. Methods A protein array was utilized to measure ferritin expression in the urine and serum of SLE patients and healthy controls. To confirm these results as well as the role of the iron transfer pathway in SLE, ELISAs were performed to measure ferritin and transferrin levels in inactive or active SLE patients and healthy controls. The relationship between ferritin/transferrin levels and inflammatory markers and anemia was next analyzed. Results Protein array results showed elevated ferritin levels in the serum and urine of lupus patients as compared to controls, which were further validated by ELISA. Increased ferritin levels correlated with measures of disease activity and anemia as well as inflammatory cytokine titers. Though active SLE patients had elevated urine transferrin, serum transferrin was reduced. Conclusion Urine ferritin and transferrin levels are elevated significantly in SLE patients and correlate with disease activity, bolstering previous reports. Most importantly, these changes correlated with the inflammatory state of the patients and anemia of chronic disease. Taken together, altered iron handling, inflammation and anemia of chronic disease constitute an ominous triad in SLE. PMID:22871034

Circulating non–transferrin-bound iron after oral administration of supplemental and fortification doses of iron to healthy women: a randomized study1234

PubMed Central

Andersson, Maria; Egli, Ines; Foman, Jasmin Tajeri; Zeder, Christophe; Westerman, Mark E; Hurrell, Richard F

2014-01-01

Background: After the oral administration of iron, the production of circulating non–transferrin-bound iron may contribute to an increased risk of illness in malaria-endemic areas that lack effective medical services. Objective: In healthy women with a range of body iron stores, we aimed to determine effects on the production of circulating non–transferrin-bound iron resulting from the oral administration of 1) a supplemental dose of iron (60 mg) with water, 2) a supplemental dose of iron (60 mg) with a standard test meal, and 3) a fortification dose of iron (6 mg) with a standard test meal. Design: With the use of serum ferritin as the indicator, healthy women with replete iron stores (ferritin concentration >25 μg/L; n = 16) and reduced iron stores (ferritin concentration ≤25 μg/L; n = 16) were enrolled in a prospective, randomized, crossover study. After the oral administration of aqueous solutions of ferrous sulfate isotopically labeled with 54Fe, 57Fe, or 58Fe, blood samples were collected for 8 h, and iron absorption was estimated by erythrocyte incorporation at 14 d. Results: At 4 h, serum non–transferrin-bound iron reached peaks with geometric mean (95% CI) concentrations of 0.81 μmol/L (0.56, 1.1 μmol/L) for 60 mg Fe with water and 0.26 μmol/L (0.15, 0.38 μmol/L) for 60 mg Fe with food but was at assay limits of detection (0.1 μmol Fe/L) for 6 mg Fe with food. For the 60 mg Fe without food, the area under the curve over 8 h for serum non–transferrin-bound iron was positively correlated with the amount of iron absorbed (R = 0.49, P < 0.01) and negatively correlated with serum ferritin (R = −0.39, P < 0.05). Conclusions: In healthy women, the production of circulating non–transferrin-bound iron is determined by the rate and amount of iron absorbed. The highest concentrations of non–transferrin-bound iron resulted from the administration of supplemental doses of iron without food. Little or no circulating non–transferrin-bound iron resulted from the consumption of a meal with a fortification dose of iron. This trial was registered at clinicaltrials.gov as NCT01404533. PMID:25057155

Circulating non-transferrin-bound iron after oral administration of supplemental and fortification doses of iron to healthy women: a randomized study.

PubMed

Brittenham, Gary M; Andersson, Maria; Egli, Ines; Foman, Jasmin Tajeri; Zeder, Christophe; Westerman, Mark E; Hurrell, Richard F

2014-09-01

After the oral administration of iron, the production of circulating non-transferrin-bound iron may contribute to an increased risk of illness in malaria-endemic areas that lack effective medical services. In healthy women with a range of body iron stores, we aimed to determine effects on the production of circulating non-transferrin-bound iron resulting from the oral administration of 1) a supplemental dose of iron (60 mg) with water, 2) a supplemental dose of iron (60 mg) with a standard test meal, and 3) a fortification dose of iron (6 mg) with a standard test meal. With the use of serum ferritin as the indicator, healthy women with replete iron stores (ferritin concentration >25 μg/L; n = 16) and reduced iron stores (ferritin concentration ≤25 μg/L; n = 16) were enrolled in a prospective, randomized, crossover study. After the oral administration of aqueous solutions of ferrous sulfate isotopically labeled with ⁵⁴Fe, ⁵⁷Fe, or ⁵⁸Fe, blood samples were collected for 8 h, and iron absorption was estimated by erythrocyte incorporation at 14 d. At 4 h, serum non-transferrin-bound iron reached peaks with geometric mean (95% CI) concentrations of 0.81 μmol/L (0.56, 1.1 μmol/L) for 60 mg Fe with water and 0.26 μmol/L (0.15, 0.38 μmol/L) for 60 mg Fe with food but was at assay limits of detection (0.1 μmol Fe/L) for 6 mg Fe with food. For the 60 mg Fe without food, the area under the curve over 8 h for serum non-transferrin-bound iron was positively correlated with the amount of iron absorbed (R = 0.49, P < 0.01) and negatively correlated with serum ferritin (R = -0.39, P < 0.05). In healthy women, the production of circulating non-transferrin-bound iron is determined by the rate and amount of iron absorbed. The highest concentrations of non-transferrin-bound iron resulted from the administration of supplemental doses of iron without food. Little or no circulating non-transferrin-bound iron resulted from the consumption of a meal with a fortification dose of iron. © 2014 American Society for Nutrition.

Effect of vitamin D3 supplementation on iron status: a randomized, double-blind, placebo-controlled trial among ethnic minorities living in Norway.

PubMed

Madar, Ahmed A; Stene, Lars C; Meyer, Haakon E; Brekke, Mette; Lagerløv, Per; Knutsen, Kirsten V

2016-08-09

Both vitamin D and iron deficiencies are widespread globally, and a relationship between these deficiencies has been suggested. However, there is a paucity of randomised controlled trials assessing the effect of vitamin D supplementation on iron status. We aimed to investigate whether 16 weeks of daily vitamin D3 supplementation had an effect on serum ferritin, haemoglobin, serum iron and transferrin saturation. Overall, 251 participants from South Asia, Middle East and Africa aged 18-50 years who were living in Norway were randomised to receive daily oral supplementation of 10 μg vitamin D3, 25 μg vitamin D3, or placebo for 16 weeks during the late winter. Blood samples from baseline and after 16 weeks were analysed for serum 25-hydroxyvitamin D (s-25(OH) D), serum ferritin, haemoglobin and serum iron. In total, 214 eligible participants completed the intervention (86 % of those randomised). Linear regression analysis were used to test the effect of vitamin D3 supplementation combined (10 or 25 μg) and separate doses 10 or 25 μg compared to placebo on change (T2-T1) in each outcome variable adjusted for baseline s-25(OH)D values. There was no difference in change in the levels of s-ferritin (1.9 μg/L, 95 % CI: -3.2, 7.0), haemoglobin (-0.02 g/dL, 95 % CI: -0.12, 0.09), s-iron (0.4 μg/L, 95 % CI: -0.5, 1.3) or transferrin saturation (0.7 %, 95 % CI: -0.6.1, 2.0) between those receiving vitamin D3 or those receiving placebo. Serum 25-hydroxyvitamin D increased from 29 nmol/L at baseline to 49 nmol/L after the intervention, with little change in the placebo group. In this population of healthy ethnic minorities from South Asia, the Middle East and Africa who had low vitamin D status, 16 weeks of daily supplementation with 10 or 25 μg of vitamin D3 did not significantly affect the haemoglobin levels or other markers of iron status.

Transferrin liposomes of docetaxel for brain-targeted cancer applications: formulation and brain theranostics.

PubMed

Sonali; Singh, Rahul Pratap; Singh, Nitesh; Sharma, Gunjan; Vijayakumar, Mahalingam R; Koch, Biplob; Singh, Sanjay; Singh, Usha; Dash, Debabrata; Pandey, Bajarangprasad L; Muthu, Madaswamy S

2016-05-01

Diagnosis and therapy of brain cancer was often limited due to low permeability of delivery materials across the blood-brain barrier (BBB) and their poor penetration into the brain tissue. This study explored the possibility of utilizing theranostic d-alpha-tocopheryl polyethylene glycol 1000 succinate mono-ester (TPGS) liposomes as nanocarriers for minimally invasive brain-targeted imaging and therapy (brain theranostics). The aim of this work was to formulate transferrin conjugated TPGS coated theranostic liposomes, which contain both docetaxel and quantum dots (QDs) for imaging and therapy of brain cancer. The theranostic liposomes with and without transferrin decoration were prepared and characterized for their particle size, polydispersity, morphology, drug encapsulation efficiency, in-vitro release study and brain theranostics. The particle sizes of the non-targeted and targeted theranostic liposomes were found below 200 nm. Nearly, 71% of drug encapsulation efficiency was achieved with liposomes. The drug release from transferrin conjugated theranostic liposomes was sustained for more than 72 h with 70% of drug release. The in-vivo results indicated that transferrin receptor-targeted theranostic liposomes could be a promising carrier for brain theranostics due to nano-sized delivery and its permeability which provided an improved and prolonged brain targeting of docetaxel and QDs in comparison to the non-targeted preparations.

The influence of maternal smoking on transferrin sialylation and fetal biometric parameters.

PubMed

Wrześniak, Marta; Królik, Małgorzata; Kepinska, Marta; Milnerowicz, Halina

2016-10-01

Transferrin is a glycosylated protein responsible for transporting iron, an essential metal responsible for proper fetal development. Tobacco is a heavily used xenobiotic having a negative impact on the human body and pregnancy outcomes. Aims of this study was to examine the influence of tobacco smoking on transferrin sialic acid residues and their connection with fetal biometric parameters in women with iron-deficiency. The study involved 173 samples from pregnant women, smokers and non-smokers, iron deficient and not. Transferrin sialylation was determined by capillary electrophoresis. The cadmium (Cd) level was measured by atomic absorption and the sialic acid concentration by the resorcinol method. Women with iron deficiencies who smoked gave birth earlier than non-smoking, non-iron-deficient women. The Cd level, but not the cotinine level, was positively correlated with transferrin sialylation in the blood of iron-deficient women who smoked; 3-, 4-, 5- and 6-sialoTf correlated negatively with fetal biometric parameters in the same group. It has been shown the relationship between Cd from tobacco smoking and fetal biometric parameters observed only in the iron deficient group suggests an additive effect of these two factors, and indicate that mothers with anemia may be more susceptible to Cd toxicity and disturbed fetal development. Copyright © 2016 Elsevier B.V. All rights reserved.

DMT1 EXPRESSION IS INCREASED IN THE LUNG OF HYPOTRANSFERRINEMIC MICE

EPA Science Inventory

Despite a lack of transferrin, hypotransferrinemic (Hp) mice demonstrate an accumulation of iron in peripheral organs including the lungs. One potential candidate for such transferrin-independent uptake of iron is divalent metal transporter-1 (DMT1), an established iron transport...

ACTIVATION OF EGF RECEPTOR IN RATS EXPOSED TO ROFA

EPA Science Inventory

Despite a lack of transferrin, hypotransferrinemic (Hp) mice demonstrate an accumulation of iron in peripheral organs including the lungs. One potential candidate for such transferrin-independent uptake of iron is DMT1, an established transporter of iron. We tested the hypothesis...

Characterization of the interaction between diferric transferrin and transferrin receptor 2 by functional assays and atomic force microscopy*

PubMed Central

Ikuta, Katsuya; Yersin, Alexandre; Ikai, Atsushi; Aisen, Philip; Kohgo, Yutaka

2010-01-01

Transferrin receptor (TfR2), a homologue of classical transferrin receptor 1 (TfR1), is found in two isoforms, α and β. Like TfR1, TfR2α is a type II membrane protein, but the β form lacks transmembrane portions and therefore is likely to be an intracellular protein. To investigate the functional properties of TfR2α we expressed the protein with FLAG-tagging in transferrin receptor-deficient Chinese hamster ovary cells. The association constant for binding of diferric transferrin (Tf) to TfR2α is 5.6 × 106 M−1, which is about 50 times lower than that of TfR1, with correspondingly reduced rates of iron uptake. Evidence for Tf internalization and recycling via TfR2α without degradation, as in the TfR1 pathway, was also found. The interaction of TfR2α with Tf was further investigated using atomic force microscopy (AFM), a powerful tool for investigation of the interaction between ligand and receptor at the single molecule level on the living cell surface. Dynamic force microscopy reveals a difference in the interactions of Tf with TfR2α and TfR1, with Tf-TfR1 unbinding characterized by 2 energy barriers, while only one is present for Tf-TfR2. We speculate that this difference may reflect Tf binding to TfR2α by a single lobe, whereas two lobes of Tf participate in binding to TfR1. The difference in the binding properties of Tf to TfR1 and TfR2α may help account for the different physiological roles of the two receptors. PMID:20096706

Flavivirus internalization is regulated by a size-dependent endocytic pathway.

PubMed

Hackett, Brent A; Cherry, Sara

2018-04-17

Flaviviruses enter host cells through the process of clathrin-mediated endocytosis, and the spectrum of host factors required for this process are incompletely understood. Here we found that lymphocyte antigen 6 locus E (LY6E) promotes the internalization of multiple flaviviruses, including West Nile virus, Zika virus, and dengue virus. Perhaps surprisingly, LY6E is dispensable for the internalization of the endogenous cargo transferrin, which is also dependent on clathrin-mediated endocytosis for uptake. Since viruses are substantially larger than transferrin, we reasoned that LY6E may be required for uptake of larger cargoes and tested this using transferrin-coated beads of similar size as flaviviruses. LY6E was indeed required for the internalization of transferrin-coated beads, suggesting that LY6E is selectively required for large cargo. Cell biological studies found that LY6E forms tubules upon viral infection and bead internalization, and we found that tubule formation was dependent on RNASEK, which is also required for flavivirus internalization, but not transferrin uptake. Indeed, we found that RNASEK is also required for the internalization of transferrin-coated beads, suggesting it functions upstream of LY6E. These LY6E tubules resembled microtubules, and we found that microtubule assembly was required for their formation and flavivirus uptake. Since microtubule end-binding proteins link microtubules to downstream activities, we screened the three end-binding proteins and found that EB3 promotes virus uptake and LY6E tubularization. Taken together, these results highlight a specialized pathway required for the uptake of large clathrin-dependent endocytosis cargoes, including flaviviruses. Copyright © 2018 the Author(s). Published by PNAS.

Serum transferrin as a prognostic indicator of spontaneous closure and mortality in gastrointestinal cutaneous fistulas.

PubMed Central

Kuvshinoff, B W; Brodish, R J; McFadden, D W; Fischer, J E

1993-01-01

OBJECTIVE: This study determined whether there are any laboratory or other features that will enable prediction of spontaneous closure in patients with gastrointestinal cutaneous fistulas. SUMMARY BACKGROUND DATA: Although the anatomic criteria for spontaneous closure of gastrointestinal cutaneous fistulas have been presented by several authors, less than 50% of such fistulas tend to close, even in the most recent series. METHODS: A group of patients with gastrointestinal cutaneous fistulas with anatomical features favorable to study were investigated with respect to a series of parameters including the usual demographic parameters, plus fistula output, number of blood transfusions, presence of sepsis, as well as metabolic parameters including serum transferrin, retinol-binding protein, thyroxin-binding prealbumin, and serum albumin. RESULTS: Of 79 patients with 116 fistulas, 16 (20.3%) died. Causes of death were uncontrolled sepsis in eight patients and cancer in five patients. Postoperative fistulas constituted 80% of the group. The presence of local sepsis, systemic sepsis, remote sepsis (such as pneumonia or line sepsis), the number of fistulas, fistula output, and the number of blood transfusions were not predictive of spontaneous closure, whereas serum transferrin was predictive of spontaneous closure. Serum transferrin, retinol-binding protein, and thyroxin-binding prealbumin were predictive of mortality. CONCLUSIONS: Serum transferrin does not appear to be an entirely independent variable, but seems to identify those patients with significant remote sepsis, systemic sepsis, and neoplasia in whom these processes are clinically significant. The results, if confirmed, and provided that nutritional needs are met, suggest that short-turnover proteins, particularly serum transferrin, might be useful in predicting which patients with gastrointestinal cutaneous fistulas should undergo surgery despite anatomic criteria favorable for spontaneous closure. PMID:8507110

Determination of Surface-Exposed, Functional Domains of Gonococcal Transferrin-Binding Protein A

PubMed Central

Yost-Daljev, Mary Kate; Cornelissen, Cynthia Nau

2004-01-01

The gonococcal transferrin receptor is composed of two distinct proteins, TbpA and TbpB. TbpA is a member of the TonB-dependent family of integral outer membrane transporters, while TbpB is lipid modified and thought to be peripherally surface exposed. We previously proposed a hypothetical topology model for gonococcal TbpA that was based upon computer predictions and similarity with other TonB-dependent transporters for which crystal structures have been determined. In the present study, the hemagglutinin epitope was inserted into TbpA to probe the surface topology of this protein and secondarily to test the functional impacts of site-specific mutagenesis. Twelve epitope insertion mutants were constructed, five of which allowed us to confirm the surface exposure of loops 2, 3, 5, 7, and 10. In contrast to the predictions set forth by the hypothetical model, insertion into the plug region resulted in an epitope that was surface accessible, while epitope insertions into two putative loops (9 and 11) were not surface accessible. Insertions into putative loop 3 and β strand 9 abolished transferrin binding and utilization, and the plug insertion mutant exhibited decreased transferrin-binding affinity concomitant with an inability to utilize it. Insertion into putative β strand 16 generated a mutant that was able to bind transferrin normally but that was unable to mediate utilization. Mutants with insertions into putative loops 2, 9, and 11 maintained wild-type binding affinity but could utilize only transferrin in the presence of TbpB. This is the first demonstration of the ability of TbpB to compensate for a mutation in TbpA. PMID:14977987

The effect of desferrioxamine on transferrin receptors, the cell cycle and growth rates of human leukaemic cells.

PubMed Central

Bomford, A; Isaac, J; Roberts, S; Edwards, A; Young, S; Williams, R

1986-01-01

The effect of the iron chelator, desferrioxamine, on transferrin binding, growth rates and the cell cycle was investigated in the human leukaemic cell line, K562. At all concentrations of the chelator (2-50 microM) binding of 125I-transferrin was increased by 24 h and reached a maximum at 72-96 h. Maximum binding (6-8-fold increased) occurred in cells treated with 20 microM-desferrioxamine, in contrast with control cells which, at 96 h, showed a 50% decrease over initial binding. Scatchard analysis at 4 degrees C showed that this increased binding was due to an increase in the number of receptors, as the Kd was similar in induced (1.8 nM) and control (1.5 nM) cells. After 96 h cells, cultured with 20 and 50 microM-desferrioxamine accumulated 59Fe from bovine transferrin at over twice the rate found with control cells, reflecting the increase in transferrin receptors. Although iron uptake was unimpaired by the chelator there was a dose-dependent inhibition of cell growth, with control cells completing three divisions in 96 h and those in 10 microM-desferrioxamine only two divisions. At the highest concentration (50 microM), cell division was abrogated although cell viability was maintained (85%). In contrast, DNA synthesis was not markedly affected, except at 50 microM-desferrioxamine when incorporation of [3H]thymidine was 52% of that in control cells. Flow cytometry revealed that there was a progressive accumulation of the cells in the active phases of their cycle (S, G2 + M). Desferrioxamine may increase transferrin receptors in two ways: by chelating a regulatory pool of iron within the cell, and by arresting cells in S phase when receptors are maximally expressed. PMID:3790074

Wide-field lifetime-based FRET imaging for the assessment of early functional distribution of transferrin-based delivery in breast tumor-bearing small animals

NASA Astrophysics Data System (ADS)

Sinsuebphon, Nattawut; Rudkouskaya, Alena; Barroso, Margarida; Intes, Xavier

2016-02-01

Targeted drug delivery is a critical aspect of successful cancer therapy. Assessment of dynamic distribution of the drug provides relative concentration and bioavailability at the target tissue. The most common approach of the assessment is intensity-based imaging, which only provides information about anatomical distribution. Observation of biomolecular interactions can be performed using Förster resonance energy transfer (FRET). Thus, FRET-based imaging can assess functional distribution and provide potential therapeutic outcomes. In this study, we used wide-field lifetime-based FRET imaging for the study of early functional distribution of transferrin delivery in breast cancer tumor models in small animals. Transferrin is a carrier for cancer drug delivery. Its interaction with its receptor is within a few nanometers, which is suitable for FRET. Alexa Fluor® 700 and Alexa Fluor® 750 were conjugated to holo-transferrin which were then administered via tail vein injection to the mice implanted with T47D breast cancer xenografts. Images were continuously acquired for 60 minutes post-injection. The results showed that transferrin was primarily distributed to the liver, the urinary bladder, and the tumor. The cellular uptake of transferrin, which was indicated by the level of FRET, was high in the liver but very low in the urinary bladder. The results also suggested that the fluorescence intensity and FRET signals were independent. The liver showed increasing intensity and increasing FRET during the observation period, while the urinary bladder showed increasing intensity but minimal FRET. Tumors gave varied results corresponding to their FRET progression. These results were relevant to the biomolecular events that occurred in the animals.

Pregnancy and variations of carbohydrate-deficient transferrin levels measured by the candidate reference HPLC method.

PubMed

Bianchi, Vincenza; Ivaldi, Alessandra; Raspagni, Alessia; Arfini, Carlo; Vidali, Matteo

2011-01-01

Contrasting data are available on the diagnostic accuracy of carbohydrate-deficient transferrin (CDT) during pregnancy. These differences may depend in part on how CDT was evaluated and expressed. Here, we report on variations of CDT levels in pregnant women using the high performance liquid chromatography (HPLC) candidate reference method. Alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, mean corpuscular volume, serum transferrin, urine and serum ethyl glucuronide and CDT were measured in 64 women, self-reporting as non-alcohol abusers (age: median 34, IQR: 28-38), at different stages of normal pregnancy (gestational weeks: median 28, IQR: 8-33). CDT was expressed as percentage of disialotransferrin to total transferrin (%CDT). Transferrin was associated with both %CDT (r = 0.66; P < 0.001) and gestational week (r = 0.68; P < 0.001). Interestingly, %CDT was highly correlated with gestational week (r = 0.77; P < 0.001), even after controlling for the effect of transferrin. Moreover, statistically significant differences in %CDT were also evident between women grouped for pregnancy trimester (first trimester: mean 1.01% (SD 0.19); second trimester: 1.30% (SD 0.14); third trimester: 1.53% (SD 0.22); ANOVA P < 0.001). Trend analysis confirmed a proportional increase of %CDT along with pregnancy trimesters (P < 0.001). %CDT, measured with the HPLC candidate reference method, is independently associated with gestational week. Differently from what has been previously reported or expected, the relationship between pregnancy and CDT could be more complex. The diagnostic accuracy of CDT for detecting alcohol abuse in a legal context may be limited in pregnant women and the effect of gestational age should be considered.

Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology.

PubMed

Ishikawa, Yuichi; Maeda, Manami; Pasham, Mithun; Aguet, Francois; Tacheva-Grigorova, Silvia K; Masuda, Takeshi; Yi, Hai; Lee, Sung-Uk; Xu, Jian; Teruya-Feldstein, Julie; Ericsson, Maria; Mullally, Ann; Heuser, John; Kirchhausen, Tom; Maeda, Takahiro

2015-04-01

Clathrin-dependent endocytosis is an essential cellular process shared by all cell types. Despite this, precisely how endocytosis is regulated in a cell-type-specific manner and how this key pathway functions physiologically or pathophysiologically remain largely unknown. PICALM, which encodes the clathrin adaptor protein PICALM, was originally identified as a component of the CALM/AF10 leukemia oncogene. Here we show, by employing a series of conditional Picalm knockout mice, that PICALM critically regulates transferrin uptake in erythroid cells by functioning as a cell-type-specific regulator of transferrin receptor endocytosis. While transferrin receptor is essential for the development of all hematopoietic lineages, Picalm was dispensable for myeloid and B-lymphoid development. Furthermore, global Picalm inactivation in adult mice did not cause gross defects in mouse fitness, except for anemia and a coat color change. Freeze-etch electron microscopy of primary erythroblasts and live-cell imaging of murine embryonic fibroblasts revealed that Picalm function is required for efficient clathrin coat maturation. We showed that the PICALM PIP2 binding domain is necessary for transferrin receptor endocytosis in erythroblasts and absolutely essential for erythroid development from mouse hematopoietic stem/progenitor cells in an erythroid culture system. We further showed that Picalm deletion entirely abrogated the disease phenotype in a Jak2(V617F) knock-in murine model of polycythemia vera. Our findings provide new insights into the regulation of cell-type-specific transferrin receptor endocytosis in vivo. They also suggest a new strategy to block cellular uptake of transferrin-bound iron, with therapeutic potential for disorders characterized by inappropriate red blood cell production, such as polycythemia vera. Copyright© Ferrata Storti Foundation.

The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure.

PubMed

Silverberg, Donald S; Schwartz, Doron; Schwartz, Idit; Ben Assa, Eyal

2013-10-03

Iron Deficiency (ID) is common in heart failure (HF), and is an independent contributor to mortality and morbidity. We examined whether patients with previously known HF who were recently hospitalized, had previous treatment for ID, were investigated for it at the time of hospitalization, and, if ID was found, were prescribed iron on discharge. We examined the records of 76 consecutive patients admitted to our hospital medical wards with a primary diagnosis of HF. Anemia (Hb<12 g/dl) was found in 42/76 patients (55.3%). In 55/76 patients (72.4%) there was no iron workup, in 6 (7.9%) an incomplete iron workup with serum iron, transferrin or ferritin lacking and in 15/76 (19.7%) a complete iron workup. If ID was defined as either a serum ferritin of <100 μg/l or a serum ferritin of 100-299 μg/l and a %Transferrin Saturation of <20% it was found in 12/15 (80%) of those with a complete workup; in 9 of 10 (90%) of the anemic patients and in 3 of 5 (60%) of those non-anemic patients. At discharge 11/15 (73.3%) of those with a complete iron workup were given iron, 10 orally and 1 IV. In those 6 with an incomplete workup 2 were started on oral iron (33.3%) and in those without any workup, 1 of 55 (1.8%) was given oral iron. ID is common in hospitalized HF patients but is usually not sought after by physicians at the time of admission. However if detected the physicians usually treated it. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Using iron studies to predict HFE mutations in New Zealand: implications for laboratory testing.

PubMed

O'Toole, Rebecca; Romeril, Kenneth; Bromhead, Collette

2017-04-01

The diagnosis of hereditary haemochromatosis (HH) is not straightforward because symptoms are often absent or non-specific. Biochemical markers of iron-overloading may be affected by other conditions. To measure the correlation between iron studies and HFE genotype to inform evidence-based recommendations for laboratory testing in New Zealand. Results from 2388 patients genotyped for C282Y, H63D and S65C in Wellington, New Zealand from 2007 to 2013 were compared with their biochemical phenotype as quantified by serum ferritin (SF), transferrin saturation (TS), serum iron (SI) and serum transferrin (ST). The predictive power of these markers was evaluated by receiver operator characteristic (ROC) curve analysis, and if a statistically significant association for a variable was seen, sensitivity, specificity and predictive values were calculated. Test ordering patterns showed that 62% of HFE genotyping tests were ordered because of an elevated SF alone and only 11% of these had a C-reactive protein test to rule out an acute phase reaction. The association between SF and significant HFE genotypes SF was low. However, TS values ≥45% predicted HH mutations with the highest sensitivity and specificity. A SF of >1000 µg/L was found in one at-risk patient (C282Y homozygote) who had a TS <45%. Our analysis highlights the need for clear guidelines for investigation of hyperferritinaemia and HH in New Zealand. Using our findings, we developed an evidence-based laboratory testing algorithm based on a TS ≥45%, a SF ≥1000 µg/L and/or a family history of HH which identified all C282Y homozygotes in this study. © 2016 Royal Australasian College of Physicians.

Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status.

PubMed

Comín-Colet, Josep; Enjuanes, Cristina; González, Gina; Torrens, Ainhoa; Cladellas, Mercè; Meroño, Oona; Ribas, Nuria; Ruiz, Sonia; Gómez, Miquel; Verdú, José Maria; Bruguera, Jordi

2013-10-01

To evaluate the effect of iron deficiency (ID) and/or anaemia on health-related quality of life (HRQoL) in patients with chronic heart failure (CHF). We undertook a post-hoc analysis of a cohort of CHF patients in a single-centre study evaluating cognitive function. At recruitment, patients provided baseline information and completed the Minnesota Living with Heart Failure questionnaire (MLHFQ) for HRQoL (higher scores reflect worse HRQoL). At the same time, blood samples were taken for serological evaluation. ID was defined as serum ferritin levels <100 ng/mL or serum ferritin <800 ng/mL with transferrin saturation <20%. Anaemia was defined as haemoglobin ≤12 g/dL. A total of 552 CHF patients were eligible for inclusion, with an average age of 72 years and 40% in NYHA class III or IV. The MLHFQ overall summary scores were 41.0 ± 24.7 among those with ID, vs. 34.4 ± 26.4 for non-ID patients (P = 0.003), indicating worse HRQoL. When adjusted for other factors associated with HRQoL, ID was significantly associated with worse MLHFQ overall summary (P = 0.008) and physical dimension scores (P = 0.002), whereas anaemia was not (both P > 0.05). Increased levels of soluble transferrin receptor were also associated with impaired HRQoL (P ≤ 0.001). Adjusting for haemoglobin and C-reactive protein, ID was more pronounced in patients with anaemia compared with those without (P < 0.001). In patients with CHF, ID but not anaemia was associated with reduced HRQoL, mostly due to physical factors.

Ferrous bisglycinate 25 mg iron is as effective as ferrous sulfate 50 mg iron in the prophylaxis of iron deficiency and anemia during pregnancy in a randomized trial.

PubMed

Milman, Nils; Jønsson, Lisbeth; Dyre, Pernille; Pedersen, Palle Lyngsie; Larsen, Lise Grupe

2014-03-01

To compare the effects of oral ferrous bisglycinate 25 mg iron/day vs. ferrous sulfate 50 mg iron/day in the prevention of iron deficiency (ID) and iron deficiency anemia (IDA) in pregnant women. Randomized, double-blind, intention-to-treat study. Antenatal care clinic. 80 healthy ethnic Danish pregnant women. Women were allocated to ferrous bisglycinate 25 mg elemental iron (Aminojern®) (n=40) or ferrous sulfate 50 mg elemental iron (n=40) from 15 to 19 weeks of gestation to delivery. Hematological status (hemoglobin, red blood cell indices) and iron status (plasma iron, plasma transferrin, plasma transferrin saturation, plasma ferritin) were measured at 15-19 weeks (baseline), 27-28 weeks and 36-37 weeks of gestation. Occurrence of ID (ferritin <15 μg/L) and IDA (ferritin <12 μg/L and hemoglobin <110 g/L). At inclusion, there were no significant differences between the bisglycinate and sulfate group concerning hematological status and iron status. The frequencies of ID and IDA were low and not significantly different in the two iron groups. The frequency of gastrointestinal complaints was lower in the bisglycinate than in the sulfate group (P=0.001). Newborns weight was slightly higher in the bisglycinate vs. the sulfate group (3601±517 g vs. 3395±426 g, P=0.09). In the prevention of ID and IDA, ferrous bisglycinate was not inferior to ferrous sulfate. Ferrous bisglycinate in a low dose of 25 mg iron/day appears to be adequate to prevent IDA in more than 95% of Danish women during pregnancy and postpartum.

Curcuma decreases serum hepcidin levels in healthy volunteers: a placebo-controlled, randomized, double-blind, cross-over study.

PubMed

Lainé, Fabrice; Laviolle, Bruno; Bardou-Jacquet, Edouard; Fatih, Nadia; Jezequel, Caroline; Collet, Nicolas; Ropert, Martine; Morcet, Jeff; Hamon, Catherine; Reymann, Jean-Michel; Loréal, Olivier

2017-10-01

Hepcidin, secreted by hepatocytes, controls iron metabolism by limiting iron egress in plasma. Hepcidin is upregulated during inflammation through the activation of the signal transducer and activator of transcription 3 (STAT3) transduction pathway, which decreases iron bioavailability and may explain the anemia of chronic inflammatory disease. In vitro, it has been shown that curcumin can decrease hepcidin synthesis by decreasing STAT3 activity. We conducted a proof-of-concept study to assess the effect of curcuma on hepcidin synthesis in human. This was a placebo-controlled, randomized, double-blind, cross-over, two-period study performed in 18 healthy male volunteers. Subjects received a single oral dose of 6 g curcuma containing 2% of curcumin or placebo. Serum hepcidin and iron parameters were assessed repeatedly until 48 h after dosing. When compared with a placebo curcuma decreased hepcidin levels significantly at 6 h (-19%, P = 0.004), 8 h (-17%, P = 0.009), and 12 h (-17%, P = 0.007) and tended to decrease hepcidin at 24 h (-15%, P = 0.076). Curcuma also significantly increased serum ferritin levels at 6 and 8 h (+7% for both times, P = 0.018, 0.030, respectively) and had no effects on serum iron, transferrin, and transferrin saturation. This pilot study showed that curcuma decreases serum hepcidin levels in human and supports the idea that curcuma could be useful in treating hepcidin overproduction during inflammatory processes. Confirmatory studies in patients with chronic inflammation are now required to determine the optimal dose and therapeutic scheme of curcuma. © 2017 Société Française de Pharmacologie et de Thérapeutique.

The hematopoietic effect of Epotin (recombinant human erythropoietin-alpha) on maintenance hemodialysis end-stage kidney disease patients.

PubMed

Al-Shohaib, S; Shaker, D S; Ghaedi, B B; Alyarim, M; Emara, S; Behairy, M

2010-04-01

Recombinant human erythropoietin (rHuEpo) has revolutionized the management of renal anemia, significantly improving patient quality of life. Great attention has been paid lately on how to optimally use this potent anti-anemic agent. Aiming to overview anemic patient management with Epotin (Julphar's rHuEpo) according to the new guidelines, we included in the study anemic (hemoglobin [Hb]or=18 years who were of iron replete (transeferene saturation (TSAT)>or=20% and serum ferritin>or=100 microg/L) with no evidence of serious inflammation (c-reactive protein (CRP)<30 mg/L) on thrice-weekly hemodialysis. The mean age and dialysis duration of 50.8+/-17 and 3.8+/-2.8 years, respectively, included 88.6% (n=31) de novo patients in the corrective phase with no previous exposure to erythropoietin. Safety-efficacy parameters showed insignificant changes throughout the 4-month study period, including iron profile that was maintained according to Kidney Disease Outcome Quality Initiative guidelines. Efficacy parameters revealed a significant increase (P<.0001) of Hb levels from a baseline of 8.5+/-1.0 to 11.1+/-1.1. Targeting an absolute increase of 2.5 g/dL in Hb throughout 3 months of the study period resulted in a 90.3% success rate. There were no dropouts due to intolerance, whereas all the recorded adverse events were classified as unrelated to the test product. In conclusion, Epotin was clinically effective to correct and maintain Hb levels in ESKD anemic patients on maintenance hemodialysis within the current recommended range and with a satisfactory safety profile consistent with previous international reports. Copyright (c) 2010 Elsevier Inc. All rights reserved.

The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin.

PubMed

Kachhap, Sushant K; Faith, Dennis; Qian, David Z; Shabbeer, Shabana; Galloway, Nathan L; Pili, Roberto; Denmeade, Samuel R; DeMarzo, Angelo M; Carducci, Michael A

2007-09-05

Cell to cell adhesion is mediated by adhesion molecules present on the cell surface. Downregulation of molecules that form the adhesion complex is a characteristic of metastatic cancer cells. Downregulation of the N-myc down regulated gene1 (NDRG1) increases prostate and breast metastasis. The exact function of NDRG1 is not known. Here by using live cell confocal microscopy and in vitro reconstitution, we report that NDRG1 is involved in recycling the adhesion molecule E-cadherin thereby stabilizing it. Evidence is provided that NDRG1 recruits on recycling endosomes in the Trans Golgi network by binding to phosphotidylinositol 4-phosphate and interacts with membrane bound Rab4aGTPase. NDRG1 specifically interacts with constitutively active Rab4aQ67L mutant protein and not with GDP-bound Rab4aS22N mutant proving NDRG1 as a novel Rab4a effector. Transferrin recycling experiments reveals NDRG1 colocalizes with transferrin during the recycling phase. NDRG1 alters the kinetics of transferrin recycling in cells. NDRG1 knockdown cells show a delay in recycling transferrin, conversely NDRG1 overexpressing cells reveal an increase in rate of transferrin recycling. This novel finding of NDRG1 as a recycling protein involved with recycling of E-cadherin will aid in understanding NDRG1 role as a metastasis suppressor protein.

Studies on the binding of fulvic acid with transferrin by spectroscopic analysis

NASA Astrophysics Data System (ADS)

Zhang, Xiu-feng; Yang, Guang; Dong, Yu; Zhao, Yan-qin; Sun, Xiao-ran; Chen, Lei; Chen, Hong-bo

2015-02-01

Transferrin has shown potential in the delivery of anticancer drugs into primarily proliferating cancer cells that over-express transferrin receptors. Fulvic acid has a wide range of biological and pharmacological activities which caused widespread concerns, the interaction of fulvic acid with human serum transferrin (Tf) has great significance for gaining a deeper insight about anticancer activities of fulvic acid. In this study, the mechanism of interaction between fulvic acid and Tf, has been investigated by using fluorescence quenching, thermodynamics, synchronous fluorescence and circular dichroism (CD) under physiological condition. Our results have shown that fulvic acid binds to Tf and form a new complex, and the calculated apparent association constants are 5.04 × 108 M-1, 5.48 × 107 M-1, 7.38 × 106 M-1 from the fluorescence quenching at 288 K, 298 K, and 310 K. The thermodynamic parameters indicate that hydrogen bonding and weak van der Waals are involved in the interaction between fulvic acid and Tf. The binding of fulvic acid to Tf causes the α-helix structure content of the protein to reduce, and resulting that peptide chains of Tf become more stretched. Our results have indicated a mechanism of the interaction between fulvic acid and Tf, which may provide information for possible design of methods to deliver drug molecules via transferrin to target tissues and cells effectively.

Angiotensin II inhibits uptake of transferrin-bound iron but not non-transferrin-bound iron by cultured astrocytes.

PubMed

Huang, Suna; Du, Fang; Li, Lan; Liu, Yong; Liu, Yuhong; Zhang, Chao; Qian, Zhong Ming

2014-06-01

The existence of all components of the renin-angiotensin system (RAS) and the iron metabolism system, and the recent findings on the functions of angiotensin II (ANGII) in peripheral iron metabolism imply that ANGII might play a role in iron homeostasis by regulating expression of iron transport proteins in the brain. Here, we investigated effects of ANGII on uptake and release of iron as well as expression of cell iron transport proteins in cultured astrocytes. We demonstrated that ANGII could significantly inhibit transferrin-bound iron (Tf-Fe) uptake and iron release as well as the expression of transferrin receptor 1 (TfR1) and the iron exporter ferroportin 1 (Fpn1) in cultured astrocytes. This indicated that the inhibitory role of ANGII on Tf-Fe uptake and iron release is mediated by its negative effect on the expression of TfR1 and Fpn1. We also provided evidence that ANGII had no effect on divalent metal transporter 1 (DMT1) expression as well as non-transferrin-bound iron (NTBI) uptake in the cells. Our findings showed that ANGII has a role to affect expression of iron transport proteins in astrocytes in vitro and also suggested that ANGII might have a physiological function in brain iron homeostasis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Separation of Albumin, Ceruloplasmin, and Transferrin from Human Plasma.

ERIC Educational Resources Information Center

Barnes, Grady; Frieden, Earl

1982-01-01

Procedures are provided for separating the principal metalloproteins (albumin, ceruloplasmin, and transferrin) from plasma using column chromatographic techniques. The experiment can be completed in two separate three-hour laboratory periods during which column chromatography is illustrated and the effect of pH on charge and affinity of a protein…

Cerebral Abscess Associated With Odontogenic Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to-Left Shunting Through Pulmonary Arteriovenous Malformations

PubMed Central

Boother, Emily J.; Brownlow, Sheila; Tighe, Hannah C.; Bamford, Kathleen B.; Jackson, James E.

2017-01-01

Abstract Background Cerebral abscess is a recognized complication of pulmonary arteriovenous malformations (PAVMs) that allow systemic venous blood to bypass the pulmonary capillary bed through anatomic right-to-left shunts. Broader implications and mechanisms remain poorly explored. Methods Between June 2005 and December 2016, at a single institution, 445 consecutive adult patients with computed tomography–confirmed PAVMs (including 403 [90.5%] with hereditary hemorrhagic telangiectasia) were recruited to a prospective series. Multivariate logistic regression was performed and detailed periabscess histories were evaluated to identify potential associations with cerebral abscess. Rates were compared to an earlier nonoverlapping series. Results Thirty-seven of the 445 (8.3%) patients experienced a cerebral abscess at a median age of 50 years (range, 19–76 years). The rate adjusted for ascertainment bias was 27 of 435 (6.2%). Twenty-nine of 37 (78.4%) patients with abscess had no PAVM diagnosis prior to their abscess, a rate unchanged from earlier UK series. Twenty-one of 37 (56.7%) suffered residual neurological deficits (most commonly memory/cognition impairment), hemiparesis, and visual defects. Isolation of periodontal microbes, and precipitating dental and other interventional events, emphasized potential sources of endovascular inoculations. In multivariate logistic regression, cerebral abscess was associated with low oxygen saturation (indicating greater right-to-left shunting); higher transferrin iron saturation index; intravenous iron use for anemia (adjusted odds ratio, 5.4 [95% confidence interval, 1.4–21.1]); male sex; and venous thromboemboli. There were no relationships with anatomic attributes of PAVMs, or red cell indices often increased due to secondary polycythemia. Conclusions Greater appreciation of the risk of cerebral abscess in undiagnosed PAVMs is required. Lower oxygen saturation and intravenous iron may be modifiable risk factors. PMID:28430880

Development and optimization of transferrin-conjugated nanostructured lipid carriers for brain delivery of paclitaxel using Box-Behnken design.

PubMed

Emami, Jaber; Rezazadeh, Mahboubeh; Sadeghi, Hojjat; Khadivar, Khashayar

2017-05-01

The treatment of brain cancer remains one of the most difficult challenges in oncology. The purpose of this study was to develop transferrin-conjugated nanostructured lipid carriers (Tf-NLCs) for brain delivery of paclitaxel (PTX). PTX-loaded NLCs (PTX-NLCs) were prepared using solvent evaporation method and the impact of various formulation variables were assessed using Box-Behnken design. Optimized PTX-NLC was coupled with transferrin as targeting ligand and in vitro cytotoxicity of it was investigated against U-87 brain cancer cell line. As a result, 14.1 mg of cholesterol, 18.5 mg of triolein, and 0.5% poloxamer were used to prepare the optimal formulation. Mean particle size (PS), zeta potential (ZP), entrapment efficiency (EE), drug loading (DL), mean release time (MRT) of adopted formulation were confirmed to be 205.4 ± 11 nm, 25.7 ± 6.22 mV, 91.8 ± 0.5%, 5.38 ± 0.03% and 29.3 h, respectively. Following conjugation of optimized PTX-NLCs with transferrin, coupling efficiency was 21.3 mg transferrin per mmol of stearylamine; PS and MRT were increased while ZP, EE and DL decreased non-significantly. Tf-PTX-NLCs showed higher cytotoxic activity compared to non-targeted NLCs and free drug. These results indicated that the Tf-PTX-NLCs could potentially be exploited as a delivery system in brain cancer cells.

Utility of urinary transferrin and ceruloplasmin in patients with systemic lupus erythematosus for differentiating patients with lupus nephritis.

PubMed

Urrego, Tomás; Ortiz-Reyes, Blanca; Vanegas-García, Adriana L; Muñoz, Carlos H; González, Luis A; Vásquez, Gloria; Gómez-Puerta, José A

2018-03-09

Diagnosis of lupus nephritis (LN) is usually based on renal biopsy, which is an invasive technique that involves multiple risks. Therefore, different biomarkers have emerged as alternatives for the diagnosis of LN. Nonetheless, studies regarding urinary biomarkers in Latin American patients are limited. The objective of this study was to assess the diagnostic value of urinary transferrin and ceruloplasmin to differentiate patients who have renal involvement from those who do not. Systemic lupus erythematosus (SLE) patients that met the revised American College of Rheumatology (ACR) classification criteria were recruited. Patients with another autoimmune disease, active infection (urinary tract or systemic infection), renal replacement therapy, human immunodeficiency virus infection or pregnancy were excluded. A urine sample was collected from each patient. LN was diagnosed according to ACR criteria. The activity and chronicity of LN were measured using the Austin indices. Urinary transferrin and ceruloplasmin levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits. Mann-Whitney U test and Student's t-test were used to compare data. Spearman's rank correlation was used to determine associations. Lastly, receiver operating characteristic (ROC) curves were created. The study involved 120 SLE patients. In all, 85% were female, 76% mestizo, the mean age was 32.8±12.1years and mean systemic lupus erythematosus disease activity index (SLEDAI) was 8.4±8.9; 64% had renal involvement. Urinary levels of the two biomarkers were significantly higher in patients with LN compared to those without LN. Similarly, urinary levels of both biomarkers were significantly higher in patients with active LN compared to those with inactive LN. Furthermore, urinary transferrin levels were significantly higher in Afro-Latin American patients. On the other hand, urinary transferrin levels correlated with SLEDAI and proteinuria, and transferrin and ceruloplasmin levels correlated with each other. The diagnostic value of ROC curves for these urinary biomarkers for LN were good. In our cohort of SLE patients, we found that transferrin and ceruloplasmin were potential biomarkers for LN, and can even differentiate active LN. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Toxicity of iron overload and iron overload reduction in the setting of hematopoietic stem cell transplantation for hematologic malignancies.

PubMed

Leitch, Heather A; Fibach, Eitan; Rachmilewitz, Eliezer

2017-05-01

Iron is an essential element for key cellular metabolic processes. However, transfusional iron overload (IOL) may result in significant cellular toxicity. IOL occurs in transfusion dependent hematologic malignancies (HM), may lead to pathological clinical outcomes, and IOL reduction may improve outcomes. In hematopoietic stem cell transplantation (SCT) for HM, IOL may have clinical importance; endpoints examined regarding an impact of IOL and IOL reduction include transplant-related mortality, organ function, infection, relapse risk, and survival. Here we review the clinical consequences of IOL and effects of IOL reduction before, during and following SCT for HM. IOL pathophysiology is discussed as well as available tests for IOL quantification including transfusion history, serum ferritin level, transferrin saturation, hepcidin, labile plasma iron and other parameters of iron-catalyzed oxygen free radicals, and organ IOL by imaging. Data-based recommendations for IOL measurement, monitoring and reduction before, during and following SCT for HM are made. Copyright © 2017 Elsevier B.V. All rights reserved.

Iron and clinical outcomes in dialysis and non-dialysis-dependent chronic kidney disease patients.

PubMed

Kovesdy, Csaba P

2009-03-01

Abnormal iron homeostasis plays an important role in the anemia of chronic kidney disease (CKD). Although iron overload was the main complication seen in the pre-erythropoiesis-stimulating agent era, relative iron deficiency is much more common today in patients with CKD. Maintaining certain "desirable" levels of commonly used markers of iron stores (such as transferrin saturation ratio and serum ferritin) have become the goal of iron management in clinical practice, yet it is unclear whether achievement and maintenance of these "desirable" levels translates into improved clinical outcomes. This review examines issues related to iron and long-term clinical outcomes from an epidemiologic perspective, with the goal to determine what an ideal therapeutic approach should be in clinical practice and what future research is required to clarify important practical questions. Particular attention is devoted to patients with non-dialysis-dependent CKD because the management of iron homeostasis in this group of patients poses additional intriguing questions.

Iron Supplementation During Pregnancy- A Necessary or Toxic Supplement?

PubMed Central

Wilmet, Stephanie; Legssyer, Rachida; Crichton, Robert R.

2003-01-01

The effects of a single intramuscular iron dose, 10mg, to pregnant rats on Day of pregnancy, on the outcome of pregnancy, with respect to foetal weight and mother’s immune function has been investigated. Despite significantly elevated hepatic iron stores after iron supplementation in pregnant rats this had no significant effect upon blood haemoglobin or transferrin saturation levels. However the mean weight of the foetuses at Day 20-21 was significantly lower than that of the non-supplemented pregnant rats. Iron supplements significantly increased the activity of NADPH oxidase in the maternal alveolar macrophages, the primary event in the formation of the phagolysosome to combat invading organisms. However inducible nitric oxide synthase activity was significantly reduced in these macrophages as shown by decreases in LPSinduced and LPS+IFNγ-induced NOS activation. Iron supplementation to rats of normal iron status at the commencement of pregnancy did not show any beneficial effects to either the foetus or the mother. PMID:18365051

Obesity as an emerging risk factor for iron deficiency.

PubMed

Aigner, Elmar; Feldman, Alexandra; Datz, Christian

2014-09-11

Iron homeostasis is affected by obesity and obesity-related insulin resistance in a many-facetted fashion. On one hand, iron deficiency and anemia are frequent findings in subjects with progressed stages of obesity. This phenomenon has been well studied in obese adolescents, women and subjects undergoing bariatric surgery. On the other hand, hyperferritinemia with normal or mildly elevated transferrin saturation is observed in approximately one-third of patients with metabolic syndrome (MetS) or nonalcoholic fatty liver disease (NAFLD). This constellation has been named the "dysmetabolic iron overload syndrome (DIOS)". Both elevated body iron stores and iron deficiency are detrimental to health and to the course of obesity-related conditions. Iron deficiency and anemia may impair mitochondrial and cellular energy homeostasis and further increase inactivity and fatigue of obese subjects. Obesity-associated inflammation is tightly linked to iron deficiency and involves impaired duodenal iron absorption associated with low expression of duodenal ferroportin (FPN) along with elevated hepcidin concentrations. This review summarizes the current understanding of the dysregulation of iron homeostasis in obesity.

N-glycan structures of human transferrin produced by Lymantria dispar (gypsy moth)cells using the LdMNPV expression system

Treesearch

One Choi; Noboru Tomiya; Jung H. Kim; James M. Slavicek; Michael J. Betenbaugh; Yuan C. Lee

2003-01-01

N-glycan structures of recombinant human serum transferrin (hTf) expressed by Lymantria dispar (gypsy moth) 652Y cells were determined. The gene encoding hTf was incorporated into a Lymantria dispar nucleopolyhedrovirus (LdMNPV) under the control of the polyhedrin promoter. This virus was then...

Influence of branched-chain amino acid composition of culture media on the synthesis of plasma proteins by serum-free cultured rat hepatocytes.

PubMed

Montoya, A; Gómez-Lechón, M J; Castell, J V

1989-04-01

Supplementation of Ham's F12 culture medium with essential amino acids (EAA) up to the rat plasma levels increased the rates of synthesis of albumin and transferrin by cultured rat hepatocytes by 1.3 and 1.7, respectively. Fifty percent of this increase could be attributed to three of the EAA: the branched-chain amino acids (BCAA: Leu Ile and Val). Non-branched-chain essential amino acids (non-BC-EAA) stimulated only 25% of the increase produced by the whole EAA mixture. When each EAA was tested individually, none of them caused an appreciable increase in albumin and transferrin in culture medium. When the concentrations of all EAA were raised to rat postprandial portal levels, albumin and transferrin synthesis rates reached a maximum, increasing by 3.2 and 3.5, respectively. Supplementation with BCAA at postprandial portal concentrations increased albumin and transferrin synthesis rates by 2.2 and 2.0, respectively, and had no noteworthy effect on the synthesis of cellular proteins. Non-BC-EAA at their postprandial portal concentrations increased albumin and transferrin synthesis rates by 1.7 and 1.9, respectively. Supplementation with alanine to reach a nitrogen content equal to that of the modified EAA-enriched medium had no stimulatory effect. Our results show that EAA have a specific effect on the synthesis of plasma proteins by cultured hepatocytes, and that BCAA at physiologic concentrations account for the major part of this stimulatory effect. Consequently, EAA and particularly BCAA concentration should be elevated in serum-free nutrient media to sustain maximum plasma protein synthesis.

Transferrin hypoglycosylation in hereditary fructose intolerance: using the clues and avoiding the pitfalls.

PubMed

Adamowicz, M; Płoski, R; Rokicki, D; Morava, E; Gizewska, M; Mierzewska, H; Pollak, A; Lefeber, D J; Wevers, R A; Pronicka, E

2007-06-01

Hereditary fructose intolerance (HFI) is caused by a deficiency of aldolase B due to mutations of the ALDOB gene. The disease poses diagnostic problems because of unspecific clinical manifestations. We report three cases of HFI all of whom had a chronic disease with neurological, nephrological or gastroenterological symptoms, whereas nutritional fructose intolerance, the pathognomonic sign of HFI, was apparent only in retrospect. In all patients a hypoglycosylated pattern of transferrin isoforms was found but was misinterpreted as a sign of CDG Ix. The correct diagnosis was achieved with marked delay (26, 36 and 24 months, respectively) by sequencing of the ALDOB gene two common mutations were identified on both alleles or on one (A150P/A175D, A150P/-, and A150P/A175D). The diagnosis was further supported by normalization of transferrin isoforms on a fructose-free diet. Data available in two patients showed that following the fructose restriction the type I pattern of carbohydrate-deficient transferrin detectable on fructose-containing diet disappeared after 3-4 weeks. These cases illustrate that in the first years of life HFI may show misleading variability in clinical presentation and that protein glycosylation analysis such as transferrin isofocusing may give important diagnostic clues. However, care should be taken not to misinterpret the abnormal results as CDG Ix as well as to remember that a normal profile does not exclude HFI due to the possibility of spontaneous fructose restriction in the diet. The presented data also emphasize the usefulness of ALDOB mutation screening for diagnosis of HFI.

Sequential assessment of pulmonary epithelial diethylene triamine penta-acetate clearance and intrapulmonary transferrin accumulation during Escherichia coli peritonitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishizaka, A.; Stephens, K.E.; Segall, G.M.

1990-03-01

The individual roles of pulmonary capillary endothelial and alveolar epithelial permeability in the pathogenesis of the adult respiratory distress syndrome (ARDS) are unclear. We developed a method for the sequential assessment of pulmonary macromolecule accumulation and small solute clearance in vivo using a gamma camera. We measured the exponential clearance coefficient of 111In-labeled diethylene triamine penta-acetate (111In-DTPA) to assess airway clearance of small solutes. We also calculated the exponential equilibration coefficient of 111In-labeled transferrin (111In-TF) to assess intrapulmonary accumulation of transferrin. We determined these parameters in guinea pigs with Escherichia coli peritonitis and compared them with a saline-treated control group,more » oleic-acid-treated groups, and a group treated with low molecular weight dextran Ringer solution. The pulmonary DTPA clearance and the intrapulmonary transferrin accumulation were significantly increased in the peritonitis group (29.4 +/- 8.2 x 10(-3) min-1, p less than 0.02, and 15.1 +/- 3.1 x 10(-3) min-1, p less than 0.02) when compared with the control group (3.1 +/- 0.8 x 10(-3) min-1 and 4.5 +/- 0.5 x 10(-3) min-1). These changes developed within 5.5 h of the initial insult. Neither increased extravascular lung water nor elevated pulmonary artery and left atrial pressures were detected in the peritonitis group. The low molecular weight dextran Ringer group did not show a significant increase in the pulmonary DTPA clearance and the intrapulmonary transferrin accumulation.« less

Rapid screening of transferrin-binders in the flowers of Bauhinia blakeana Dunn by on-line high-performance liquid chromatography-diode-array detector-electrospray ionization-ion-trap-time-of-flight-mass spectrometry-transferrin-fluorescence detection system.

PubMed

Liu, Meixian; Dong, Jing; Lin, Zongtao; Niu, Yanyan; Zhang, Xiaotian; Jiang, Haixiu; Guo, Ning; Li, Wei; Wang, Hong; Chen, Shizhong

2016-06-10

Transferrin (Transferrin, TRF, TF) has drawn increasing attention in cancer therapy due to its potential applications in drug delivery. TF receptor, highly expressed in tumor cells, recognizes and transports Fe(3+)-TF into cells to release iron into cytoplasm. Thus, discovering TF-binding compounds has become an active research area and is of great importance for target therapy. In this study, an on-line analysis method was established for screening TF-binding compounds from the flowers of Bauhinia blakeana Dunn using a high-performance liquid chromatography-diode-array detector-multi-stage mass spectrometry-transferrin-fluorescence detector (HPLC-DAD-MS(n)-TF-FLD) method. As a result, 33 of 80 identified or tentatively characterized compounds in the sample were TF-binding active. Twenty-five flavonol glycosides and eight phenolic acids were identified as TF-binders. Twelve of these active compounds together with six standard compounds were used to study the dose-response effects and structure-activity relationships of flavonoids and phenolic acids. The method was validated by vitexin with a good linearity in the range of concentrations used in the study. The limit of detection for vitexin was 0.1596 nmol. Our study indicated that the established method is simple, rapid and sensitive for screening TF-binding active compounds in the extract of Bauhinia blakeana Dunn, and therefore is important for discovering potential anti-cancer ingredients from complex samples for TF related drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Nerves and Tissue Repair.

DTIC Science & Technology

1992-05-21

complete dependence on nerves. Organ culture of sciatic nerves, combined with an assay for axolotl transferrin developed earlier, allows quantitative study...axonal release of various unknown proteins. Combining this approach with the ELISA for quantitative measurement of axolotl transferrin developed with...light microscope autoradiographic analysis following binding of radiolabelled Tf. Studies of Tf synthesis will employ cDNA probes for axolotl Tf mRNA

Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy.

PubMed

Nogueira-Librelotto, Daniele R; Codevilla, Cristiane F; Farooqi, Ammad; Rolim, Clarice M B

2017-01-01

A lot of effort has been devoted to achieving active targeting for cancer therapy in order to reach the right cells. Hence, increasingly it is being realized that active-targeted nanocarriers notably reduce off-target effects, mainly because of targeted localization in tumors and active cellular uptake. In this context, by taking advantage of the overexpression of transferrin receptors on the surface of tumor cells, transferrin-conjugated nanodevices have been designed, in hope that the biomarker grafting would help to maximize the therapeutic benefit and to minimize the side effects. Notably, active targeting nanoparticles have shown improved therapeutic performances in different tumor models as compared to their passive targeting counterparts. In this review, current development of nano-based devices conjugated with transferrin for active tumor-targeting drug delivery are highlighted and discussed. The main objective of this review is to provide a summary of the vast types of nanomaterials that have been used to deliver different chemotherapeutics into tumor cells, and to ultimately evaluate the progression on the strategies for cancer therapy in view of the future research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Detection of cerebrospinal fluid leakage by specific measurement of transferrin glycoforms.

PubMed

Kwon, Seok-Joon; Zhang, Fuming; Dordick, Jonathan S; Sonstein, William J; Linhardt, Robert J

2015-10-01

A simple and rapid detection of cerebrospinal fluid (CSF) leakage would benefit spine surgeons making critical postoperative decisions on patient care. We have assessed novel approaches to selectively determine CSF β2-transferrin (β2TF), an asialo-transferrin (aTF) biomarker, without interference from serum sialo-transferrin (sTF) in test samples. First, we performed mild periodate oxidation to selectively generate aldehyde groups in sTF for capture with magnetic hydrazide microparticles, and selective removal with a magnetic separator. Using this protocol sTF was selectively removed from mixtures of CSF and serum containing CSF aTF (β2TF) and serum sTF, respectively. Second, a two-step enzymatic method was developed with neuraminidase and galactose oxidase for generating aldehyde groups in sTF present in CSF and serum mixtures for magnetic hydrazide microparticle capture. After selectively removing sTF from mixtures of CSF and serum, ELISA could detect significant TF signal only in CSF, while the TF signal in serum was negligible. The new approach for selective removal of only sTF in test samples will be promising for the required intervention by a spine surgeon. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lentiviral Nef suppresses iron uptake in a strain specific manner through inhibition of Transferrin endocytosis

PubMed Central

2014-01-01

Background Increased cellular iron levels are associated with high mortality in HIV-1 infection. Moreover iron is an important cofactor for viral replication, raising the question whether highly divergent lentiviruses actively modulate iron homeostasis. Here, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains. Results Surface Transferrin receptor (TfR) levels are unaffected by Nef proteins of HIV-1 and its simian precursors but elevated in cells expressing Nefs from most other primate lentiviruses due to reduced TfR internalization. The SIV Nef-mediated reduction of TfR endocytosis is dependent on an N-terminal AP2 binding motif that is not required for downmodulation of CD4, CD28, CD3 or MHCI. Importantly, SIV Nef-induced inhibition of TfR endocytosis leads to the reduction of Transferrin uptake and intracellular iron concentration and is accompanied by attenuated lentiviral replication in macrophages. Conclusion Inhibition of Transferrin and thereby iron uptake by SIV Nef might limit viral replication in myeloid cells. Furthermore, this new SIV Nef function could represent a virus-host adaptation that evolved in natural SIV-infected monkeys. PMID:24383984

Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mintun, M.A.; Dennis, D.R.; Welch, M.J.

1987-11-01

We quantified pulmonary vascular permeability with positron emission tomography (PET) and gallium-68-(/sup 68/Ga) labeled transferrin. Six dogs with oleic acid-induced lung injury confined to the left lower lobe, two normal human volunteers, and two patients with the adult respiratory distress syndrome (ARDS) were evaluated. Lung tissue-activity measurements were obtained from sequential 1-5 min PET scans collected over 60 min, after in vivo labeling of transferrin through intravenous administration of (/sup 68/Ga)citrate. Blood-activity measurements were measured from simultaneously obtained peripheral blood samples. A forward rate constant describing the movement of transferrin from pulmonary vascular to extravascular compartments, the pulmonary transcapillary escapemore » rate (PTCER), was then calculated from these data using a two-compartment model. In dogs, PTCER was 49 +/- 18 in normal lung tissue and 485 +/- 114 10(-4) min-1 in injured lung. A repeat study in these dogs 4 hr later showed no significant change. Values in the human subjects showed similarly marked differences between normal and abnormal lung tissue. We conclude that PET will be a useful method of evaluating vascular permeability changes after acute lung injury.« less

Redox, iron, and nutritional status of children during swimming training.

PubMed

Kabasakalis, Athanasios; Kalitsis, Konstantinos; Nikolaidis, Michalis G; Tsalis, George; Kouretas, Dimitris; Loupos, Dimitris; Mougios, Vassilis

2009-11-01

Effects of exercise training on important determinants of children's long-term health, such as redox and iron status, have not been adequately investigated. The aim of the present study was to examine changes in markers of the redox, iron and nutritional status of boy and girl swimmers during a prolonged period of training. 11 boys and 13 girls, aged 10-11 years, were members of a swimming club. They were assessed at the beginning of the training season, at 13 weeks and at 23 weeks through blood sampling and recording of the diet. Reduced glutathione increased at 13 and 23 weeks, whereas oxidised glutathione decreased at 13 weeks, resulting in an increase of the reduced/oxidised glutathione ratio at 13 and 23 weeks. Total antioxidant capacity, catalase, thiobarbituric acid-reactive substances, hemoglobin, transferrin saturation and ferritin did not change significantly. Carbohydrate intake was below 50% of energy and fat intake was above 40% of energy. Intakes of saturated fatty acids and cholesterol were excessive. Iron intake was adequate but intakes of folate, vitamin E, calcium and magnesium did not meet the recommended daily allowances. No significant differences were found between sexes in any of the parameters measured. In conclusion, child swimmers improved the redox status of glutathione during training, although the intake of antioxidant nutrients did not change. The iron status was not impaired by training. Suboptimal intake of several nutrients suggests the need for nutritional monitoring and education of children athletes.

Serum proteomic MRM identify peptide ions of transferrin as new fibrosis markers in chronic hepatitis B.

PubMed

Xu, Ming-Yi; Qu, Ying; Jia, Xiao-Fang; Wang, Mei-Ling; Liu, Heng; Wang, Xing-Peng; Zhang, Li-Jun; Lu, Lun-Gen

2013-09-01

Because of the limitations of liver biopsy, reliable non-invasive serum biomarkers of liver fibrosis are needed. The aim of this study was to identify such markers by the use of serum proteomics in chronic hepatitis B (CHB). Two-dimensional gel electrophoresis (2-DE) was used to identify differentially expressed protein spots in sera from 40 CHB patients [20 with mild fibrosis (S0-S1) and 20 with severe fibrosis (S3-S4)]. Mass spectrometry (MS) based multiple reaction monitoring (MRM) was used to quantify peptide ions of differential protein spots in another set of sera from 86 CHB patients with different liver fibrosis (S0-S4). Seven differentially expressed protein spots were found by 2-DE. Fourteen peptide ions of seven target protein spots were quantified by MS-based MRM. Summed peak areas ratio (SPAR) values of peptide ions from protein spot 1, 4 and 8, identified as apo serum transferrin, complement component C3c and transferrin, were significantly different from non-fibrosis (S0) to fibrosis stage 4. AUROCs of models established by peptide ions (protein spot 1, 4, 8) and model consisting of a combination of all ions were 0.848∼0.966 (S2-S4 versus S0-S1) and 0.785∼0.875 (S3-S4 versus S0-S2). Only the peptide ions model of transferrin had better sensitivity and specificity for predicting fibrosis stages than did aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4 and Forn's index. Serum peptide ions of transferrin, detected by proteomic MRM, are new and promising biomarkers for staging liver fibrosis in CHB patients. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo.

PubMed

He, Qing; Bouley, Richard; Liu, Zun; Wein, Marc N; Zhu, Yan; Spatz, Jordan M; Wang, Chia-Yu; Divieti Pajevic, Paola; Plagge, Antonius; Babitt, Jodie L; Bastepe, Murat

2017-11-07

Alterations in the activity/levels of the extralarge G protein α-subunit (XLαs) are implicated in various human disorders, such as perinatal growth retardation. Encoded by GNAS , XLαs is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. Following an initial proteomic screen, we identified sorting nexin-9 (SNX9) and dynamins, key components of clathrin-mediated endocytosis, as binding partners of XLαs. Overexpression of XLαs in HEK293 cells inhibited internalization of transferrin, a process that depends on clathrin-mediated endocytosis, while its ablation by CRISPR/Cas9 in an osteocyte-like cell line (Ocy454) enhanced it. Similarly, primary cardiomyocytes derived from XLαs knockout (XLKO) pups showed enhanced transferrin internalization. Early postnatal XLKO mice showed a significantly higher degree of cardiac iron uptake than wild-type littermates following iron dextran injection. In XLKO neonates, iron and ferritin levels were elevated in heart and skeletal muscle, where XLαs is normally expressed abundantly. XLKO heart and skeletal muscle, as well as XLKO Ocy454 cells, showed elevated SNX9 protein levels, and siRNA-mediated knockdown of SNX9 in XLKO Ocy454 cells prevented enhanced transferrin internalization. In transfected cells, XLαs also inhibited internalization of the parathyroid hormone and type 2 vasopressin receptors. Internalization of transferrin and these G protein-coupled receptors was also inhibited in cells expressing an XLαs mutant missing the Gα portion, but not Gsα or an N-terminally truncated XLαs mutant unable to interact with SNX9 or dynamin. Thus, XLαs restricts clathrin-mediated endocytosis and plays a critical role in iron/transferrin uptake in vivo. Published under the PNAS license.

From tissue iron retention to low systemic haemoglobin levels, new pathophysiological biomarkers of human abdominal aortic aneurysm.

PubMed

Martinez-Pinna, R; Lindholt, J S; Madrigal-Matute, J; Blanco-Colio, L M; Esteban-Salan, M; Torres-Fonseca, M M; Lefebvre, T; Delbosc, S; Laustsen, J; Driss, F; Vega de Ceniga, M; Gouya, L; Weiss, G; Egido, J; Meilhac, O; Michel, J-B; Martin-Ventura, J

2014-07-03

Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3-5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.

Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology.

PubMed

Skjørringe, Tina; Burkhart, Annette; Johnsen, Kasper Bendix; Moos, Torben

2015-01-01

Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail.

Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology

PubMed Central

Skjørringe, Tina; Burkhart, Annette; Johnsen, Kasper Bendix; Moos, Torben

2015-01-01

Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail. PMID:26106291

The habenula and iron metabolism in cerebral mouse models of multiple sclerosis

PubMed Central

Sands, Scott A.; Tsau, Sheila; LeVine, Steven M.

2015-01-01

Iron accumulates in the CNS of patients with multiple sclerosis, but our understanding of the mechanism accounting for this accumulation is unclear. Mouse models of cerebral experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mice were used together with a histochemical stain for iron and immunohistochemical stains for transferrin receptor, synaptophysin, iron regulatory protein 1 (IRP1) and/or IRP2 to investigate the role of disease activity on CNS iron metabolism. The expression of transferrin receptor, but not IRP1 or IRP2, increased in the medial habenula, which is adjacent to the third ventricle, in response to both types of cerebral EAE. In the habenula, the elevated expression of transferrin receptor in C57BL/6 mice with cerebral EAE was generally restricted to the medial habenula while the expression in SJL mice with cerebral EAE was more diffusely expressed. Iron levels were increased in all regions of the habenula in C57BL/6 mice with cerebral EAE, and in the medial and medial lateral but not the lateral habenula in SJL mice with cerebral EAE. Synaptophysin, which has been observed previously in endocytic vesicles together with the transferrin receptor, was concentrated at the medial habenula, but its levels did not increase with disease in C57BL/6 mice with cerebral EAE. Our results support the model that the medial habenula responds to disease activity by upregulating transferrin receptor to facilitate the movement of iron into the brain from the third ventricle, raising the possibility that a similar mechanism accounts for iron accumulation in deep gray matter structures in patients with multiple sclerosis. PMID:26362814

Possible Mechanism for Denervation Effect on Wound Healing.

DTIC Science & Technology

1990-12-14

investigation was the regenerating limb of the axolotl , in which growth is strictly dependent on unknown factors from peripheral nerves. The rationale of the...that axons transport transferrin to cells of the regenerating tissues. Before experiments of this nature could be undertaken, axolotl transferrin and...other tissues from axolotls . These goals were accomplished in the first phase of the project and during the last phase the immunoassay was used to

Relationship of IgG, C3 and transferrin with opsonising and bacteriostatic activity of peritoneal fluid from CAPD patients and the incidence of peritonitis.

PubMed

McGregor, S J; Brock, J H; Briggs, J D; Junor, B J

1987-01-01

IgG, C3 and transferrin in peritoneal dialysis effluent of patients undergoing continuous ambulatory peritoneal dialysis (CAPD) were 1%-2% of those in serum. In contrast, the values in normal peritoneal fluid were not significantly different from those in serum. The three proteins correlated with each other in peritoneal dialysis effluent, but were independent of the amount in the corresponding patients' sera. There was also an overall inverse correlation between total protein in peritoneal dialysis effluent and time on CAPD during the first 6 months of treatment but not thereafter, which suggests that changes in membrane permeability occur during the early months. In peritoneal dialysis effluent, but not in normal peritoneal fluid, there was a correlation between opsonising capacity and IgG or C3 concentrations. An inverse correlation between opsonic activity of peritoneal dialysis effluent and frequency of peritonitis was also found. Peritoneal dialysis effluent permitted significantly faster multiplication of Staphylococcus epidermidis than sera or normal peritoneal fluid, and the growth rate correlated inversely with the transferrin levels in peritoneal dialysis effluent. Overall IgG, C3 and transferrin in peritoneal dialysis effluent are inadequate for optimal opsonising and bacteriostatic activity, and the peritoneal cavities of CAPD patients are therefore immunocompromised sites.

Iron deficiency was not the major cause of anemia in rural women of reproductive age in Sidama zone, southern Ethiopia: A cross-sectional study

PubMed Central

Gebreegziabher, Tafere; Stoecker, Barbara J.

2017-01-01

Background Anemia, which has many etiologies, is a moderate/severe public health problem in young children and women of reproductive age in many developing countries. The aim of this study was to investigate prevalence of iron deficiency, anemia, and iron deficiency anemia using multiple biomarkers and to evaluate their association with food insecurity and food consumption patterns in non-pregnant women from a rural area of southern Ethiopia. Methods A cross-sectional study was conducted in 202 rural women of reproductive age in southern Ethiopia. Anthropometrics and socio-demographic data were collected. A venipuncture blood sample was analyzed for hemoglobin (Hb) and for biomarkers of iron status. Biomarkers were skewed and were log transformed before analysis. Mean, median, Pearson’s correlations and ordinary least-squares regressions were calculated. Results Median (IQR) Hb was 138 (127, 151) g/L. Based on an altitude-adjusted (1708 m) cutoff of 125 g/L for Hb, 21.3% were anemic. Plasma ferritin was <15 μg/L in 18.6% of the women. Only one woman had α-1-acid glycoprotein (AGP) >1.0 g/L; four women (2%) had > 5 mg/L of C-reactive protein (CRP). Of the 43 women who were anemic, 23.3% (10 women) had depleted iron stores based on plasma ferritin. Three of these had elevated soluble transferrin receptors (sTfR). Hemoglobin (Hb) concentration was negatively correlated with sTfR (r = -0.24, p = 0.001), and positively correlated with ferritin (r = 0.17, p = 0.018), plasma iron (r = 0.15, p = 0.046), transferrin saturation (TfS) (r = 0.15, p = 0.04) and body iron (r = 0.14, p = 0.05). Overall prevalence of iron deficiency anemia was only 5%. Conclusion Iron deficiency anemia was not prevalent in the study population, despite the fact that anemia would be classified as a moderate public health problem. PMID:28898272

Iron deficiency was not the major cause of anemia in rural women of reproductive age in Sidama zone, southern Ethiopia: A cross-sectional study.

PubMed

Gebreegziabher, Tafere; Stoecker, Barbara J

2017-01-01

Anemia, which has many etiologies, is a moderate/severe public health problem in young children and women of reproductive age in many developing countries. The aim of this study was to investigate prevalence of iron deficiency, anemia, and iron deficiency anemia using multiple biomarkers and to evaluate their association with food insecurity and food consumption patterns in non-pregnant women from a rural area of southern Ethiopia. A cross-sectional study was conducted in 202 rural women of reproductive age in southern Ethiopia. Anthropometrics and socio-demographic data were collected. A venipuncture blood sample was analyzed for hemoglobin (Hb) and for biomarkers of iron status. Biomarkers were skewed and were log transformed before analysis. Mean, median, Pearson's correlations and ordinary least-squares regressions were calculated. Median (IQR) Hb was 138 (127, 151) g/L. Based on an altitude-adjusted (1708 m) cutoff of 125 g/L for Hb, 21.3% were anemic. Plasma ferritin was <15 μg/L in 18.6% of the women. Only one woman had α-1-acid glycoprotein (AGP) >1.0 g/L; four women (2%) had > 5 mg/L of C-reactive protein (CRP). Of the 43 women who were anemic, 23.3% (10 women) had depleted iron stores based on plasma ferritin. Three of these had elevated soluble transferrin receptors (sTfR). Hemoglobin (Hb) concentration was negatively correlated with sTfR (r = -0.24, p = 0.001), and positively correlated with ferritin (r = 0.17, p = 0.018), plasma iron (r = 0.15, p = 0.046), transferrin saturation (TfS) (r = 0.15, p = 0.04) and body iron (r = 0.14, p = 0.05). Overall prevalence of iron deficiency anemia was only 5%. Iron deficiency anemia was not prevalent in the study population, despite the fact that anemia would be classified as a moderate public health problem.

Myogenic Growth Factor Present in Skeletal Muscle is Purified by Heparin-Affinity Chromatography

NASA Astrophysics Data System (ADS)

Kardami, Elissavet; Spector, Dennis; Strohman, Richard C.

1985-12-01

A myogenic growth factor has been purified from a skeletal muscle, the anterior latissimus dorsi, of adult chickens. In the range of 1-10 ng, this factor stimulates DNA synthesis as well as protein and muscle-specific myosin accumulation in myogenic cell cultures. Purification is achieved through binding of the factor to heparin. The factor is distinct from transferrin and works synergistically with transferrin in stimulating myogenesis in vitro.

Intracellular Delivery of a Planar DNA Origami Structure by the Transferrin-Receptor Internalization Pathway.

PubMed

Schaffert, David H; Okholm, Anders H; Sørensen, Rasmus S; Nielsen, Jesper S; Tørring, Thomas; Rosen, Christian B; Kodal, Anne Louise B; Mortensen, Michael R; Gothelf, Kurt V; Kjems, Jørgen

2016-05-01

DNA origami provides rapid access to easily functionalized, nanometer-sized structures making it an intriguing platform for the development of defined drug delivery and sensor systems. Low cellular uptake of DNA nanostructures is a major obstacle in the development of DNA-based delivery platforms. Herein, significant strong increase in cellular uptake in an established cancer cell line by modifying a planar DNA origami structure with the iron transport protein transferrin (Tf) is demonstrated. A variable number of Tf molecules are coupled to the origami structure using a DNA-directed, site-selective labeling technique to retain ligand functionality. A combination of confocal fluorescence microscopy and quantitative (qPCR) techniques shows up to 22-fold increased cytoplasmic uptake compared to unmodified structures and with an efficiency that correlates to the number of transferrin molecules on the origami surface. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Plasmonic Nanodiamonds – Targeted Core-shell Type Nanoparticles for Cancer Cell Thermoablation

PubMed Central

Rehor, Ivan; Lee, Karin L.; Chen, Kevin; Hajek, Miroslav; Havlik, Jan; Lokajova, Jana; Masat, Milan; Slegerova, Jitka; Shukla, Sourabh; Heidari, Hamed; Bals, Sara

2015-01-01

Targeted biocompatible nanostructures with controlled plasmonic and morphological parameters are promising materials for cancer treatment based on selective thermal ablation of cells. Here, core-shell plasmonic nanodiamonds consisting of a silica-encapsulated diamond nanocrystal coated in a gold shell is designed and synthesized. The architecture of particles is analyzed and confirmed in detail using 3-dimensional transmission electron microscope tomography. The particles are biocompatibilized using a PEG polymer terminated with bioorthogonally reactive alkyne groups. Azide-modified transferrin is attached to these particles, and their high colloidal stability and successful targeting to cancer cells overexpressing the transferrin receptor is demonstrated. The particles are nontoxic to the cells and they are readily internalized upon binding to the transferrin receptor. The high plasmonic cross section of the particles in the near-infrared region is utilized to quantitatively ablate the cancer cells with a short, one-minute irradiation by a pulse 750-nm laser. PMID:25336437

Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors

NASA Astrophysics Data System (ADS)

Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.; Broome, Ann-Marie

2015-01-01

Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.

Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors

PubMed Central

Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.

2015-01-01

Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to un-targeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging. PMID:25519743

Anti-transferrin receptor-modified amphotericin B-loaded PLA-PEG nanoparticles cure Candidal meningitis and reduce drug toxicity.

PubMed

Tang, Xiaolong; Liang, Yong; Zhu, Yongqiang; Xie, Chunmei; Yao, Aixia; Chen, Li; Jiang, Qinglin; Liu, Tingting; Wang, Xiaoyu; Qian, Yunyun; Wei, Jia; Ni, Wenxuan; Dai, Jingjing; Jiang, Zhenyou; Hou, Wei

2015-01-01

Fatal fungal infections in central nervous system (CNS) can occur through hematogenous spread or direct extension. At present, hydrophobic amphotericin B (AMB) is the most effective antifungal drug in clinical trials. However, AMB is hydrophobic and therefore penetrates poorly into the CNS, and therapeutic levels of AMB are hard to achieve. The transferrin receptor (TfR/CD71) located at the blood-brain barrier mediates transferrin transcytosis. In order to enhance the receptor-mediated delivery of AMB into CNS with therapeutic level, an anti-TfR antibody (OX26)-modified AMB-loaded PLA (poly[lactic acid])-PEG (polyethylene glycol)-based micellar drug delivery system was constructed. The prepared OX26-modified AMB-loaded nanoparticles (OX26-AMB-NPs) showed significant reduction of CNS fungal burden and an increase of mouse survival time. In conclusion, OX26-AMB-NPs represent a promising novel drug delivery system for intracerebral fungal infection.

Angiotensin II inhibits iron uptake and release in cultured neurons.

PubMed

Liu, Yong; Huang, Suna; Du, Fang; Yang, Guang; Jiang, Li Rong; Zhang, Chao; Qian, Zhong-ming

2014-05-01

Based on the well-confirmed roles of angiotensin II (ANGII) in iron transport of peripheral organs and cells, the causative link of excess brain iron with and the involvement of ANGII in neurodegenerative disorders, we speculated that ANGII might also have an effect on expression of iron transport proteins in the brain. In the present study, we investigated effects of ANGII on iron uptake and release using the radio-isotope methods as well as expression of cell iron transport proteins by Western blot analysis in cultured neurons. Our findings demonstrated for the first time that ANGII significantly reduced transferrin-bound iron and non-transferrin bound iron uptake and iron release as well as expression of two major iron uptake proteins transferrin receptor 1 and divalent metal transporter 1 and the key iron exporter ferroportin 1 in cultured neurons. The findings suggested that endogenous ANGII might have a physiological significance in brain iron metabolism.

Transferrin receptor facilitates TGF-β and BMP signaling activation to control craniofacial morphogenesis

PubMed Central

Lei, R; Zhang, K; Liu, K; Shao, X; Ding, Z; Wang, F; Hong, Y; Zhu, M; Li, H; Li, H

2016-01-01

The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel's cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS. PMID:27362800

Cerebral Abscess Associated With Odontogenic Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to-Left Shunting Through Pulmonary Arteriovenous Malformations.

PubMed

Boother, Emily J; Brownlow, Sheila; Tighe, Hannah C; Bamford, Kathleen B; Jackson, James E; Shovlin, Claire L

2017-08-15

Cerebral abscess is a recognized complication of pulmonary arteriovenous malformations (PAVMs) that allow systemic venous blood to bypass the pulmonary capillary bed through anatomic right-to-left shunts. Broader implications and mechanisms remain poorly explored. Between June 2005 and December 2016, at a single institution, 445 consecutive adult patients with computed tomography-confirmed PAVMs (including 403 [90.5%] with hereditary hemorrhagic telangiectasia) were recruited to a prospective series. Multivariate logistic regression was performed and detailed periabscess histories were evaluated to identify potential associations with cerebral abscess. Rates were compared to an earlier nonoverlapping series. Thirty-seven of the 445 (8.3%) patients experienced a cerebral abscess at a median age of 50 years (range, 19-76 years). The rate adjusted for ascertainment bias was 27 of 435 (6.2%). Twenty-nine of 37 (78.4%) patients with abscess had no PAVM diagnosis prior to their abscess, a rate unchanged from earlier UK series. Twenty-one of 37 (56.7%) suffered residual neurological deficits (most commonly memory/cognition impairment), hemiparesis, and visual defects. Isolation of periodontal microbes, and precipitating dental and other interventional events, emphasized potential sources of endovascular inoculations. In multivariate logistic regression, cerebral abscess was associated with low oxygen saturation (indicating greater right-to-left shunting); higher transferrin iron saturation index; intravenous iron use for anemia (adjusted odds ratio, 5.4 [95% confidence interval, 1.4-21.1]); male sex; and venous thromboemboli. There were no relationships with anatomic attributes of PAVMs, or red cell indices often increased due to secondary polycythemia. Greater appreciation of the risk of cerebral abscess in undiagnosed PAVMs is required. Lower oxygen saturation and intravenous iron may be modifiable risk factors. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

New targeted therapies and diagnostic methods for iron overload diseases.

PubMed

Kolnagou, Annita; Kontoghiorghe, Christina N; Kontoghiorghes, George John

2018-01-01

Millions of people worldwide suffer from iron overload toxicity diseases such as transfusional iron overload in thalassaemia and hereditary haemochromatosis. The accumulation and presence of toxic focal iron deposits causing tissue damage can also be identified in Friedreich's ataxia, Alzheimer's, Parkinson's, renal and other diseases. Different diagnostic criteria of toxicity and therapeutic interventions apply to each disease of excess or misplaced iron. Magnetic resonance imaging relaxation times T2 and T2* for monitoring iron deposits in organs and iron biomarkers such as serum ferritin and transferrin iron saturation have contributed in the elucidation of iron toxicity mechanisms and pathways, and also the evaluation of the efficacy and mode of action of chelating drugs in the treatment of diseases related to iron overload, toxicity and metabolism. Similarly, histopathological and electron microscopy diagnostic methods have revealed mechanisms of iron overload toxicity at cellular and sub-cellular levels. These new diagnostic criteria and chelator dose adjustments could apply in different or special patient categories e.g. thalassaemia patients with normal iron stores, where iron deficiency and over-chelation toxicity should be avoided.

Steric and not structure-specific factors dictate the endocytic mechanism of glycosylphosphatidylinositol-anchored proteins

PubMed Central

Bhagatji, Pinkesh; Leventis, Rania; Comeau, Jonathan; Refaei, Mohammad

2009-01-01

Diverse glycosylphosphatidylinositol (GPI)-anchored proteins enter mammalian cells via the clathrin- and dynamin-independent, Arf1-regulated GPI-enriched early endosomal compartment/clathrin-independent carrier endocytic pathway. To characterize the determinants of GPI protein targeting to this pathway, we have used fluorescence microscopic analyses to compare the internalization of artificial lipid-anchored proteins, endogenous membrane proteins, and membrane lipid markers in Chinese hamster ovary cells. Soluble proteins, anchored to cell-inserted saturated or unsaturated phosphatidylethanolamine (PE)-polyethyleneglycols (PEGs), closely resemble the GPI-anchored folate receptor but differ markedly from the transferrin receptor, membrane lipid markers, and even protein-free PE-PEGs, both in their distribution in peripheral endocytic vesicles and in the manner in which their endocytic uptake responds to manipulations of cellular Arf1 or dynamin activity. These findings suggest that the distinctive endocytic targeting of GPI proteins requires neither biospecific recognition of their GPI anchors nor affinity for ordered-lipid microdomains but is determined by a more fundamental property, the steric bulk of the lipid-anchored protein. PMID:19687251

HFE gene mutations and Wilson's disease in Sardinia.

PubMed

Sorbello, Orazio; Sini, Margherita; Civolani, Alberto; Demelia, Luigi

2010-03-01

Hypocaeruloplasminaemia can lead to tissue iron storage in Wilson's disease and the possibility of iron overload in long-term overtreated patients should be considered. The HFE gene encodes a protein that is intimately involved in intestinal iron absorption. The aim of this study was to determine the prevalence of the HFE gene mutation, its role in iron metabolism of Wilson's disease patients and the interplay of therapy in copper and iron homeostasis. The records of 32 patients with Wilson's disease were reviewed for iron and copper indices, HFE gene mutations and liver biopsy. Twenty-six patients were negative for HFE gene mutations and did not present significant alterations of iron metabolism. The HFE mutation was significantly associated with increased hepatic iron content (P<0.02) and transferrin saturation index (P<0.03). After treatment period, iron indices were significantly decreased only in HFE gene wild-type. The HFE gene mutations may be an addictional factor in iron overload in Wilson's disease. Our results showed that an adjustment of dosage of drugs could prevent further iron overload induced by overtreatment only in patients HFE wild-type. 2009. Published by Elsevier Ltd.

Triumph and tragedy: anemia management in chronic kidney disease.

PubMed

Novak, James E; Szczech, Lynda A

2008-11-01

Recent trial data have resulted in a reevaluation of the management of anemia in chronic kidney disease, including the use of erythropoiesis-stimulating agents, intravenous iron, and novel pharmaceuticals. In this review, we evaluate the latest research on anemia management in chronic kidney disease. Clinical trials of erythropoiesis-stimulating agents indicate that targeting the complete correction of anemia in patients with chronic kidney disease results in a greater risk of morbidity and mortality despite improved hemoglobin and quality of life. Conversely, intravenous iron has been found effective and relatively well tolerated in treating anemia in chronic kidney disease, even in patients with elevated ferritin. New agents to manage anemia, including long-acting erythropoietin derivatives, are also in active development. Erythropoiesis-stimulating agents should be used to target hemoglobin 11-12 g/dl in patients with chronic kidney disease. Intravenous iron may be beneficial for patients with hemoglobin less than 11 g/dl and transferrin saturation less than 25% despite elevated ferritin (500-1200 ng/ml). An upcoming placebo-controlled trial of darbepoetin should help to define the role of erythropoiesis-stimulating agents in chronic kidney disease.

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

PubMed Central

Aigner, Elmar; Weiss, Günter; Datz, Christian

2015-01-01

Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID:25729473

Obesity as an Emerging Risk Factor for Iron Deficiency

PubMed Central

Aigner, Elmar; Feldman, Alexandra; Datz, Christian

2014-01-01

Iron homeostasis is affected by obesity and obesity-related insulin resistance in a many-facetted fashion. On one hand, iron deficiency and anemia are frequent findings in subjects with progressed stages of obesity. This phenomenon has been well studied in obese adolescents, women and subjects undergoing bariatric surgery. On the other hand, hyperferritinemia with normal or mildly elevated transferrin saturation is observed in approximately one-third of patients with metabolic syndrome (MetS) or nonalcoholic fatty liver disease (NAFLD). This constellation has been named the “dysmetabolic iron overload syndrome (DIOS)”. Both elevated body iron stores and iron deficiency are detrimental to health and to the course of obesity-related conditions. Iron deficiency and anemia may impair mitochondrial and cellular energy homeostasis and further increase inactivity and fatigue of obese subjects. Obesity-associated inflammation is tightly linked to iron deficiency and involves impaired duodenal iron absorption associated with low expression of duodenal ferroportin (FPN) along with elevated hepcidin concentrations. This review summarizes the current understanding of the dysregulation of iron homeostasis in obesity. PMID:25215659

[Iron deficiency anaemia: clinical presentation, biological diagnosis and management].

PubMed

Espanel, C; Kafando, E; Hérault, B; Petit, A; Herault, O; Binet, C

2007-05-01

The iron deficiency is the first cause of anaemia. In healthy young adult, anemia is well tolerated because of its progressive installation. The most common symptoms of anemia are pallor, fatigue and dyspnea. In biological exams, anemia is classically associated with microcytosis and hypochromia. The origins of microcytic anemia are iron deficiency, inflammatory aetiologies, thalassemia and sideroblastic anaemia. The iron-deficiency diagnosis includes two explorations: biological and clinical. The biological exploration is based on interpretation of serum biologics tests as blood iron, ferritin, transferrin with saturation, total iron-binding capacity and its soluble receptors. This interpretation is simple if it is not associated with clinical disorders influencing the internal iron cycle. The clinical exploration must always be followed by a careful assessment of the underlying cause as blood loss. The most common causes in women of reproductive age are gynaecologic. In men and menopausal women, the gastrointestinal tract bleeding is source of anemia. Therapeutic management of anemia is oral iron therapy. Etiological diagnostic of microcytosis is essential before iron therapy. If not, the treatment could be inefficient or it could mask or delay the etiological diagnostic.

Relationship between brain R(2) and liver and serum iron concentrations in elderly men.

PubMed

House, Michael J; St Pierre, Timothy G; Milward, Elizabeth A; Bruce, David G; Olynyk, John K

2010-02-01

Studies of iron overload in humans and animals suggest that brain iron concentrations may be related in a regionally specific way to body iron status. However, few quantitative studies have investigated the associations between peripheral and regional brain iron in a normal elderly cohort. To examine these relationships, we used MRI to measure the proton transverse relaxation rate (R(2)) in 13 gray and white matter brain regions in 18 elderly men (average age, 75.5 years) with normal cognition. Brain R(2) values were compared with liver iron concentrations measured using the FerriScan MRI technique and serum iron indices. R(2) values in high-iron gray matter regions were significantly correlated (positively) with liver iron concentrations (globus pallidus, ventral pallidum) and serum transferrin saturation (caudate nucleus, globus pallidus, putamen) measured concurrently with brain R(2), and with serum iron concentrations (caudate nucleus, globus pallidus) measured three years before the current study. Our results suggest that iron levels in specific gray matter brain regions are influenced by systemic iron status in elderly men.

Mineral metabolism in a black-necked swan (Cygnus melanocoryphus) population from southern Chile.

PubMed

Norambuena, M Cecilia; Bozinovic, Francisco

2009-12-01

A population of black-necked swans (Cygnus melanocoryphus) residing in a perturbed habitat revealed a low body mass, malnutrition, and hyperferremia during 2005; the swans main dietary item, Egeria densa, was lost during an environmental crisis which occurred in 2004. The objective of this study was to monitor the diet and nutritional status of this population during 2006, as well as to verify how the consumption of sediment, as part of their new diet, may explain the mineral disorders observed in these birds. Results revealed that swans increased their body mass and had an adequate protein, lipid, and iron metabolism, in spite of the fact that they maintained the same new diet (sediment and roots) during 2005-2006. In addition, transferrine saturation was indicative of the high endogenous iron load in birds which agrees with the high iron load of their environment. On the other hand, the consumption of the Cayumapu River sediment in the diet (25%) did not affect the body mass nor the nutritional and hepatic function in domestic geese over a 45-day period.

Insights into the diagnosis and management of iron deficiency in inflammatory bowel disease.

PubMed

Bou-Fakhredin, Rayan; Halawi, Racha; Roumi, Joseph; Taher, Ali

2017-09-01

Iron deficiency is a frequent comorbidity of chronic diseases such as inflammatory bowel disease that can severely impact the health and quality of life of affected individuals. It can exist as a silent condition and manifest in non-specific symptoms even in the absence of anemia. Even though iron deficiency anemia is the most common complication and extra-intestinal manifestation of inflammatory bowel disease, the majority of inflammatory bowel disease patients who are diagnosed with iron deficiency anemia are not treated. Areas covered: In this review, we discuss iron deficiency and iron deficiency anemia in patients with inflammatory bowel disease, and review diagnostic and therapeutic options. Expert commentary: We invite international gastroenterological societies and associations to refine the practice guidelines and include iron deficiency as a potential morbidity associated with IBD in analogy to arthritis, uveitis or any other extra intestinal manifestations. There should a more unanimous agreement among different societies on the specific diagnostic cutoff values for C-reactive protein levels, serum ferritin, and transferrin saturation in order to differentiate iron deficiency anemia from anemia of chronic disease.

Anemia and Iron Status Among Different Body Size Phenotypes in Chinese Adult Population: a Nation-Wide, Health and Nutrition Survey.

PubMed

Li, Jiang; Xiao, Cheng; Yang, Hui; Zhou, Yun; Wang, Rui; Cao, Yongtong

2017-12-09

Previous studies have shown that there is a controversial relationship between iron homeostasis and obesity. This study aims to explore the relationship of anemia and iron status with different body size phenotypes in adult Chinese population. Using information on iron status-related parameters and lifestyle data from 8462 participants of the 2009 wave of China Health and Nutrition Survey (2009 CHNS), we performed multivariable logistic regression analyses to estimate the odds ratios (ORs) for the risk of anemia and iron parameters according to different body size phenotypes. Participants with higher body mass index (BMI) had a lower anemia prevalence with significant trends in both metabolic status groups (P < 0.001). Serum ferritin, transferrin, and soluble transferrin receptor (sTfR)/log ferritin index were significant in different metabolic status groups and in different body size phenotypes, respectively. The ORs for higher ferritin and transferrin increased across different body size phenotypes in both genders, and for sTfR/log ferritin index decreased (P < 0.01 for trend). This association was still statistically significant after adjustment for multiple confounders. We found an inverse association of BMI levels with the prevalence of anemia and strong association of serum ferritin and transferrin with higher risk of obesity or overweight in both metabolic status groups.

Interaction of imatinib mesylate with human serum transferrin: The comparative spectroscopic studies

NASA Astrophysics Data System (ADS)

Śliwińska-Hill, Urszula

2017-02-01

Imatinib mesylate (Imt) is a tyrosine kinase inhibitor mainly used in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph + CML). Human serum transferrin is the most abundant serum protein responsible for the transport of iron ions and many endogenous and exogenous ligands. In this study the mechanism of interactions between the imatinib mesylate and all states of transferrin (apo-Tf, Htf and holo-Tf) has been investigated by fluorescence, ultraviolet-visible (UV-vis), circular dichroism (CD) and zeta potential spectroscopic methods. Based on the experimental results it was proved that under physiological conditions the imatinib mesylate binds to the each form of transferrin with a binding constant c.a. 105 M- 1. The thermodynamic parameters indicate that hydrogen bonds and van der Waals were involved in the interaction of apo-Tf with the drug and hydrophobic and ionic strength participate in the reaction of Htf and holo-Tf with imatinib mesylate. Moreover, it was shown that common metal ions, Zn2 + and Ca2 + strongly influenced apo-Tf-Imt binding constant. The CD studies showed that there are no conformational changes in the secondary structure of the proteins. No significant changes in secondary structure of the proteins upon binding with the drug and instability of apo-Tf-Imt system are the desirable effects from pharmacological point of view.

Automated measurement of carbohydrate-deficient transferrin using the Bio-Rad %CDT by the HPLC test on a Variant HPLC system: evaluation and comparison with other routine procedures.

PubMed

Schellenberg, François; Mennetrey, Louise; Girre, Catherine; Nalpas, Bertrand; Pagès, Jean Christophe

2008-01-01

In this study, we evaluated the new %CDT by the HPLC method (Bio-Rad, Germany) on a Varianttrade mark HPLC system (Bio-Rad), checked the correlation with well-known methods and calculated the diagnostic value of the test. Intra-run and day-to-day precision values were calculated for samples with extreme serum transferrin concentrations, high trisialotransferrin and interfering conditions (haemolysed, lactescent and icteric samples). The method was compared with two routine procedures, the %CDT TIA (Bio-Rad, Hercules, CA, USA) and the Capillarystrade mark CDT (Sebia, France). A total of 350 clinical sera samples were used for a case-control study. Precision values were better in high CDT and medium CDT pools than in low CDT pools. The serum transferrin concentration had no effect on CDT measurement, except in samples with serum transferrin <1 g/L. Haemolysis was the only interfering situation. The method showed high correlation (r(2) > 0.95) with the two other methods (%CDT TIA and CZE %CDT). The global predictive value of the test was >0.90 at 1.9% cut-off. These results demonstrate that the %CDT by the HPLC test is suitable for CDT routine measurement; the results from the high-throughput Varianttrade mark system are well correlated with other methods and are of high diagnostic value.

Tyrosines of Human and Mouse Transferrin Covalently Labeled by Organophosphorus Agents: A New Motif for Binding to Proteins that Have No Active Site Serine

PubMed Central

Li, Bin; Schopfer, Lawrence M.; Grigoryan, Hasmik; Thompson, Charles M.; Hinrichs, Steven H.; Masson, Patrick; Lockridge, Oksana

2009-01-01

The expectation from the literature is that organophosphorus (OP) agents bind to proteins that have an active site serine. However, transferrin, a protein with no active site serine, was covalently modified in vitro by 0.5mM 10-fluoroethoxyphosphinyl-N-biotinamido pentyldecanamide, chlorpyrifos oxon, diisopropylfluorophosphate, dichlorvos, sarin, and soman. The site of covalent attachment was identified by analyzing tryptic peptides in the mass spectrometer. Tyr 238 and Tyr 574 in human transferrin and Tyr 238, Tyr 319, Tyr 429, Tyr 491, and Tyr 518 in mouse transferrin were labeled by OP. Tyrosine in the small synthetic peptide ArgTyrThrArg made a covalent bond with diisopropylfluorophosphate, chlorpyrifos oxon, and dichlorvos at pH 8.3. These results, together with our previous demonstration that albumin and tubulin bind OP on tyrosine, lead to the conclusion that OP bind covalently to tyrosine, and that OP binding to tyrosine is a new OP-binding residue. The OP-reactive tyrosines are activated by interaction with Arg or Lys. It is suggested that many proteins in addition to those already identified may be modified by OP on tyrosine. The extent to which tyrosine modification by OP can occur in vivo and the toxicological implications of such modifications require further investigation. PMID:18930948

Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface.

PubMed

Tan, Shumin; Noto, Jennifer M; Romero-Gallo, Judith; Peek, Richard M; Amieva, Manuel R

2011-05-01

Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche.

Helicobacter pylori Perturbs Iron Trafficking in the Epithelium to Grow on the Cell Surface

PubMed Central

Tan, Shumin; Noto, Jennifer M.; Romero-Gallo, Judith; Peek, Richard M.; Amieva, Manuel R.

2011-01-01

Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche. PMID:21589900

One-chip biosensor for simultaneous disease marker/calibration substance measurement in human urine by electrochemical surface plasmon resonance method.

PubMed

Nakamoto, Kohei; Kurita, Ryoji; Niwa, Osamu

2010-12-15

We have developed a miniaturized electrochemical surface plasmon resonance biosensor for measuring two biomolecules that have very different molecular sizes, one is transferrin (MW=75 kDa) as a disease marker protein, the other is creatinine (MW=113) as a calibration marker for the accurate measurement of human urinary samples. The sensor has a PDMS based microchannel that is 2 mm wide and 20 μm deep. Two gold films were integrated in the microchannel; one was modified with anti-transferrin antibody for immuno-reaction, and the other was modified with osmium-poly-vinylpyridine wired horseradish peroxidase (Os-gel-HRP). We further immobilized a tri-enzyme layer of creatininase, creatinase and sarcosine oxidase in order to measure creatinine by converting it to hydrogen peroxide in the upstream channel. We measured the transferrin concentration from the refractive index change involved in an immuno-complex formation, and we were simultaneously able to measure creatinine by employing the refractive index change in the Os-gel-HRP caused by oxidation with the hydrogen peroxide produced from creatinine by the tri-enzyme. The effects of ascorbic acid and uric acid in urine samples were sufficiently eliminated by adding ascorbate oxidase and uricase to the urine samples during sampling. We were able to measure two analyte concentrations within 15 min by one simple injection of 50 μL of diluted human urine into our sensor. The detectable transferrin and creatinine ranges were 20 ng/mL to 10 μg/mL, and 10 μM to 10 mM, respectively, which are sufficient levels for clinical tests. Finally, we compared the results obtained using our sensor with those obtained with a conventional immunoassay and the Jaffe method. We obtained a similar trend that can reduce the fluctuation in the urinary transferrin concentration from three different samples by calibrating the creatinine concentration. Copyright © 2010 Elsevier B.V. All rights reserved.

[Iron status with particular consideration of soluble transferrin receptors in children and youth with gastritis, with or without Helicobacter pylori infection].

PubMed

Mierzwa, Grazyna; Augustyńska, Beata; Czerwionka-Szaflarska, Mieczysława; Tyrakowski, Tomasz

2006-09-01

Role of Helicobacter pylori infection in chronic gastritis and gastric and/or duodenal ulcers is well known. Simultaneously there are some articles in literature considering H. pylori as a cause of extra-gastrointestinal illnesses such as atopic dermatitis, chronic urticaria or acne rosacea, hypotrophy, Schoenlein-Henoch disease, atherosclerosis or hypochromic anaemia. The aim of the study. was to asses iron status in aspect of plasmatic transferrin receptors concentration among children and youth with chronic gastritis with or without Helicobacter pylori infection. Forty one patients were included as a study group. Range of age was 9-18 years. All patients were diagnosed due to chronic abdominal pains. There were 13 males and 28 females. Blood was collected from every patient for blood cell count, iron, transferrin and transferrin receptors concentration (sTfR) assessment before endoscopy of upper gastrointestinal tract. Concentration of sTfR was higher than age norm among 29 (71%) of patients. Among patients with higher level of sTfR 20 (69%) had normal haemoglobin concentration and in this group 10 patients had H. pylori infection. During analysis of 12 patients with nornal level of sTfR normal haemoglobin concentration was found and among five of them H. pylori infection was stated. Among 21 patients without H. pylori infection 14 had normal level of sTfR and 7 had higher level of sTfR which means that 33% had hidden iron deficiency (involuntary of normal Hb concentrations). Among 15 of 20 patients with H. pylori infection level of sTfR was higher which means that 75% patients with infection had hidden iron deficiency (involuntary of normal Hb concentrations). Level of plasmatic transferrin receptors can be good and sensitive indicator of iron deficiency and can be helpful in differential diagnosis of hypochromic anaemia and anaemia caused by chronic illness including chronic gastritis with Helicobacter pylori infection.

Modulation of transferrin receptor mRNA by transferrin-gallium in human myeloid HL60 and lymphoid CCRF-CEM leukaemic cells.

PubMed Central

Ul-Haq, R; Chitambar, C R

1993-01-01

Gallium binds to the iron transport protein transferrin (Tf), is incorporated into cells through transferrin receptors (TfR) and inhibits iron-dependent DNA synthesis. Since cellular TfR expression is tightly regulated by the availability of iron, we investigated the effects of transferrin-gallium (Tf-Ga) on TfR mRNA levels in myeloid HL60 and lymphoid CCRF-CEM cells. In HL60 cells, Tf-Ga increased TfR mRNA levels in a dose-dependent fashion. This increase in TfR mRNA was blocked by Tf-Fe and by cycloheximide. Analysis of the rate of mRNA decay in the presence of actinomycin D revealed that the half-life of TfR mRNA was increased in HL60 cells incubated with Tf-Ga. The rate of transcription of TfR mRNA was not increased by Tf-Ga. In contrast with HL60 cells, CCRF-CEM cells displayed a decrease in the level of TfR mRNA after incubation with Tf-Ga. Tf-Ga inhibited iron uptake in both HL60 and CCRF-CEM cells but increased the level of TfR mRNA only in HL60 cells, suggesting that the Tf-Ga induction of TfR mRNA was not solely due to inhibition of cellular iron uptake. At growth-inhibitory concentrations, Tf-Ga increased the TfR mRNA level in HL60 cells but decreased it in CCRF-CEM cells. Our studies suggest that in HL60 cells, gallium regulates TfR expression at the post-transcriptional level by mechanisms which require de novo protein synthesis and involve interaction with iron. The divergent effects of Tf-Ga on TfR mRNA in myeloid HL60 and lymphoid CCRF-CEM cells suggest that differences exist in the regulation of TfR expression between these two cell types. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8379943

Credibility of the measurement of serum ferritin and transferrin receptor as indicators of iron deficiency anemia in hemodialysis patients.

PubMed

Mahdavi, M R; Makhlough, A; Kosaryan, M; Roshan, P

2011-10-01

Anemia is a common complication in uremic patients. Erythropoietin therapy is prescribed in these cases; however, this treatment is not successful in iron deficient patients. Ferritin-based diagnosis of iron deficiency in these patients is a challenging task, as serum ferritin level may be high due to chronic inflammation and mask iron deficiency. In the current study we evaluated the credibility of another indicator of body iron supply, serum transferrin receptor, in hemodialysis patients in two University-based Hospitals in North of Iran. In a cross-sectional study, 53 hemodialysis patients with a mean age of 56 +/- 18.7 years and 30 persons with iron deficiency and normal renal function with a mean age of 20.1 +/- 14.4 years were examined. All hemodialysis patients were on hemodialysis 2-3 times per week for 3-4 hours. All cases were examined for blood hemoglobin content, serum iron, CRP, serum ferritin and serum transferrin receptor levels. The reference ranges introduced by manufacturers were considered as standard ranges for analysis of the results. Using one sample T-test and Fisher's exact test, data were analyzed. p<0.05 was considered as significant. Hemodialysis patients had blood hemoglobin content below normal range (p<0.05 for men, p<0.001 for women) and CRP levels above normal range (p<0.001). In hemodialysis patients, serum ferritin level was significantly higher than control group (p<0.001), whilst serum transferrin receptor levels in the two groups were not significantly different (p=0.69), and both were above defined normal upper limit (p<0.001 for iron deficient patients; p<0.05 for hemodialysis patients). This study showed measurement of serum ferritin in the presence of chronic inflammation induced by renal failure cannot be a credible indicator of body iron supply, while under this certain condition serum transferrin receptor can more appropriately reflect the amount of body iron supply.

Anemia management trends in hospital-based dialysis centers (HBDCs), 2010 to 2013.

PubMed

Coritsidis, George N; Maglinte, Gregory A; Acharya, Anjali; Saxena, Anjali; Chang, Chun-Lan; Hill, Jerrold; Gitlin, Matthew; Lafayette, Richard A

2014-03-01

Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients. Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease-related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013. Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing. From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels <10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%. These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Silver vanadate nanoribbons: A label-free bioindicator in the conversion between human serum transferrin and apotransferrin via surface-enhanced Raman scattering

NASA Astrophysics Data System (ADS)

Zhou, Qing; Shao, Mingwang; Que, Ronghui; Cheng, Liang; Zhuo, Shujuan; Tong, Yanhua; Lee, Shuit-Tong

2011-05-01

Silver vanadate nanoribbons were synthesized via a hydrothermal process, which exhibited surface-enhanced Raman scattering effect. This surface-enhanced substrate was stable and reproducible for identifying human serum transferrin and human serum apotransferrin in the concentration of 1×10-5 M, which further exhibited significant sensitivity in monitoring the conversion of these two proteins in turn. This result showed that the silver vanadate nanoribbon might be employed as biomonitor in such systems.

Regulation of cellular iron metabolism

PubMed Central

Wang, Jian; Pantopoulos, Kostas

2011-01-01

Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance. PMID:21348856

Plasmonic nanodiamonds: targeted core-shell type nanoparticles for cancer cell thermoablation.

PubMed

Rehor, Ivan; Lee, Karin L; Chen, Kevin; Hajek, Miroslav; Havlik, Jan; Lokajova, Jana; Masat, Milan; Slegerova, Jitka; Shukla, Sourabh; Heidari, Hamed; Bals, Sara; Steinmetz, Nicole F; Cigler, Petr

2015-02-18

Targeted biocompatible nanostructures with controlled plasmonic and morphological parameters are promising materials for cancer treatment based on selective thermal ablation of cells. Here, core-shell plasmonic nanodiamonds consisting of a silica-encapsulated diamond nanocrystal coated in a gold shell are designed and synthesized. The architecture of particles is analyzed and confirmed in detail using electron tomography. The particles are biocompatibilized using a PEG polymer terminated with bioorthogonally reactive alkyne groups. Azide-modified transferrin is attached to these particles, and their high colloidal stability and successful targeting to cancer cells overexpressing the transferrin receptor are demonstrated. The particles are nontoxic to the cells and they are readily internalized upon binding to the transferrin receptor. The high plasmonic cross section of the particles in the near-infrared region is utilized to quantitatively ablate the cancer cells with a short, one-minute irradiation by a pulse 750-nm laser. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Iron metabolism mutant hbd mice have a deletion in Sec15l1, which has homology to a yeast gene for vesicle docking.

PubMed

White, Robert A; Boydston, Leigh A; Brookshier, Terri R; McNulty, Steven G; Nsumu, Ndona N; Brewer, Brandon P; Blackmore, Krista

2005-12-01

Defects in iron absorption and utilization lead to iron deficiency and anemia. While iron transport by transferrin receptor-mediated endocytosis is well understood, it is not completely clear how iron is transported from the endosome to the mitochondria where heme is synthesized. We undertook a positional cloning project to identify the causative mutation for the hemoglobin-deficit (hbd) mouse mutant, which suffers from a microcytic, hypochromic anemia apparently due to defective iron transport in the endocytosis cycle. As shown by previous studies, reticulocyte iron accumulation in homozygous hbd/hbd mice is deficient despite normal binding of transferrin to its receptor and normal transferrin uptake in the cell. We have identified a strong candidate gene for hbd, Sec15l1, a homologue to yeast SEC15, which encodes a key protein in vesicle docking. The hbd mice have an exon deletion in Sec15l1, which is the first known mutation of a SEC gene homologue in mammals.

Snx3 regulates recycling of the transferrin receptor and iron assimilation

PubMed Central

Chen, Caiyong; Garcia-Santos, Daniel; Ishikawa, Yuichi; Seguin, Alexandra; Li, Liangtao; Fegan, Katherine H.; Hildick-Smith, Gordon J.; Shah, Dhvanit I.; Cooney, Jeffrey D.; Chen, Wen; King, Matthew J.; Yien, Yvette Y.; Schultz, Iman J.; Anderson, Heidi; Dalton, Arthur J.; Freedman, Matthew L.; Kingsley, Paul D.; Palis, James; Hattangadi, Shilpa M.; Lodish, Harvey F.; Ward, Diane M.; Kaplan, Jerry; Maeda, Takahiro; Ponka, Prem; Paw, Barry H.

2013-01-01

SUMMARY Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc), and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism. PMID:23416069

Photometric flow analysis system for biomedical investigations of iron/transferrin speciation in human serum.

PubMed

Strzelak, Kamil; Rybkowska, Natalia; Wiśniewska, Agnieszka; Koncki, Robert

2017-12-01

The Multicommutated Flow Analysis (MCFA) system for the estimation of clinical iron parameters: Serum Iron (SI), Unsaturated Iron Binding Capacity (UIBC) and Total Iron Binding Capacity (TIBC) has been proposed. The developed MCFA system based on simple photometric detection of iron with chromogenic agent (ferrozine) enables a speciation of transferrin (determination of free and Fe-bound protein) in human serum. The construction of manifold was adapted to the requirements of measurements under changing conditions. In the course of studies, a different effect of proteins on SI and UIBC determination has been proven. That was in turn the reason to perform two kinds of calibration methods. For measurements in acidic medium for SI/holotransferrin determination, the calibration curve method was applied, characterized by limit of determination and limit of quantitation on the level of 3.4 μmol L -1 and 9.1 μmol L -1 , respectively. The determination method for UIBC parameter (related to apotransferrin level) in physiological medium of pH 7.4 forced the use of standard addition method due to the strong influence of proteins on obtaining analytical signals. These two different methodologies, performed in the presented system, enabled the estimation of all three clinical iron/transferrin parameters in human serum samples. TIBC corresponding to total transferrin level was calculated as a sum of SI and UIBC. Copyright © 2017 Elsevier B.V. All rights reserved.

Transferrin receptor-1 gene polymorphisms are associated with type 2 diabetes.

PubMed

Fernández-Real, José Manuel; Mercader, Josep Maria; Ortega, Francisco José; Moreno-Navarrete, Jose Maria; López-Romero, Pedro; Ricart, Wifredo

2010-07-01

Iron is involved in oxidative stress and type 2 diabetes (T2D). Transferrin receptor (TFRC) constitutes the major receptor by which most cells take up iron. The aim of this study was to evaluate whether TFRC gene polymorphisms are associated with T2D. We evaluated TFRC gene polymorphism (rs3817672, 210AG, S142G) in a sample of T2D patients and nondiabetic controls (n = 722), and 39 SNPs within the TFRC genomic region analysed by the Welcome Trust Case Control Consortium (WTCCC) (1921 T2D subjects and 3000 controls). In a subset of subjects, glucose tolerance and insulin sensitivity were also studied. The frequency of the G allele at the position 210 of the TFRC gene was significantly higher in T2D patients. Both GG and GA genotypes had a 69% (P < 0.01) greater risk of developing T2D estimated under a dominant model. The increased prevalence of the G allele run in parallel to increased sex-adjusted log-serum ferritin and slightly increased soluble transferrin receptor among patients with T2D. Furthermore, post-load glucose and insulin sensitivity were significantly associated with circulating soluble transferrin receptor, and insulin sensitivity was significantly associated with serum ferritin among G allele carriers, (r = -0.33, P = 0.001) but not in AA homozygotes. Sixteen other TFRC SNPs were also associated to T2D according to the Welcome Trust Case Control Consortium data. TFRC gene variants are associated with T2D.

The use of multiplexed MRM for the discovery of biomarkers to differentiate iron-deficiency anemia from anemia of inflammation.

PubMed

Domanski, Dominik; Cohen Freue, Gabriela V; Sojo, Luis; Kuzyk, Michael A; Ratkay, Leslie; Parker, Carol E; Goldberg, Y Paul; Borchers, Christoph H

2012-06-27

In this study we demonstrate the use of a multiplexed MRM-based assay to distinguish among normal (NL) and iron-metabolism disorder mouse models, particularly, iron-deficiency anemia (IDA), inflammation (INFL), and inflammation and anemia (INFL+IDA). Our initial panel of potential biomarkers was based on the analysis of 14 proteins expressed by candidate genes involved in iron transport and metabolism. Based on this study, we were able to identify a panel of 8 biomarker proteins: apolipoprotein A4 (APO4), transferrin, transferrin receptor 1, ceruloplasmin, haptoglobin, lactoferrin, hemopexin, and matrix metalloproteinase-8 (MMP8) that clearly distinguish among the normal and disease models. Within this set of proteins, transferrin showed the best individual classification accuracy over all samples (72%) and within the NL group (94%). Compared to the best single-protein biomarker, transferrin, the use of the composite 8-protein biomarker panel improved the classification accuracy from 94% to 100% in the NL group, from 50% to 72% in the INFL group, from 66% to 96% in the IDA group, and from 79% to 83% in the INFL+IDA group. Based on these findings, validation of the utility of this potentially important biomarker panel in human samples in an effort to differentiate IDA, inflammation, and combinations thereof, is now warranted. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. Copyright © 2011 Elsevier B.V. All rights reserved.

Encapsulation of zinc-rifampicin complex into transferrin-conjugated silver quantum-dots improves its antimycobacterial activity and stability and facilitates drug delivery into macrophages

PubMed Central

Pati, Rashmirekha; Sahu, Rojalin; Panda, Jagannath; Sonawane, Avinash

2016-01-01

In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and also to develop more efficient drug delivery systems. Here, we synthesized a novel anti-TB drug complex consisting of zinc and rifampicin (Zn-RIF), and encapsulated it into transferrin-conjugated silver quantum-dots (Zn-RIF-Tf-QD) to improve delivery in macrophages. Successful synthesis of Zn-RIF and Zn-RIF-Tf-QD was confirmed by UV/Vis-spectroscopy, TEM, FTIR, photoluminescence, XRD, XPS, and NMR. The sizes of silver QDs and transferrin-conjugated QDs were found to be in the range of 5–20 nm. Activity assays showed that Zn-RIF-Tf-QD exhibited 10-fold higher antibacterial activity against Mycobacterium smegmatis and Mycobacterium bovis-BCG as compared to Zn-RIF, RIF and Zn. Immunofluorescence studies showed that Zn-RIF-Tf-QD-conjugates were actively endocytosed by macrophages and dendritic cells, but not by lung epithelial cells. Treatment with Zn-RIF-Tf-QD efficiently killed mycobacteria residing inside macrophages without exhibiting cytotoxicity and genotoxicity. Moreover, the conjugates remained stable for upto 48 h, were taken up into the late endosomal compartment of macrophages, and released the drug in a sustainable manner. Our data demonstrate that Zn-RIF-Tf-QDs have a great potential as anti-TB drugs. In addition, transferrin-conjugated QDs may constitute an effective drug delivery system for tuberculosis therapy. PMID:27113139

A statistical method to calculate blood contamination in the measurement of salivary hormones in healthy women.

PubMed

Behr, Guilherme A; Patel, Jay P; Coote, Marg; Moreira, Jose C F; Gelain, Daniel P; Steiner, Meir; Frey, Benicio N

2017-05-01

Previous studies have reported that salivary concentrations of certain hormones correlate with their respective serum levels. However, most of these studies did not control for potential blood contamination in saliva. In the present study we developed a statistical method to test the amount of blood contamination that needs to be avoided in saliva samples for the following hormones: cortisol, estradiol, progesterone, testosterone and oxytocin. Saliva and serum samples were collected from 38 healthy, medication-free women (mean age=33.8±7.3yr.; range=19-45). Serum and salivary hormonal levels and the amount of transferrin in saliva samples were determined using enzyme immunoassays. Salivary transferrin levels did not correlate with salivary cortisol or estradiol (up to 3mg/dl), but they were positively correlated with salivary testosterone, progesterone and oxytocin (p<0.05). After controlling for blood contamination, only cortisol (r=0.65, P<0.001) and progesterone levels (r=0.57, P=0.002) displayed a positive correlation between saliva and serum. Our analyses suggest that transferrin levels higher than 0.80, 0.92 and 0.64mg/dl should be avoided for testosterone, progesterone and oxytocin salivary analyses, respectively. We recommend that salivary transferrin is measured in research involving salivary hormones in order to determine the level of blood contamination that might affect specific hormonal salivary concentrations. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Protocol to determine accurate absorption coefficients for iron containing transferrins

PubMed Central

James, Nicholas G.; Mason, Anne B.

2008-01-01

An accurate protein concentration is an essential component of most biochemical experiments. The simplest method to determine a protein concentration is by measuring the A280, using an absorption coefficient (ε), and applying the Beer-Lambert law. For some metalloproteins (including all transferrin family members) difficulties arise because metal binding contributes to the A280 in a non-linear manner. The Edelhoch method is based on the assumption that the ε of a denatured protein in 6 M guanidine-HCl can be calculated from the number of the tryptophan, tyrosine, and cystine residues. We extend this method to derive ε values for both apo- and iron-bound transferrins. The absorbance of an identical amount of iron containing protein is measured in: 1) 6 M guanidine-HCl (denatured, no iron); 2) pH 7.4 buffer (non-denatured with iron); and 3) pH 5.6 (or lower) buffer with a chelator (non-denatured without iron). Since the iron free apo-protein has an identical A280 under non-denaturing conditions, the difference between the reading at pH 7.4 and the lower pH directly reports the contribution of the iron. The method is fast and consumes ~1 mg of sample. The ability to determine accurate ε values for transferrin mutants that bind iron with a wide range of affinities has proven very useful; furthermore a similar approach could easily be followed to determine ε values for other metalloproteins in which metal binding contributes to the A280. PMID:18471984

Green Tea Polyphenols Require the Mitochondrial Iron Transporter, mitoferrin, for Lifespan Extension in Drosophila melanogaster

PubMed Central

Lopez, Terry E.; Pham, Hoang M.; Nguyen, Benjamin V.; Tahmasian, Yerazik; Ramsden, Shannon; Coskun, Volkan; Schriner, Samuel E.; Jafari, Mahtab

2016-01-01

Green tea has been found to increase the lifespan of various experimental animal models including the fruit fly, Drosophila melanogaster. High in polyphenolic content, green tea has been shown to reduce oxidative stress in part by its ability to bind free iron, a micronutrient that is both essential for and toxic to all living organisms. Due to green tea’s iron-binding properties, we questioned whether green tea acts to increase the lifespan of the fruit fly by modulating iron regulators, specifically, mitoferrin, a mitochondrial iron transporter, and transferrin, found in the hemolymph of flies. Publicly available hypomorph mutants for these iron-regulators were utilized to investigate the effect of green tea on lifespan and fertility. We identified that green tea could not increase the lifespan of mitoferrin mutants but did rescue the reduced male fertility phenotype. The effect of green tea on transferrin mutant lifespan and fertility were comparable to w1118 flies, as observed in our previous studies, in which green tea increased male fly lifespan and reduced male fertility. Expression levels in both w1118 flies and mutant flies, supplemented with green tea, showed an up-regulation of mitoferrin but not transferrin. Total body and mitochondrial iron levels were significantly reduced by green tea supplementation in w1118 and mitoferrin mutants but not transferrin mutant flies. Our results demonstrate that green tea may act to increase the lifespan of Drosophila in part by the regulation of mitoferrin and reduction of mitochondrial iron. PMID:27696504

In Vitro and In Vivo Biological Activities of Iron Chelators and Gallium Nitrate against Acinetobacter baumannii

PubMed Central

Harris, Greg; KuoLee, Rhonda; Chen, Wangxue

2012-01-01

We investigated the ability of compounds interfering with iron metabolism to inhibit the growth of Acinetobacter baumannii. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibited A. baumannii growth in vitro. Gallium nitrate alone was moderately effective at reducing A. baumannii growth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium-based therapies shows promise for the control of multidrug-resistant A. baumannii. PMID:22825117

In vitro and in vivo biological activities of iron chelators and gallium nitrate against Acinetobacter baumannii.

PubMed

de Léséleuc, Louis; Harris, Greg; KuoLee, Rhonda; Chen, Wangxue

2012-10-01

We investigated the ability of compounds interfering with iron metabolism to inhibit the growth of Acinetobacter baumannii. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibited A. baumannii growth in vitro. Gallium nitrate alone was moderately effective at reducing A. baumannii growth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium-based therapies shows promise for the control of multidrug-resistant A. baumannii.

Molecular cloning and nucleotide sequence of a transforming gene detected by transfection of chicken B-cell lymphoma DNA

NASA Astrophysics Data System (ADS)

Goubin, Gerard; Goldman, Debra S.; Luce, Judith; Neiman, Paul E.; Cooper, Geoffrey M.

1983-03-01

A transforming gene detected by transfection of chicken B-cell lymphoma DNA has been isolated by molecular cloning. It is homologous to a conserved family of sequences present in normal chicken and human DNAs but is not related to transforming genes of acutely transforming retroviruses. The nucleotide sequence of the cloned transforming gene suggests that it encodes a protein that is partially homologous to the amino terminus of transferrin and related proteins although only about one tenth the size of transferrin.

Indicators of nutritional status in restricting-type anorexia nervosa patients: a 1-year follow-up study.

PubMed

Nova, Esther; Lopez-Vidriero, Irene; Varela, Pilar; Toro, Olga; Casas, J José; Marcos, A Ascensión

2004-12-01

Despite severely reduced intakes, anorexia nervosa (AN) patients seem to maintain serum biochemical parameters within the safe limit. The aim of this study was to assess the evolution of some traditional serum biochemical indicators of nutritional status in a 1-year follow-up of patients with restricting-type AN. 14 adolescent female patients were studied at four different time points: (1) on hospital admission (t0), (2) 1 month later (t1), (3) 6 months after admission (t6) and (4) 12 months after admission (t12). At each time point serum albumin, prealbumin, retinol-binding protein, transferrin, complement factors C3 and C4, zinc and iron status were analysed. 15 healthy adolescents formed the control group. Among the liver-synthesised proteins, a significant time effect was only demonstrated on transferrin and C3 and C4 (ANOVA, P<0.05). Transferrin level in patients on admission was lower than in controls, increased significantly during the first month and showed an opposite pattern in subjects gaining and non-gaining weight between t1 and t12, decreasing only in the group failing to gain further weight. C3 and C4 decreased significantly in t12. Changes in ferritin and zinc showed significant negative correlations with changes in anthropometrical parameters. The changes in transferrin, C3 and C4 levels during the out-patient treatment reveal an increased risk of relapses after 1 year since hospital admission. Ferritin and zinc levels seem to be affected by the nutrient requirements for anabolic processes during nutritional recovery.

Primary care requests for anaemia chemistry tests in Spain: potential iron, transferrin and folate over-requesting.

PubMed

Salinas, Maria; López-Garrigós, Maite; Flores, Emilio; Leiva-Salinas, Carlos

2017-09-01

To study the regional variability of requests for anaemia chemistry tests in primary care in Spain and the associated economic costs of potential over-requesting. Requests for anaemia tests were examined in a cross-sectional study. Clinical laboratories from different autonomous communities (AACCs) were invited to report on primary care anaemia chemistry tests requested during 2014. Demand for iron, ferritin, vitamin B12 and folate tests per 1000 inhabitants and the ratios of the folate/vitamin B12 and transferrin/ferritin requests were compared between AACCs. We also calculated reagent costs and the number of iron, transferrin and folate tests and the economic saving if every AACC had obtained the results achieved by the AACC with best practice. 110 laboratories participated (59.8% of the Spanish population). More than 12 million tests were requested, resulting in reagent costs exceeding €16.5 million. The serum iron test was the most often requested, and the ferritin test was the most costly (over €7 million). Close to €4.5 million could potentially have been saved if iron, transferrin and folate had been appropriately requested (€6 million when extrapolated to the whole Spanish population). The demand for and expenditure on anaemia chemistry tests in primary care in Spain is high, with significant regional differences between different AACCs. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

How the Binding of Human Transferrin Primes the Transferrin Receptor Potentiating Iron Release at Endosomal pH

DOE Office of Scientific and Technical Information (OSTI.GOV)

B Eckenroth; A Steere; N Chasteen

2011-12-31

Delivery of iron to cells requires binding of two iron-containing human transferrin (hTF) molecules to the specific homodimeric transferrin receptor (TFR) on the cell surface. Through receptor-mediated endocytosis involving lower pH, salt, and an unidentified chelator, iron is rapidly released from hTF within the endosome. The crystal structure of a monoferric N-lobe hTF/TFR complex (3.22-{angstrom} resolution) features two binding motifs in the N lobe and one in the C lobe of hTF. Binding of Fe{sub N}hTF induces global and site-specific conformational changes within the TFR ectodomain. Specifically, movements at the TFR dimer interface appear to prime the TFR to undergomore » pH-induced movements that alter the hTF/TFR interaction. Iron release from each lobe then occurs by distinctly different mechanisms: Binding of His349 to the TFR (strengthened by protonation at low pH) controls iron release from the C lobe, whereas displacement of one N-lobe binding motif, in concert with the action of the dilysine trigger, elicits iron release from the N lobe. One binding motif in each lobe remains attached to the same {alpha}-helix in the TFR throughout the endocytic cycle. Collectively, the structure elucidates how the TFR accelerates iron release from the C lobe, slows it from the N lobe, and stabilizes binding of apohTF for return to the cell surface. Importantly, this structure provides new targets for mutagenesis studies to further understand and define this system.« less

An immunohistochemical study of placental syncytiotrophoblasts in neonatal hemochromatosis.

PubMed

Shimono, Aiko; Imoto, Yuko; Sakamoto, Haruhiko; Chiba, Yoichi; Matsumoto, Koichi; Kawauchi, Machi; Kusaka, Takashi; Tanaka, Hirokazu; Hata, Toshiyuki; Kushida, Yoshio; Ueno, Masaki

2016-12-01

Neonatal hemochromatosis (NH) is a rare neonatal disorder that results in liver cirrhosis with hemosiderin deposition in the liver and other organs, similarly to hereditary hemochromatosis. Excess iron is transferred from the mother to fetus through the placenta in NH. We examined the expression of iron metabolism-related substances in placental syncytiotrophoblasts (STB) by immunostaining to clarify how the transfer of iron through STB increases in NH. Immunostaining was performed using formalin-fixed, paraffin-embedded sections of placentae from three NH cases, four gestational age-matched controls, and, depending on the antibody examined, five to seven full-term controls. The reactivity of immunostaining was assessed by averages of scores assigned by 3 researchers. On the microvillar surface of STB, the reactions of the antibodies against transferrin receptor 1 (TFR1), transferrin, ferritin, hepcidin, ferroportin, divalent metal transporter-1 (DMT1), hephaestin, and HFE were stronger in NH than in controls. In the cytoplasm, the reactions of antibodies against TFR1, transferrin, ferritin, hepcidin, DMT1, hephaestin, HFE, and ZIP 14 were stronger in NH than in gestational age-matched controls. Among these reactions, those of anti-TFR1 antibody on the surface of STB in NH was especially marked. In the placenta of NH, increases in expressions of TFR1, transferrin, and ferritin of which those of TFR1 were especially marked, reflect increased iron influx from the mother to fetus. The hepcidin observed on the surface and in the cytoplasm of STB of NH is suggested to be from the mother, possibly to compensate for the decreased fetal liver-derived hepcidin. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biodegradable Eri silk nanoparticles as a delivery vehicle for bovine lactoferrin against MDA-MB-231 and MCF-7 breast cancer cells

PubMed Central

Roy, Kislay; Patel, Yogesh S; Kanwar, Rupinder K; Rajkhowa, Rangam; Wang, Xungai; Kanwar, Jagat R

2016-01-01

This study used the Eri silk nanoparticles (NPs) for delivering apo-bovine lactoferrin (Apo-bLf) (~2% iron saturated) and Fe-bLf (100% iron saturated) in MDA-MB-231 and MCF-7 breast cancer cell lines. Apo-bLf and Fe-bLf-loaded Eri silk NPs with sizes between 200 and 300 nm (±10 nm) showed a significant internalization within 4 hours in MDA-MB-231 cells when compared to MCF-7 cells. The ex vivo loop assay with chitosan-coated Fe-bLf-loaded silk NPs was able to substantiate its future use in oral administration and showed the maximum absorption within 24 hours by ileum. Both Apo-bLf and Fe-bLf induced increase in expression of low-density lipoprotein receptor-related protein 1 and lactoferrin receptor in epidermal growth factor (EGFR)-positive MDA-MB-231 cells, while transferrin receptor (TfR) and TfR2 in MCF-7 cells facilitated the receptor-mediated endocytosis of NPs. Controlled and sustained release of both bLf from silk NPs was shown to induce more cancer-specific cytotoxicity in MDA-MB-231 and MCF-7 cells compared to normal MCF-10A cells. Due to higher degree of internalization, the extent of cytotoxicity and apoptosis was significantly higher in MDA-MB-231 (EGFR+) cells when compared to MCF-7 (EGFR−) cells. The expression of a prominent anticancer target, survivin, was found to be downregulated at both gene and protein levels. Taken together, all the observations suggest the potential use of Eri silk NPs as a delivery vehicle for an anti-cancer milk protein, and indicate bLf for the treatment of breast cancer. PMID:26730188

Characterization of iron uptake from transferrin by murine endothelial cells.

PubMed

Hallmann, R; Savigni, D L; Morgan, E H; Baker, E

2000-01-01

Iron is required by the brain for normal function, however, the mechanisms by which it crosses the blood-brain barrier (BBB) are poorly understood. The uptake and efflux of transferrin (Tf) and Fe by murine brain-derived (bEND3) and lymph node-derived (m1END1) endothelial cell lines was compared. The effects of iron chelators, metabolic inhibitors and the cellular activators, lipopolysaccharide (LPS) and tumour necrosis factor-alpha (TNF-alpha), on Tf and Fe uptake were investigated. Cells were incubated with 59Fe-125I-Tf; Fe uptake was shown to increase linearly over time for both cell lines, while Tf uptake reached a plateau within 2 h. Both Tf and Fe uptake were saturable. bEND3 cells were shown to have half as many Tf receptors as m1END1 cells, but the mean cycling times of a Tf molecule were the same. Tf and Fe efflux from the cells were measured over time, revealing that after 2 h only 25% of the Tf but 80% of the Fe remained associated with the cells. Of 7 iron chelators, only deferriprone (L1) markedly decreased Tf uptake. However, Fe uptake was reduced by more than 50% by L1, pyridoxal isonicotinoyl hydrazone (PIH) and desferrithiocin (DFT). The cellular activators TNF-alpha or LPS had little effect on Tf turnover, but they accelerated Fe uptake in both endothelial cell types. Phenylarsenoxide (PhAsO) and N-ethyl maleimide (NEM), inhibitors of Tf endocytosis, reduced both Tf and Fe uptake in both cell lines, while bafilomycin A1, an inhibitor of endosomal acidification, reduced Fe uptake but did not affect Tf uptake. The results suggest that Tf and Fe uptake by both bEND3 and m1END1 is via receptor-mediated endocytosis with release of Fe from Tf within the cell and recycling of apo-Tf. On the basis of Tf- and Fe-metabolism both cell lines are similar and therefore well suited for use in in vitro models for Fe transport across the BBB.

Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency.

PubMed

Sultana, Tanjim; DeVita, Maria V; Michelis, Michael F

2016-09-01

Functional iron deficiency (FID) is a major cause of persistent anemia in dialysis patients and also contributes to a suboptimal response to erythropoietin (Epo) administration. Vitamin C acts as an enzyme cofactor and enhances mobilization of the ferrous form of iron to transferrin thus increasing its bioavailability. High-dose intravenous vitamin C has been shown to decrease the Epo requirement and improve hemoglobin levels in previous studies. This study assessed the effect of low-dose oral vitamin C on possible reduction in Epo dose requirements in stable hemodialysis patients with FID. This prospective study included 22 stable hemodialysis patients with FID defined as transferrin saturation (T sat) <30 % and ferritin levels of >100 mcg/L with Epo requirement of ≥4000 U/HD session. Patients received oral vitamin C 250 mg daily for 3 months. Hemoglobin, iron and T sat levels were recorded monthly. No one received iron supplementation during the study period. There was a significant reduction in median Epo dose requirement in the 15 patients who completed the study, from 203.1 U/kg/week (95 % CI 188.4-270.6) to 172.8 U/kg/week (95 % CI 160.2-214.8), (P = 0.01). In the seven responders, there was 33 % reduction in Epo dose from their baseline. Despite adjustment of Epo dose, the mean hemoglobin level was significantly increased from 10.1 ± 0.6 to 10.7 ± 0.6 mg/dL (P = 0.03). No adverse effects of oral vitamin C were observed. Daily low-dose oral vitamin C supplementation reduced Epo dose requirements in hemodialysis patients with FID. Limitations of this study include a small sample size and the lack of measurements of vitamin C and oxalate levels. Despite concerns regarding oral vitamin C absorption in dialysis patients, this study indicates vitamin C was well tolerated by all participants without reported adverse effect.

Evaluation of a workplace hemochromatosis screening program.

PubMed

Stave, G M; Mignogna, J J; Powell, G S; Hunt, C M

1999-05-01

Hemochromatosis is a common inherited disorder of iron metabolism with significant health consequences for the employed population. Although screening for hemochromatosis has been recommended, workplace screening programs remain uncommon. In the first year of a newly initiated corporate screening program, 1968 employees were tested. The screening algorithm included measurement of serum iron and transferrin and subsequent ferritin levels in those employees with elevated iron/transferrin ratios. Thirteen percent of men and 21% of women had elevated iron/transferrin ratios. Of these, 14 men and 2 women had elevated ferritin levels. Of these 16, three had liver biopsies and all three have hemochromatosis. The cost of the screening program was $27,850. The cost per diagnosis was $9283 and the cost per year of life saved was $928. These costs compare very favorably with other common workplace screening programs. Several barriers to obtaining definitive diagnoses on all patients with a positive screening result were identified; strategies to overcome these barriers would further enhance the cost effectiveness of the program. We conclude that workplace hemochromatosis screening is highly cost effective and should be incorporated into health promotion/disease prevention programs.

Polydopamine-based functional composite particles for tumor cell targeting and dual-mode cellular imaging.

PubMed

Zhou, Yalei; Zhou, Jie; Wang, Feng; Yang, Haifeng

2018-05-01

Particles which bear tumor cell targeting and multimode imaging capabilities are promising in tumor diagnosis and cancer therapy. A simple and versatile method to fabricate gold/polydopamine-Methylene Blue@Bovine Serum Albumin-glutaraldehyde-Transferrin composite particles (Au/PDA-MB@BSA-GA-Tf NPs) for tumor cell targeting and fluorescence (FL) / surface-enhanced Raman scattering (SERS) dual-modal imaging were reported in this work. Polydopamine (PDA) spheres played an important role in gold ion reduction, gold nanoparticle (Au NPs) binding and methylene blue (MB) adsorption, MB were employed as both fluorescence label and Raman reporter. In addition, glutaraldehyde (GA) crosslinked bovine serum albumin (BSA) in the outer layer of Au/PDA-MB nanoparticles can prevent MB from dissociation and leakage. The composite nanoparticles were further conjugated with transferrin (Tf) to target transferrin receptor (TfR)-overexpressed cancer cells. The targeting ability as well as the intracellular location of the probe was investigated through SERS mapping and fluorescence imaging. Their excellent biocompatibility was demonstrated by low cytotoxicity against breast cancer cell (4T1 cell). Copyright © 2018 Elsevier B.V. All rights reserved.

Phylogenetic survey of soluble saxitoxin-binding activity in pursuit of the function and molecular evolution of saxiphilin, a relative of transferrin.

PubMed Central

Llewellyn, L E; Bell, P M; Moczydlowski, E G

1997-01-01

Saxiphilin is a soluble protein of unknown function which binds the neurotoxin, saxitoxin (STX), with high affinity. Molecular characterization of saxiphilin from the North American bullfrog, Rana catesbeiana, has previously shown that it is a member of the transferrin family. In this study we surveyed various animal species to investigate the phylogenetic distribution of saxiphilin, as detected by the presence of soluble [3H]STX binding activity in plasma, haemolymph or tissue extracts. We found that saxiphilin activity is readily detectable in a wide variety of arthropods, fish, amphibians, and reptiles. The pharmacological characteristics of [3H]STX binding activity in phylogenetically diverse species indicates that a protein homologous to bullfrog saxiphilin is likely to be constitutively expressed in many ectothermic animals. The results suggest that the saxiphilin gene is evolutionarily as old as an ancestral gene encoding bilobed transferrin, an Fe(2+)-binding and transport protein which has been identified in several arthropods and all the vertebrates which have been studied. PMID:9225480

Tucum-Do-Cerrado (Bactris setosa Mart.) Consumption Modulates Iron Homeostasis and Prevents Iron-Induced Oxidative Stress in the Rat Liver

PubMed Central

Fustinoni-Reis, Adriana M.; Arruda, Sandra F.; Dourado, Lívia P. S.; da Cunha, Marcela S. B.; Siqueira, Egle M. A.

2016-01-01

This study investigated the effect of tucum-do-cerrado consumption in the oxidative status of iron-supplemented rats. Four groups of rats were treated: Control (AIN-93G), Tuc (AIN-93G added of tucum-do-cerrado), Fe (AIN-93G iron-enriched), or TucFe (AIN-93G with tucum-do-cerrado and iron-enriched) diet, for 30 days. Iron-enriched diet increased serum, liver, spleen, and intestine iron levels; transferrin saturation; liver lipid oxidation; mRNA levels of hepatic Hamp and Bmp6, and Nrf2 in the intestine. Tucum-do-cerrado consumption reduced spleen lipid and protein oxidation; mRNA levels of hepatic Hamp and Ftl, and increased serum antioxidant capacity and hepatic mRNA levels of Bmp6, Hmox1, Nqo1, and Nrf2. TucFe diet consumption abrogated the liver Hamp iron-induced up-regulation, prevented intestinal iron accumulation; hepatic lipid peroxidation; splenic protein damage, and the increase of catalase, glutathione reductase, and glutathione peroxidase activity in some tissues. These results suggest that tucum-do-cerrado protects tissues against oxidative damage, by reducing iron availability in liver and consequently inhibiting liver Hamp expression. PMID:26901220

Association between sex, systemic iron variation and probability of Parkinson's disease.

PubMed

Mariani, S; Ventriglia, M; Simonelli, I; Bucossi, S; Siotto, M; Donno, S; Vernieri, F; Squitti, R

2016-01-01

Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD. In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins. The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation. This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex.

Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study.

PubMed

Cançado, Rodolfo; Melo, Murilo R; de Moraes Bastos, Roberto; Santos, Paulo C J L; Guerra-Shinohara, Elivira M; Chiattone, Carlos; Ballas, Samir K

2015-12-01

This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Polyglobulia and bronchopneumopathies: correlations of ferritin and other ferric parameters with various erythrocytic indexes].

PubMed

Sánchez Sánchez, M L; Ciriza de los Ríos, C; Arroyo Vicente, M; Ortega de Heredia, D; Arroyo Ordóñez, M J; Rubio Pérez, P

1993-08-01

In 15 patients with chronic bronchopneumopathy (7 with polyglobulia and 8 without it), we observed that polyglobulic patients had higher average levels of sideremia and basal saturation of transferrin and lower levels of HCM, CHCM and VCM. No significant differences were observed in the average levels of ferritin between both groups. Overall, in this series of 15 patients, a significant inverse correlation was observed between sideremia and HCM (r = -0.52; p < 0.05) and between sideremia and CHCM (r = -0.55, p < 0.5), as well as a trend towards a direct correlation between sideremia and the red blood cells count (r = 0.45, N.S.). There was also a direct correlation between serum ferritin and the sedimentation rate (r = 0.72, p < 0.01) and trends towards inverse correlations although not significant, between ferritin and sideremia (r = -0.25, N.S.). These data reflect a hyperconsumption of iron in the respiratory polyglobulia, with some relative deficit, suggesting as well that serum ferritin is not a good enough criteria in these cases for the evaluation of iron deposits, because it behaves like the sedimentation rate with respect to acute phase reactants when there is inflammation.

Factors affecting response and tolerability to ferumoxytol in nondialysis chronic kidney disease patients.

PubMed

Fishbane, Steven; Bolton, W Kline; Winkelmayer, Wolfgang C; Strauss, William; Li, Zhu; Pereira, Brian J G

2012-09-01

Ferumoxytol is a unique intravenous (i.v.) iron therapy. This report examines factors affecting hemoglobin response to i.v. ferumoxytol, and the relationship between hematologic parameters, concomitant erythropoiesis-stimulating agents (ESA), and adverse events (AEs) in nondialysis CKD patients. A series of post-hoc efficacy and safety analyses were performed using pooled data from two identically designed Phase III studies in 608 nondialysis CKD patients randomized to receive two 510 mg i.v. injections of ferumoxytol within 5 ± 3 days versus oral iron. Ferumoxytol resulted in a significant increase in hemoglobin in the presence and absence of ESA, and across a range of baseline hemoglobin, transferrin saturation, ferritin, and reticulocyte hemoglobin content levels. Adverse event rates with ferumoxytol were similar across quartiles of change in hemoglobin; there were no trends suggesting an increased rate of cardiovascular AEs with higher maximum achieved hemoglobin or faster rate of hemoglobin rise. There was no meaningful difference in the rate of AEs, serious AEs, and cardiovascular AEs between patients receiving or not receiving ESA. These analyses add to the knowledge of predictors of response and safety outcomes associated with i.v. iron therapy in nondialysis CKD patients.

New Insights on β-Thalassemia in the Palestinian Population of Gaza: High Frequency and Milder Phenotype Among Homozygous IVS-I-1 (HBB: c.92+1G>A) Patients with High Levels of Hb F.

PubMed

Ghoti, Hussam; Fibach, Eitan; Rachmilewitz, Eliezer A; Jeadi, Hisham; Filon, Dvora

2017-03-01

β-Thalassemia (β-thal) is a very common disease in the Palestinian population of the Gaza Strip. We studied their mutation frequency and clinical features. Thirteen different mutations were identified. The most common mutation was IVS-I-1 (G>A) (HBB: c.92+1G>A), which was prevalent in 31.5% of the thalassemia alleles studied. The IVS-I-110 (G>A) (HBB: c.93-21G>A) mutation was found in 25.0% of the alleles. Homozygotes for the IVS-I-1 mutation had higher mean hemoglobin (Hb) levels, required less blood transfusions, and lower transferrin saturation than the homozygotes for the IVS-I-110 mutation. This milder phenotype was, most likely, the result of the persistent production of Hb F; it was 9-fold higher in absolute terms (g/dL) and 7.7-fold higher in relative terms (percentage of total Hb). About half of our IVS-I-1 patients carried the XmnI polymorphism, which is known to be associated with elevated Hb F levels.

[Marked hemosiderosis in myelodysplastic syndrome].

PubMed

Klinz, C

1999-01-29

A 68-year-old man was admitted because of symptoms of lumbar pain. He was known to have chronic anemia with ring sideroblasts and diabetes melitus and to be in heart failure. Three months before he had been given 7 units of red cell concentrate. On admission the outstanding features were brown discoloration of the skin, absent body hair, tachycardia, hepatomegaly and small testicles. He had a normocytic anemia, hyperglycemia and raised transaminases, hypogonadism and vitamin D3 deficiency. The serum levels of iron, transferrin saturation and feritin were markedly elevated. Liver iron content/g dried liver was 4.2 g (by biomagnetometer). Radiology of the lumbar vertebrae showed osteoporosis and sonography confirmed hepatomegaly. The known myelodysplastic syndrome (MDS) had fed to secondary hemosiderosis with heart failure, liver involvement, diabetes mellitus, hypogonadism and osteoporosis. Symptomatic treatment was unsuccessfully complemented by desferoxamine (up to 4 g/12 h) to release iron. But very good iron excretion was then achieved with deferiprone (3 x 1 g/d). The patient later died of the sequelae of hemosiderosis. Even when they have not required transfusions, patients with long-standing MDS should be examined regularly for the possible development of secondary hemosiderosis so that iron-chelating agents can be administered as needed.

Iron-Dependent Regulation of Hepcidin in Hjv−/− Mice: Evidence That Hemojuvelin Is Dispensable for Sensing Body Iron Levels

PubMed Central

Daba, Alina; Wagner, John; Sebastiani, Giada; Pantopoulos, Kostas

2014-01-01

Hemojuvelin (Hjv) is a bone morphogenetic protein (BMP) co-receptor involved in the control of systemic iron homeostasis. Functional inactivation of Hjv leads to severe iron overload in humans and mice due to marked suppression of the iron-regulatory hormone hepcidin. To investigate the role of Hjv in body iron sensing, Hjv−/− mice and isogenic wild type controls were placed on a moderately low, a standard or a high iron diet for four weeks. Hjv−/− mice developed systemic iron overload under all regimens. Transferrin (Tf) was highly saturated regardless of the dietary iron content, while liver iron deposition was proportional to it. Hepcidin mRNA expression responded to fluctuations in dietary iron intake, despite the absence of Hjv. Nevertheless, iron-dependent upregulation of hepcidin was more than an order of magnitude lower compared to that seen in wild type controls. Likewise, iron signaling via the BMP/Smad pathway was preserved but substantially attenuated. These findings suggest that Hjv is not required for sensing of body iron levels and merely functions as an enhancer for iron signaling to hepcidin. PMID:24409331

Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients.

PubMed

Repnik, Katja; Koder, Silvo; Skok, Pavel; Ferkolj, Ivan; Potočnik, Uroš

2016-08-01

Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients.

Separation by hydrophobic interaction chromatography and structural determination by mass spectrometry of mannosylated glycoforms of a recombinant transferrin-exendin-4 fusion protein from yeast.

PubMed

Zolodz, Melissa D; Herberg, John T; Narepekha, Halyna E; Raleigh, Emily; Farber, Matthew R; Dufield, Robert L; Boyle, Denis M

2010-01-08

Obtaining sufficient amounts of pure glycoprotein variants to characterize their structures is an important goal in both functional biology and the biotechnology industry. We have developed preparative HIC conditions that resolve glycoform variants on the basis of overall carbohydrate content for a recombinant transferrin-exendin-4 fusion protein. The fusion protein was expressed from the yeast Saccharomyces cerevisiae from high density fermentation and is post-translationally modified with mannose sugars through O-glycosidic linkages. Overall hydrophobic behavior appeared to be dominated by the N-terminal 39 amino acids from the exendin-4 and linker peptide sequences as compared to the less hydrophobic behavior of human transferrin alone. In addition, using LC techniques that measure total glycans released from the pure protein combined with new high resolution technologies using mass spectrometry, we have determined the locations and chain lengths of mannose residues on specific peptides derived from tryptic maps of the transferrin-exendin-4 protein. Though the protein is large (80,488kDa) and contains 78 possible serine and threonine residues as potential sites for sugar addition, mannosylation was observed on only two tryptic peptides located within the first 55 amino acids of the N-terminus. These glycopeptides were highly heterogeneous and contained between 1 and 10 mannose residues scattered among the various serine and threonine sites which were identified by electron transfer dissociation mass spectrometry. Glycan sequences from 1 to 6 linear mannose residues were detected, but mannose chain lengths of 3 or 4 were more common and formed 80% of the total oligosaccharides. This work introduces new technological capabilities for the purification and characterization of glycosylated variants of therapeutic recombinant proteins. Copyright 2009 Elsevier B.V. All rights reserved.

Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells.

PubMed

Mizutani, Taketoshi; Ishizaka, Aya; Nihei, Coh-Ichi

2016-02-05

As a possible route for invasion of the CNS, circulating poliovirus (PV) in the blood is believed to traverse the blood-brain barrier (BBB), resulting in paralytic poliomyelitis. However, the underlying mechanism is poorly understood. In this study, we demonstrated that mouse transferrin receptor 1 (mTfR1) is responsible for PV attachment to the cell surface, allowing invasion into the CNS via the BBB. PV interacts with the apical domain of mTfR1 on mouse brain capillary endothelial cells (MBEC4) in a dose-dependent manner via its capsid protein (VP1). We found that F-G, G-H, and H-I loops in VP1 are important for this binding. However, C-D, D-E, and E-F loops in VP1-fused Venus proteins efficiently penetrate MBEC4 cells. These results imply that the VP1 functional domain responsible for cell attachment is different from that involved in viral permeation of the brain capillary endothelium. We observed that co-treatment of MBEC4 cells with excess PV particles but not dextran resulted in blockage of transferrin transport into cells. Using the Transwell in vitro BBB model, transferrin co-treatment inhibited permeation of PV into MBEC4 cells and delayed further viral permeation via mTfR1 knockdown. With mTfR1 as a positive mediator of PV-host cell attachment and PV permeation of MBEC4 cells, our results indicate a novel role of TfR1 as a cellular receptor for human PV receptor/CD155-independent PV invasion of the CNS. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Effect of dietary cadmium on iron metabolism in growing rats.

PubMed

Crowe, A; Morgan, E H

1997-07-01

Little is known regarding the interactions between iron and cadmium during postnatal development. This study examined the effect of altered levels of dietary iron and cadmium loading on the distribution of cadmium and iron in developing rats ages 15, 21, and 63 days. The uptake of iron, transferrin, and cadmium into various organs was also examined using 59Fe, [125I]transferrin, and 109Cd. Dietary cadmium loading reduced packed cell volume and plasma iron and nonheme iron levels in the liver and kidneys, evidence of the inducement of an iron deficient state. Dietary iron loading was able to reverse these effects, suggesting that they were the result of impaired intestinal absorption of iron. Cadmium loading resulted in cadmium concentrations in the liver and kidneys up to 20 microg/g in rats age 63 days, while cadmium levels in the brain reached only 0.16 microg/g, indicating that the blood-brain barrier restricts the entry of cadmium into the brain. Iron loading had little effect on cadmium levels in the organs and cadmium feeding did not lower tissue iron levels in iron loaded animals. These results suggest that cadmium inhibits iron absorption only at low to normal levels of dietary iron and that at high levels of intake iron and cadmium are largely absorbed by other, noncompetitive mechanisms. It was shown that 109Cd is removed from the plasma extremely quickly irrespective of iron status and deposits mainly in the liver. One of the most striking effects of cadmium loading on iron metabolism was increased uptake of [125I]transferrin by the heart, possibly by disrupting the process of receptor-mediated endocytosis and recycling of transferrin by heart muscle.

Elevated temperature inhibits recruitment of transferrin-positive vesicles and induces iron-deficiency genes expression in Aiptasia pulchella host-harbored Symbiodinium.

PubMed

Song, Po-Ching; Wu, Tsung-Meng; Hong, Ming-Chang; Chen, Ming-Chyuan

2015-10-01

Coral bleaching is the consequence of disruption of the mutualistic Cnidaria-dinoflagellate association. Elevated seawater temperatures have been proposed as the most likely cause of coral bleaching whose severity is enhanced by a limitation in the bioavailability of iron. Iron is required by numerous organisms including the zooxanthellae residing inside the symbiosome of cnidarian cells. However, the knowledge of how symbiotic zooxanthellae obtain iron from the host cells and how elevated water temperature affects the association is very limited. Since cellular iron acquisition is known to be mediated through transferrin receptor-mediated endocytosis, a vesicular trafficking pathway specifically regulated by Rab4 and Rab5, we set out to examine the roles of these key proteins in the iron acquisition by the symbiotic Symbiodinium. Thus, we hypothesized that the iron recruitments into symbiotic zooxanthellae-housed symbiosomes may be dependent on rab4/rab5-mediated fusion with vesicles containing iron-bound transferrins and will be retarded under elevated temperature. In this study, we cloned a novel monolobal transferrin (ApTF) gene from the tropical sea anemone Aiptasia pulchella and confirmed that the association of ApTF with A. pulchella Rab4 (ApRab4) or A. pulchella Rab5 (ApRab5) vesicles is inhibited by elevated temperature through immunofluorescence analysis. We confirmed the iron-deficient phenomenon by demonstrating the induced overexpression of iron-deficiency-responsive genes, flavodoxin and high-affinity iron permease 1, and reduced intracellular iron concentration in zooxanthellae under desferrioxamine B (iron chelator) and high temperature treatment. In conclusion, our data are consistent with algal iron deficiency being a contributing factor for the thermal stress-induced bleaching of symbiotic cnidarians. Copyright © 2015 Elsevier Inc. All rights reserved.

A nanocomposite of Au-AgI core/shell dimer as a dual-modality contrast agent for x-ray computed tomography and photoacoustic imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orza, Anamaria; Wu, Hui; Li, Yuancheng

Purpose: To develop a core/shell nanodimer of gold (core) and silver iodine (shell) as a dual-modal contrast-enhancing agent for biomarker targeted x-ray computed tomography (CT) and photoacoustic imaging (PAI) applications. Methods: The gold and silver iodine core/shell nanodimer (Au/AgICSD) was prepared by fusing together components of gold, silver, and iodine. The physicochemical properties of Au/AgICSD were then characterized using different optical and imaging techniques (e.g., HR- transmission electron microscope, scanning transmission electron microscope, x-ray photoelectron spectroscopy, energy-dispersive x-ray spectroscopy, Z-potential, and UV-vis). The CT and PAI contrast-enhancing effects were tested and then compared with a clinically used CT contrast agentmore » and Au nanoparticles. To confer biocompatibility and the capability for efficient biomarker targeting, the surface of the Au/AgICSD nanodimer was modified with the amphiphilic diblock polymer and then functionalized with transferrin for targeting transferrin receptor that is overexpressed in various cancer cells. Cytotoxicity of the prepared Au/AgICSD nanodimer was also tested with both normal and cancer cell lines. Results: The characterizations of prepared Au/AgI core/shell nanostructure confirmed the formation of Au/AgICSD nanodimers. Au/AgICSD nanodimer is stable in physiological conditions for in vivo applications. Au/AgICSD nanodimer exhibited higher contrast enhancement in both CT and PAI for dual-modality imaging. Moreover, transferrin functionalized Au/AgICSD nanodimer showed specific binding to the tumor cells that have a high level of expression of the transferrin receptor. Conclusions: The developed Au/AgICSD nanodimer can be used as a potential biomarker targeted dual-modal contrast agent for both or combined CT and PAI molecular imaging.« less

Serum protein polymorphisms in a Liberian population.

PubMed

Willcox, M; Beckman, G; Beckman, L

1986-01-01

Serum protein variations were studied in a Liberian population living in Buchanan town. Of the alpha 1-antitrypsin genes only M1 and M3 were polymorphic. The frequencies of the haptoglobin and Gc genes were in accordance with earlier known estimates in African populations. There was, however, a relatively low frequency of Hp 0 which may be related to the low malarial parasite prevalence in this group. The transferrin C2 gene was found in a significantly lower frequency among Liberians compared to European and Asiatic populations. A new transferrin variant was observed by isoelectric focusing. This variant could not be identified with conventional starch or polyacrylamide electrophoresis.

High Throughput ELISAs to Measure a Unique Glycan on Transferrin in Cerebrospinal Fluid: A Possible Extension toward Alzheimer's Disease Biomarker Development

PubMed Central

Shirotani, Keiro; Futakawa, Satoshi; Nara, Kiyomitsu; Hoshi, Kyoka; Saito, Toshie; Tohyama, Yuriko; Kitazume, Shinobu; Yuasa, Tatsuhiko; Miyajima, Masakazu; Arai, Hajime; Kuno, Atsushi; Narimatsu, Hisashi; Hashimoto, Yasuhiro

2011-01-01

We have established high-throughput lectin-antibody ELISAs to measure different glycans on transferrin (Tf) in cerebrospinal fluid (CSF) using lectins and an anti-transferrin antibody (TfAb). Lectin blot and precipitation analysis of CSF revealed that PVL (Psathyrella velutina lectin) bound an unique N-acetylglucosamine-terminated N-glycans on “CSF-type” Tf whereas SSA (Sambucus sieboldiana agglutinin) bound α2,6-N-acetylneuraminic acid-terminated N-glycans on “serum-type” Tf. PVL-TfAb ELISA of 0.5 μL CSF samples detected “CSF-type” Tf but not “serum-type” Tf whereas SSA-TfAb ELISA detected “serum-type” Tf but not “CSF-type” Tf, demonstrating the specificity of the lectin-TfAb ELISAs. In idiopathic normal pressure hydrocephalus (iNPH), a senile dementia associated with ventriculomegaly, amounts of the SSA-reactive Tf were significantly higher than in non-iNPH patients, indicating that Tf glycan analysis by the high-throughput lectin-TfAb ELISAs could become practical diagnostic tools for iNPH. The lectin-antibody ELISAs of CSF proteins might be useful for diagnosis of the other neurological diseases. PMID:21876827

High Throughput ELISAs to Measure a Unique Glycan on Transferrin in Cerebrospinal Fluid: A Possible Extension toward Alzheimer's Disease Biomarker Development.

PubMed

Shirotani, Keiro; Futakawa, Satoshi; Nara, Kiyomitsu; Hoshi, Kyoka; Saito, Toshie; Tohyama, Yuriko; Kitazume, Shinobu; Yuasa, Tatsuhiko; Miyajima, Masakazu; Arai, Hajime; Kuno, Atsushi; Narimatsu, Hisashi; Hashimoto, Yasuhiro

2011-01-01

We have established high-throughput lectin-antibody ELISAs to measure different glycans on transferrin (Tf) in cerebrospinal fluid (CSF) using lectins and an anti-transferrin antibody (TfAb). Lectin blot and precipitation analysis of CSF revealed that PVL (Psathyrella velutina lectin) bound an unique N-acetylglucosamine-terminated N-glycans on "CSF-type" Tf whereas SSA (Sambucus sieboldiana agglutinin) bound α2,6-N-acetylneuraminic acid-terminated N-glycans on "serum-type" Tf. PVL-TfAb ELISA of 0.5 μL CSF samples detected "CSF-type" Tf but not "serum-type" Tf whereas SSA-TfAb ELISA detected "serum-type" Tf but not "CSF-type" Tf, demonstrating the specificity of the lectin-TfAb ELISAs. In idiopathic normal pressure hydrocephalus (iNPH), a senile dementia associated with ventriculomegaly, amounts of the SSA-reactive Tf were significantly higher than in non-iNPH patients, indicating that Tf glycan analysis by the high-throughput lectin-TfAb ELISAs could become practical diagnostic tools for iNPH. The lectin-antibody ELISAs of CSF proteins might be useful for diagnosis of the other neurological diseases.

Transferrin receptor-like proteins control the degradation of a yeast metal transporter

PubMed Central

Stimpson, Helen E M; Lewis, Michael J; Pelham, Hugh R B

2006-01-01

Plasma membrane transporters are often downregulated by their substrates. The yeast manganese transporter Smf1 is subject to two levels of regulation: heavy metals induce its sequestration within the cell, and also its ubiquitination and degradation in the vacuole. Degradation requires Bsd2, a membrane protein with a PPxY motif that recruits the ubiquitin ligase Rsp5, and which has a role in the quality control of membrane proteins, that expose hydrophilic residues to the lipid bilayer. We show that degradation of Smf1 requires in addition one of a pair of related yeast proteins, Tre1 and Tre2, that also contain PPxY motifs. Tre1 can partially inhibit manganese uptake without Bsd2, but requires Bsd2 to induce Smf1 degradation. It has a relatively hydrophilic transmembrane domain and binds to Bsd2. We propose that the Tre proteins specifically link Smf1 to the Bsd2-dependent quality control system. Their luminal domains are related to the transferrin receptor, but these are dispensable for Smf1 regulation. Tre proteins and the transferrin receptors appear to have evolved independently from the same family of membrane-associated proteases. PMID:16456538

A Lectin Purified from Blood Red Bracket Mushroom, Pycnoporus sanguineus (Agaricomycetidae), Mycelium Displayed Affinity Toward Bovine Transferrin.

PubMed

Albores, Silvana; Moros, Maria; Cerdeiras, Maria Pia; de la Fuente, Jesus Martinez; Grazu, Valeria; Fraguas, Laura Franco

2016-01-01

Fungal lectins constitute excellent ligands for development of affinity adsorbents useful in affinity chromatography. In this work, a lectin was purified from Pycnoporus sanguineus (PSL) mycelium using 3 procedures: by affinity chromatography, using magnetic galactosyl-nanoparticles or galactose coupled to Sepharose, and by ionic exchange chromatography (IEC). The highest lectin yield was achieved by IEC (55%); SDS-PAGE of PSL showed 2 bands with molecular mass of 68.7 and 55.2 kDa and IEC displayed 2 bands at pi 5.5 and 5.2. The lectin agglutinates rat erythrocytes, exhibiting broad specificity toward several monosaccharides, including galactose. The agglutination was also inhibited by the glycoproteins fetal calf fetuin, bovine lactoferrin, bovine transferrin, and horseradish peroxidase. The lectin was then used to synthesize an affinity adsorbent (PSL-Sepharose) and the interaction with glycoproteins was evaluated by analyzing their chromatographic behaviors. The strongest interaction with the PSL-derivative was observed with transferrin, although lower interactions were also displayed toward fetuin and lactoferrin. These results indicate that the purified PSL constitutes an interesting ligand for the design of affinity adsorbents to be used (i.e., in glycoprotein purification).

A new LC-MS based method to quantitate exogenous recombinant transferrin in cerebrospinal fluid: a potential approach for pharmacokinetic studies of transferrin-based therapeutics in the central nervous system

PubMed Central

Wang, Shunhai; Bobst, Cedric E.; Kaltashov, Igor A.

2018-01-01

Transferrin (Tf) is an 80 kDa iron-binding protein which is viewed as a promising drug carrier to target the central nervous system due to its ability to penetrate the blood-brain barrier (BBB). Among the many challenges during the development of Tf-based therapeutics, sensitive and accurate quantitation of the administered Tf in cerebrospinal fluid (CSF) remains particularly difficult due to the presence of abundant endogenous Tf. Herein, we describe the development of a new LC-MS based method for sensitive and accurate quantitation of exogenous recombinant human Tf in rat CSF. By taking advantage of a His-tag present in recombinant Tf and applying Ni affinity purification, the exogenous hTf can be greatly enriched from rat CSF, despite the presence of the abundant endogenous protein. Additionally, we applied a newly developed O18-labeling technique that can generate internal standards at the protein level, which greatly improved the accuracy and robustness of quantitation. The developed method was investigated for linearity, accuracy, precision and lower limit of quantitation, all of which met the commonly accepted criteria for bioanalytical method validation. PMID:26307718

Iron-Binding Protein Degradation by Cysteine Proteases of Naegleria fowleri.

PubMed

Martínez-Castillo, Moisés; Ramírez-Rico, Gerardo; Serrano-Luna, Jesús; Shibayama, Mineko

2015-01-01

Naegleria fowleri causes acute and fulminant primary amoebic meningoencephalitis. This microorganism invades its host by penetrating the olfactory mucosa and then traveling up the mesaxonal spaces and crossing the cribriform plate; finally, the trophozoites invade the olfactory bulbs. During its invasion, the protozoan obtains nutrients such as proteins, lipids, carbohydrates, and cationic ions (e.g., iron, calcium, and sodium) from the host. However, the mechanism by which these ions are obtained, particularly iron, is poorly understood. In the present study, we evaluated the ability of N. fowleri to degrade iron-binding proteins, including hololactoferrin, transferrin, ferritin, and hemoglobin. Zymography assays were performed for each substrate under physiological conditions (pH 7 at 37°C) employing conditioned medium (CM) and total crude extracts (TCEs) of N. fowleri. Different degradation patterns with CM were observed for hololactoferrin, transferrin, and hemoglobin; however, CM did not cause ferritin degradation. In contrast, the TCEs degraded only hololactoferrin and transferrin. Inhibition assays revealed that cysteine proteases were involved in this process. Based on these results, we suggest that CM and TCEs of N. fowleri degrade iron-binding proteins by employing cysteine proteases, which enables the parasite to obtain iron to survive while invading the central nervous system.

Iron-Binding Protein Degradation by Cysteine Proteases of Naegleria fowleri

PubMed Central

Ramírez-Rico, Gerardo; Serrano-Luna, Jesús; Shibayama, Mineko

2015-01-01

Naegleria fowleri causes acute and fulminant primary amoebic meningoencephalitis. This microorganism invades its host by penetrating the olfactory mucosa and then traveling up the mesaxonal spaces and crossing the cribriform plate; finally, the trophozoites invade the olfactory bulbs. During its invasion, the protozoan obtains nutrients such as proteins, lipids, carbohydrates, and cationic ions (e.g., iron, calcium, and sodium) from the host. However, the mechanism by which these ions are obtained, particularly iron, is poorly understood. In the present study, we evaluated the ability of N. fowleri to degrade iron-binding proteins, including hololactoferrin, transferrin, ferritin, and hemoglobin. Zymography assays were performed for each substrate under physiological conditions (pH 7 at 37°C) employing conditioned medium (CM) and total crude extracts (TCEs) of N. fowleri. Different degradation patterns with CM were observed for hololactoferrin, transferrin, and hemoglobin; however, CM did not cause ferritin degradation. In contrast, the TCEs degraded only hololactoferrin and transferrin. Inhibition assays revealed that cysteine proteases were involved in this process. Based on these results, we suggest that CM and TCEs of N. fowleri degrade iron-binding proteins by employing cysteine proteases, which enables the parasite to obtain iron to survive while invading the central nervous system. PMID:26090408

The Recycling Endosome of Madin-Darby Canine Kidney Cells Is a Mildly Acidic Compartment Rich in Raft Components

PubMed Central

Gagescu, Raluca; Demaurex, Nicolas; Parton, Robert G.; Hunziker, Walter; Huber, Lukas A.; Gruenberg, Jean

2000-01-01

We present a biochemical and morphological characterization of recycling endosomes containing the transferrin receptor in the epithelial Madin-Darby canine kidney cell line. We find that recycling endosomes are enriched in molecules known to regulate transferrin recycling but lack proteins involved in early endosome membrane dynamics, indicating that recycling endosomes are distinct from conventional early endosomes. We also find that recycling endosomes are less acidic than early endosomes because they lack a functional vacuolar ATPase. Furthermore, we show that recycling endosomes can be reached by apically internalized tracers, confirming that the apical endocytic pathway intersects the transferrin pathway. Strikingly, recycling endosomes are enriched in the raft lipids sphingomyelin and cholesterol as well as in the raft-associated proteins caveolin-1 and flotillin-1. These observations may suggest that a lipid-based sorting mechanism operates along the Madin-Darby canine kidney recycling pathway, contributing to the maintenance of cell polarity. Altogether, our data indicate that recycling endosomes and early endosomes differ functionally and biochemically and thus that different molecular mechanisms regulate protein sorting and membrane traffic at each step of the receptor recycling pathway. PMID:10930469

HO-1-mediated macroautophagy: a mechanism for unregulated iron deposition in aging and degenerating neural tissues.

PubMed

Zukor, Hillel; Song, Wei; Liberman, Adrienne; Mui, Jeannie; Vali, Hojatollah; Fillebeen, Carine; Pantopoulos, Kostas; Wu, Ting-Di; Guerquin-Kern, Jean-Luc; Schipper, Hyman M

2009-05-01

Oxidative stress, deposition of non-transferrin iron, and mitochondrial insufficiency occur in the brains of patients with Alzheimer disease (AD) and Parkinson disease (PD). We previously demonstrated that heme oxygenase-1 (HO-1) is up-regulated in AD and PD brain and promotes the accumulation of non-transferrin iron in astroglial mitochondria. Herein, dynamic secondary ion mass spectrometry (SIMS) and other techniques were employed to ascertain (i) the impact of HO-1 over-expression on astroglial mitochondrial morphology in vitro, (ii) the topography of aberrant iron sequestration in astrocytes over-expressing HO-1, and (iii) the role of iron regulatory proteins (IRP) in HO-1-mediated iron deposition. Astroglial hHO-1 over-expression induced cytoplasmic vacuolation, mitochondrial membrane damage, and macroautophagy. HO-1 promoted trapping of redox-active iron and sulfur within many cytopathological profiles without impacting ferroportin, transferrin receptor, ferritin, and IRP2 protein levels or IRP1 activity. Thus, HO-1 activity promotes mitochondrial macroautophagy and sequestration of redox-active iron in astroglia independently of classical iron mobilization pathways. Glial HO-1 may be a rational therapeutic target in AD, PD, and other human CNS conditions characterized by the unregulated deposition of brain iron.

Iron metabolism and related genetic diseases: A cleared land, keeping mysteries.

PubMed

Brissot, Pierre; Loréal, Olivier

2016-02-01

Body iron has a very close relationship with the liver. Physiologically, the liver synthesizes transferrin, in charge of blood iron transport; ceruloplasmin, acting through its ferroxidase activity; and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron. The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor 2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease. It is less involved in the usual (type A) form of ferroportin disease which targets primarily the macrophagic system. Hereditary aceruloplasminemia raises important pathophysiological issues in light of its peculiar organ iron distribution. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Iron-binding antioxidant capacity is impaired in diabetes mellitus.

PubMed

Van Campenhout, Ann; Van Campenhout, Christel; Lagrou, Albert R; Moorkens, Greta; De Block, Christophe; Manuel-y-Keenoy, Begoña

2006-05-15

Increased lipid peroxidation contributes to diabetic complications and redox-active iron is known to play an important role in catalyzing peroxidation reactions. We aimed to investigate if diabetes affects the capacity of plasma to protect against iron-driven lipid peroxidation and to identify underlying factors. Glycemic control, serum iron, proteins involved in iron homeostasis, plasma iron-binding antioxidant capacity in a liposomal model, and non-transferrin-bound iron were measured in 40 type 1 and 67 type 2 diabetic patients compared to 100 nondiabetic healthy control subjects. Iron-binding antioxidant capacity was significantly lower in the plasma of diabetic subjects (83 +/- 6 and 84 +/- 5% in type 1 and type 2 diabetes versus 88 +/- 6% in control subjects, p < 0.0005). The contribution of transferrin, ceruloplasmin, and albumin concentrations to the iron-binding antioxidant capacity was lost in diabetes (explaining only 4.2 and 6.3% of the variance in type 1 and type 2 diabetes versus 13.9% in control subjects). This observation could not be explained by differences in Tf glycation, lipid, or inflammatory status and was not associated with higher non-transferrin-bound iron levels. Iron-binding antioxidant capacity is decreased in diabetes mellitus.

Quantitative analysis of the protein corona on FePt nanoparticles formed by transferrin binding

PubMed Central

Jiang, Xiue; Weise, Stefan; Hafner, Margit; Röcker, Carlheinz; Zhang, Feng; Parak, Wolfgang J.; Nienhaus, G. Ulrich

2010-01-01

Nanoparticles are finding a rapidly expanding range of applications in research and technology, finally entering our daily life in medical, cosmetic or food products. Their ability to invade all regions of an organism including cells and cellular organelles offers new strategies for medical diagnosis and therapy (nanomedicine), but their safe use requires a deep knowledge about their interactions with biological systems at the molecular level. Upon incorporation, nanoparticles are exposed to biological fluids from which they adsorb proteins and other biomolecules to form a ‘protein corona’. These nanoparticle–protein interactions are still poorly understood and quantitative studies to characterize them remain scarce. Here we have quantitatively analysed the adsorption of human transferrin onto small (radius approx. 5 nm) polymer-coated FePt nanoparticles by using fluorescence correlation spectroscopy. Transferrin binds to the negatively charged nanoparticles with an affinity of approximately 26 µM in a cooperative fashion and forms a monolayer with a thickness of 7 nm. By using confocal fluorescence microscopy, we have observed that the uptake of FePt nanoparticles by HeLa cells is suppressed by the protein corona compared with the bare nanoparticles. PMID:19776149

A Novel Isoquinoline Derivative Anticancer Agent and Its Targeted Delivery to Tumor Cells Using Transferrin-Conjugated Liposomes

PubMed Central

Yang, Xuewei; Yang, Shuang; Chai, Hongyu; Yang, Zhaogang; Lee, Robert J.; Liao, Weiwei; Teng, Lesheng

2015-01-01

We have screened 11 isoquinoline derivatives and α-methylene-γ-butyrolactones using the 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay in HeLa and HEK-293T cells. Compound 2 was identified as potential anticancer agent. To further improve its therapeutic potential, this agent was incorporated into transferrin (Tf)-conjugated liposomes (LPs) for targeted delivery to tumor cells. We have demonstrated Tf-LP-Compound 2 have superior antitumor activity compared to non-targeted controls and the free drug. These data show Tf-LP-Compound 2 to be a promising agent that warrants further evaluation. PMID:26309138

Elevated Serum Hepcidin Levels during an Intensified Training Period in Well-Trained Female Long-Distance Runners

PubMed Central

Ishibashi, Aya; Maeda, Naho; Sumi, Daichi; Goto, Kazushige

2017-01-01

Iron is essential for providing oxygen to working muscles during exercise, and iron deficiency leads to decreased exercise capacity during endurance events. However, the mechanism of iron deficiency among endurance athletes remains unclear. In this study, we compared iron status between two periods involving different training regimens. Sixteen female long-distance runners participated. Over a seven-month period, fasting blood samples were collected during their regular training period (LOW; middle of February) and during an intensified training period (INT; late of August) to determine blood hematological, iron, and inflammatory parameters. Three-day food diaries were also assessed. Body weight and lean body mass did not differ significantly between LOW and INT, while body fat and body fat percentage were significantly lower in INT (p < 0.05). Blood hemoglobin, serum ferritin, total protein, and iron levels, total iron-binding capacity, and transferrin saturation did not differ significantly between the two periods. Serum hepcidin levels were significantly higher during INT than LOW (p < 0.05). Carbohydrate and iron intakes from the daily diet were significantly higher during INT than LOW (p < 0.05). In conclusion, an elevated hepcidin level was observed during an intensified training period in long-distance runners, despite an apparently adequate daily intake of iron. PMID:28335426

Elevated Serum Hepcidin Levels during an Intensified Training Period in Well-Trained Female Long-Distance Runners.

PubMed

Ishibashi, Aya; Maeda, Naho; Sumi, Daichi; Goto, Kazushige

2017-03-14

Iron is essential for providing oxygen to working muscles during exercise, and iron deficiency leads to decreased exercise capacity during endurance events. However, the mechanism of iron deficiency among endurance athletes remains unclear. In this study, we compared iron status between two periods involving different training regimens. Sixteen female long-distance runners participated. Over a seven-month period, fasting blood samples were collected during their regular training period (LOW; middle of February) and during an intensified training period (INT; late of August) to determine blood hematological, iron, and inflammatory parameters. Three-day food diaries were also assessed. Body weight and lean body mass did not differ significantly between LOW and INT, while body fat and body fat percentage were significantly lower in INT ( p < 0.05). Blood hemoglobin, serum ferritin, total protein, and iron levels, total iron-binding capacity, and transferrin saturation did not differ significantly between the two periods. Serum hepcidin levels were significantly higher during INT than LOW ( p < 0.05). Carbohydrate and iron intakes from the daily diet were significantly higher during INT than LOW ( p < 0.05). In conclusion, an elevated hepcidin level was observed during an intensified training period in long-distance runners, despite an apparently adequate daily intake of iron.

Iron acquisition by Haemophilus influenzae.

PubMed Central

Pidcock, K A; Wooten, J A; Daley, B A; Stull, T L

1988-01-01

The mechanisms for acquisition of iron by Haemophilus influenzae and their role in pathogenesis are not known. Heme and nonheme sources of iron were evaluated for their effect on growth of type b and nontypable strains of H. influenzae in an iron-restricted, defined medium. All 13 strains acquired iron from heme, hemoglobin, hemoglobin-haptoglobin, and heme-hemopexin. Among nonheme sources of protein-bound iron, growth of H. influenzae was enhanced by partially saturated human transferrin but not by lactoferrin or ferritin. Purified ferrienterochelin and ferridesferrioxamine failed to provide iron to H. influenzae, and the supernatants of H. influenzae E1a grown in iron-restricted medium failed to enhance iron-restricted growth of siderophore-dependent strains of Escherichia coli, Salmonella typhimurium, and Arthrobacter terregens. Marked alterations in the profile of outer membrane proteins of H. influenzae were observed when the level of free iron was varied between 1 microM and 1 mM. Catechols were not detected in the supernatants of strain E1a; however, iron-related hydroxamate production was detected by two biochemical assays. We conclude that the sources of iron for H. influenzae are diverse. The significance of hydroxamate production and iron-related outer membrane proteins to H. influenzae iron acquisition is not yet clear. Images PMID:2964410

Guidelines for quantifying iron overload.

PubMed

Wood, John C

2014-12-05

Both primary and secondary iron overload are increasingly prevalent in the United States because of immigration from the Far East, increasing transfusion therapy in sickle cell disease, and improved survivorship of hematologic malignancies. This chapter describes the use of historical data, serological measures, and MRI to estimate somatic iron burden. Before chelation therapy, transfusional volume is an accurate method for estimating liver iron burden, whereas transferrin saturation reflects the risk of extrahepatic iron deposition. In chronically transfused patients, trends in serum ferritin are helpful, inexpensive guides to relative changes in somatic iron stores. However, intersubject variability is quite high and ferritin values may change disparately from trends in total body iron load over periods of several years. Liver biopsy was once used to anchor trends in serum ferritin, but it is invasive and plagued by sampling variability. As a result, we recommend annual liver iron concentration measurements by MRI for all patients on chronic transfusion therapy. Furthermore, it is important to measure cardiac T2* by MRI every 6-24 months depending on the clinical risk of cardiac iron deposition. Recent validation data for pancreas and pituitary iron assessments are also presented, but further confirmatory data are suggested before these techniques can be recommended for routine clinical use. © 2014 by The American Society of Hematology. All rights reserved.

Serum iron parameters in liver cirrhosis

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Maail, W.

2018-03-01

The liver plays a fundamental role in iron homeostasis. Iron parameters change, especially ferritin, need to be evaluated in patients with liver cirrhosis. Serum ferritin could predict the prognosis of patients with decompensated cirrhosis since it reflects immunemediated and infectious stimuli. Ferritin could express the severity of liver disease and possible subsequent complications. Finally, it might reflect an iron overload condition resulting in significant morbidity and early mortality. 70 patients with decompensated liver cirrhosis divided into three Child-Pugh subgroups. Serum iron parameters include serum iron (SI), total iron binding capacity (TIBC) and ferritin was measured in these groups. From these 70 patients, 30 (42.9%) with HbsAg positive, 26 (37.1%) with anti-HCV positive and 14 (20%) with both HbsAg and anti-HCV positive. Of the 70 patients, 14 (20%) had CTP Class A cirrhosis, 17 (24.3%) had CTP Class B cirrhosis, and 39 (55.7%) had CTP C cirrhosis. The median (range) value of serum iron was 36 (10-345) μg/dl, TIBC was 160 (59-520) μg/dl, Ferritin was 253.5 (8-6078) ng/ml and the transferrin saturation was 22.9 (3.65-216.98) %.We found a significant difference in serum ferritin level with CTP score. Ferritin levels increased as Child-Pugh class progressed (p<0.001).

Oral iron acutely elevates bacterial growth in human serum.

PubMed

Cross, James H; Bradbury, Richard S; Fulford, Anthony J; Jallow, Amadou T; Wegmüller, Rita; Prentice, Andrew M; Cerami, Carla

2015-11-23

Iron deficiency is the most common nutrient deficiency worldwide and routine supplementation is standard policy for pregnant mothers and children in most low-income countries. However, iron lies at the center of host-pathogen competition for nutritional resources and recent trials of iron administration in African and Asian children have resulted in significant excesses of serious adverse events including hospitalizations and deaths. Increased rates of malaria, respiratory infections, severe diarrhea and febrile illnesses of unknown origin have all been reported, but the mechanisms are unclear. We here investigated the ex vivo growth characteristics of exemplar sentinel bacteria in adult sera collected before and 4 h after oral supplementation with 2 mg/kg iron as ferrous sulfate. Escherichia coli, Yersinia enterocolitica and Salmonella enterica serovar Typhimurium (all gram-negative bacteria) and Staphylococcus epidermidis (gram-positive) showed markedly elevated growth in serum collected after iron supplementation. Growth rates were very strongly correlated with transferrin saturation (p < 0.0001 in all cases). Growth of Staphylococcus aureus, which preferentially scavenges heme iron, was unaffected. These data suggest that even modest oral supplements with highly soluble (non-physiological) iron, as typically used in low-income settings, could promote bacteremia by accelerating early phase bacterial growth prior to the induction of immune defenses.

Role of alcohol in the regulation of iron metabolism

PubMed Central

Harrison-Findik, Duygu Dee

2007-01-01

Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury. PMID:17854133

Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox.

PubMed

Lescano, Manuel A; Tavares, Letícia C; Santos, Paulo C J L

2017-10-16

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 μmol/g; reference value < 36 μmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox

PubMed Central

Lescano, Manuel A; Tavares, Letícia C; Santos, Paulo C J L

2017-01-01

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 μmol/g; reference value < 36 μmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms. PMID:29085829

Iron deficiency in young Lebanese children: association with elevated blood lead levels.

PubMed

Muwakkit, Samar; Nuwayhid, Iman; Nabulsi, Mona; al Hajj, Rima; Khoury, Ruby; Mikati, Mohamad; Abboud, Miguel R

2008-05-01

To measure the prevalence of transferrin saturation (TS) <12%, and iron-deficiency anemia (IDA) in Lebanese children, and their association with dietary habits, sociodemographic characteristics, and blood lead levels. A cross-sectional study was performed over a period of 2 years. Of 268 children studied, 142 (53%) were boys and 126 (47%) were girls with an age range of 11 to 75 months. Information collected included nutritional status, blood counts, TS, and blood lead levels. The total prevalence of TS<12% and IDA were 33.6% and 20.5%, respectively, and were associated with not having received iron supplements. IDA was more prevalent among males (P=0.04). TS<12% and IDA were significantly associated with elevated blood lead levels in the first age group (11 to 23 mo) (P=0.04, odds ratio=3.19) and (P=0.006, odds ratio=4.59), respectively. IDA is common in Lebanese children and is associated with increased blood lead levels, lack of iron supplementation, and cultural dietary habits. Remedial measures such as iron fortification of commonly consumed food are needed on the national level. Lead exposure must be controlled and awareness must be raised about the potentially devastating consequences of combined iron deficiency and lead poisoning on young children.

Serum Iron Status of Under-Five Children with Sickle Cell Anaemia in Lagos, Nigeria

PubMed Central

Akodu, S. O.; Diaku-Akinwumi, I. N.; Kehinde, O. A.; Njokanma, O. F.

2013-01-01

Background. Iron status in patients with sickle cell anaemia is a matter of continuing investigation. Objective. This paper aims to determine the serum iron status of under-five, sickle cell anaemia patients. Methods. The study spanned from December 2009 to February 2010 at the Consultant Outpatient Clinics involving 97 HbSS subjects and 97 age- and sex-matched HbAA controls. Biochemical iron status was assayed in subjects and controls. Results. Age range of the children was seven months to five years, with a mean of 30.6 (±15.97) months. Irrespective of gender, mean serum iron values were higher in HbAA controls than their HbSS counterparts but the observed difference was not significant (P = 0.299 and 0.111, resp.). The mean total iron binding capacity values of males and females were also not significantly different for sickle cell anaemia subjects and controls (P > 0.05). Males and females with HbAA had significantly lower serum ferritin when compared with their HbSS counterparts. Irrespective of gender, mean transferrin saturation was lower in HbSS subjects but the difference was not statistically significant (P > 0.05). Conclusion. Children with sickle cell anaemia have higher serum ferritin than controls, implying relatively higher iron content in the reticuloendothelial cells. PMID:24288599

Supportive therapy in medical therapy of head and neck tumors

PubMed Central

Link, Hartmut

2012-01-01

Fever during neutropenia may be a symptom of severe life threatening infection, which must be treated immediately with antibiotics. If signs of infection persist, therapy must be modified. Diagnostic measures should not delay treatment. If the risk of febrile neutropenia after chemotherapy is ≥20%, then prophylactic therapy with G-CSF is standard of care. After protocols with a risk of febrile neutropenia of 10–20%, G-CSF is necessary, in patients older than 65 years or with severe comorbidity, open wounds, reduced general condition. Anemia in cancer patients must be diagnosed carefully, even preoperatively. Transfusions of red blood cells are indicated in Hb levels below 7–8 g/dl. Erythropoiesis stimulating agents (ESA) are recommended after chemotherapy only when hemoglobin levels are below 11 g/dl. The Hb-level must not be increased above 12 g/dl. Anemia with functional iron deficiency (transferrin saturation <20%) should be treated with intravenous iron, as oral iron is ineffective being not absorbed. Nausea or emesis following chemotherapy can be classified as minimal, low, moderate and high. The antiemetic prophylaxis should be escalated accordingly. In chemotherapy with low emetogenic potential steroids are sufficient, in the moderate level 5-HT3 receptor antagonists (setrons) are added, and in the highest level Aprepitant as third drug. PMID:23320053

Successful pregnancy outcome following maternal intravenous immunoglobulin treatment in a woman with recurrent perinatal haemochromatosis.

PubMed

Venkat-Raman, Narayanaswamy; Venkata-Krishnan, Radha V; Howarth, Edmund S

2006-12-01

We report a case of successful pregnancy outcome following maternal intravenous immunoglobulin treatment in a woman with previous history of recurrent fetal hydrops secondary to perinatal haemochromatosis. A 32-year old woman had two successive pregnancies complicated by fetal hydrops and perinatal deaths. Pathological examination of the fetus showed severe liver destruction with siderosis of hepatocytes at extrahepatic sites, but sparing of the reticulo-endothelial elements, consistent with the diagnosis of perinatal haemochromatosis. In the subsequent pregnancy, maternal intravenous immunoglobulin was administered weekly from the 18th week of gestation until delivery by elective caesarean section at 38 weeks. The infant was treated with desferrioxamine, N-acetylcysteine, vitamins K and E. The infant was born in good health, but had high serum ferritin levels, markedly elevated percent transferrin saturation, and mild transient derangement of liver and coagulation function. The infant made an excellent recovery and the treatment was stopped at 7 weeks of age. The liver and coagulation parameters and the serum ferritin levels returned to normal values. Haemochromatosis should be considered in the differential diagnosis of hydrops fetalis. The recurrence risk is high, and immunomodulation with intravenous immunoglobulin treatment appears to alter the course of the disease with better infant survival. Copyright (c) 2006 John Wiley & Sons, Ltd.

Screening for hemochromatosis by measuring ferritin levels: a more effective approach

PubMed Central

Waalen, Jill; Felitti, Vincent J.; Gelbart, Terri

2008-01-01

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 μg/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 μg/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who do not have hemochromatosis genotypes. Because the ferritin level of the majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels less than or equal to 1000 μg/L should not result in missed opportunities for early treatment of patients who could benefit. PMID:18025154

The Interaction between HIV and Intestinal Helminth Parasites Coinfection with Nutrition among Adults in KwaZulu-Natal, South Africa

PubMed Central

Mabaso, M.; Mamba, T.; Napier, C. E.; Mkhize-Kwitshana, Z. L.

2017-01-01

In South Africa few studies have examined the effects of the overlap of HIV and helminth infections on nutritional status. This cross-sectional study investigated the interaction between HIV and intestinal helminths coinfection with nutritional status among KwaZulu-Natal adults. Participants were recruited from a comprehensive primary health care clinic and stratified based on their HIV, stool parasitology, IgE, and IgG4 results into four groups: the uninfected, HIV infected, helminth infected, and HIV-helminth coinfected groups. The nutritional status was assessed using body mass index, 24-hour food recall, micro-, and macronutrient biochemical markers. Univariate and multivariate multinomial probit regression models were used to assess nutritional factors associated with singly and dually infected groups using the uninfected group as a reference category. Biochemically, the HIV-helminth coinfected group was associated with a significantly higher total protein, higher percentage of transferrin saturation, and significantly lower ferritin. There was no significant association between single or dual infections with HIV and helminths with micro- and macronutrient deficiency; however general obesity and low micronutrient intake patterns, which may indicate a general predisposition to micronutrient and protein-energy deficiency, were observed and may need further investigations. PMID:28421202

Effect of diet composition and mixture of selected food additives on the erythrocytic system and iron metabolism in peripheral blood of male rats.

PubMed

Sadowska, Joanna; Kuchlewska, Magdalena

2011-01-01

Metabolic processes of food additives which are "exogenous xenobiotics" are catalysed, primarily, by enzymes located in microsomes of hepatocytes affiliated to P-450 cytochrome superfamily, containing iron. The aim of the study was to investigate the effect of diet composition and selected food additives on the erythrocyte system and iron metabolism in peripheral blood of male rats. The experiment was carried out on 30 male rats sorted into three equinumerous groups. For drinking animals received pure, settled tap water, animals from group III were receiving additionally an aqueous solution of sodium (nitrate), potassium nitrite, benzoic acid, sorbic acid and monosodium glutamate. Ascertained a significant effect of changes in diet composition on the increase in hematocrit marker value and the count of red blood cells in blood of animals examined. Used food additives diminished hemoglobin concentration, hematocrit value and red blood cell count, diminishing also iron concentration in serum, the total iron binding capacity and transferrin saturation with iron. Analysis of the results allowed ascertain adverse changes in values of the erythrocytic system markers, occurring under the influence of the applied mixture of food additives. Used food additives change the iron metabolism, most likely from the necessity of applied xenobiotics biotransformation by heme-containing monoxygenases of P-450 cytochrome.

Transferrin-Conjugated SNALPs Encapsulating 2′-O-Methylated miR-34a for the Treatment of Multiple Myeloma

PubMed Central

Scognamiglio, Immacolata; Di Martino, Maria Teresa; Campani, Virginia; Virgilio, Antonella; Galeone, Aldo; Gullà, Annamaria; Gallo Cantafio, Maria Eugenia; Tagliaferri, Pierosandro; Tassone, Pierfrancesco; Caraglia, Michele

2014-01-01

Stable nucleic acid lipid vesicles (SNALPs) encapsulating miR-34a to treat multiple myeloma (MM) were developed. Wild type or completely 2′-O-methylated (OMet) MiR-34a was used in this study. Moreover, SNALPs were conjugated with transferrin (Tf) in order to target MM cells overexpressing transferrin receptors (TfRs). The type of miR-34a chemical backbone did not significantly affect the characteristics of SNALPs in terms of mean size, polydispersity index, and zeta potential, while the encapsulation of an OMet miR-34a resulted in a significant increase of miRNA encapsulation into the SNALPs. On the other hand, the chemical conjugation of SNALPs with Tf resulted in a significant decrease of the zeta potential, while size characteristics and miR-34a encapsulation into SNALPs were not significantly affected. In an experimental model of MM, all the animals treated with SNALPs encapsulating miR-34a showed a significant inhibition of the tumor growth. However, the use of SNALPs conjugated with Tf and encapsulating OMet miR-34a resulted in the highest increase of mice survival. These results may represent the proof of concept for the use of SNALPs encapsulating miR-34a for the treatment of MM. PMID:24683542

A new liquid chromatography-mass spectrometry-based method to quantitate exogenous recombinant transferrin in cerebrospinal fluid: a potential approach for pharmacokinetic studies of transferrin-based therapeutics in the central nervous systems.

PubMed

Wang, Shunhai; Bobst, Cedric E; Kaltashov, Igor A

2015-01-01

Transferrin (Tf) is an 80 kDa iron-binding protein that is viewed as a promising drug carrier to target the central nervous system as a result of its ability to penetrate the blood-brain barrier. Among the many challenges during the development of Tf-based therapeutics, the sensitive and accurate quantitation of the administered Tf in cerebrospinal fluid (CSF) remains particularly difficult because of the presence of abundant endogenous Tf. Herein, we describe the development of a new liquid chromatography-mass spectrometry-based method for the sensitive and accurate quantitation of exogenous recombinant human Tf in rat CSF. By taking advantage of a His-tag present in recombinant Tf and applying Ni affinity purification, the exogenous human serum Tf can be greatly enriched from rat CSF, despite the presence of the abundant endogenous protein. Additionally, we applied a newly developed (18)O-labeling technique that can generate internal standards at the protein level, which greatly improved the accuracy and robustness of quantitation. The developed method was investigated for linearity, accuracy, precision, and lower limit of quantitation, all of which met the commonly accepted criteria for bioanalytical method validation.

Relationship of aging and nutritional status to innate immunity in tube-fed bedridden patients.

PubMed

Takeuchi, Yoshiaki; Tashiro, Tomoe; Yamamura, Takuya; Takahashi, Seiichiro; Katayose, Kozo; Kohga, Shin; Takase, Mitsunori; Imawari, Michio

2017-01-01

Aging and malnutrition are known to influence immune functions. The aim of this study was to investigate the relationship of aging and malnutrition to innate immune functions in tube-fed bedridden patients. A cross-sectional survey was performed in 71 tube-fed bedridden patients aged 50-95 years (mean age±SD, 80.2±8.5 years) with serum albumin concentrations between 2.5 and 3.5 g/dL. We evaluated associations of age and nutritional variables with natural-killer cell activity, neutrophilphagocytic activity, and neutrophil-sterilizing activity. Nutritional variables included body mass index, weightadjusted energy intake, total lymphocyte count, and serum concentrations of albumin, transferrin, prealbumin, total cholesterol, C-reactive protein, and zinc. Natural-killer cell activity, neutrophil-phagocytic activity, and neutrophil-sterilizing activity were normal or increased in 67 (94%), 63 (89%), and 69 (97%) patients, respectively. Multiple linear regression analysis with a backward elimination method showed that natural-killer cell activity correlated negatively with aging and lymphocyte counts (p<0.01 for both) but positively with body mass index and transferrin (p<0.01 for both). Neutrophil-phagocytic and neutrophil-sterilizing activities were not associated with any variables. In tube-fed bedridden patients with hypo-albuminemia, natural-killer cell activity may be associated with aging, body mass index, transferrin, and lymphocyte counts.

A computational study of the open and closed forms of the N-lobe human serum transferrin apoprotein.

PubMed

Rinaldo, David; Field, Martin J

2003-12-01

Human serum transferrin tightly binds ferric ions in the blood stream but is able to release them in cells by a process involving receptor-mediated endocytosis and decrease in pH. Iron binding and release are accompanied by a large conformation change. In this study, we investigate theoretically the open and closed forms of the N-lobe human serum transferrin apoprotein by performing pKa calculations and molecular dynamics and free-energy simulations. In agreement with the hypothesis based on the x-ray crystal structures, our calculations show that there is a shift in the pKa values of the lysines forming the dilysine trigger when the conformation changes. We argue, however, that simple electrostatic repulsion between the lysines is not sufficient to trigger domain opening and, instead, propose an alternative explanation for the dilysine-trigger effect. Analysis of the molecular dynamics and free-energy results indicate that the open form is more mobile than the closed form and is much more stable at pH 5.3, in large part due to entropic effects. Despite a lower free energy, the dynamics simulation of the open form shows that it is flexible enough to sample conformations that are consistent with iron binding.

Requirement for serum in medium supplemented with insulin-transferrin-selenium for hydrodynamic cultivation of engineered cartilage.

PubMed

Yang, Yueh-Hsun; Barabino, Gilda A

2011-08-01

Achievement of viable engineered tissues through in vitro cultivation in bioreactor systems requires a thorough understanding of the complex interplay between hydrodynamic forces and biochemical cues such as serum. To this end, chondrocyte-seeded constructs were cultured under continuous fluid-induced shear forces with reduced serum content (0%-2%, v/v), which was partially or completely replaced by a potential substitute, insulin-transferrin-selenium, to minimize deleterious effects associated with the use of culture media containing high levels of serum (10%-20%). Low-serum cultures yielded constructs with similar biochemical properties to those cultivated with high-serum supplements, whereas the serum-free constructs exhibited poor cell proliferation, insufficient extracellular matrix production, and rapid degradation of and/or shear-induced damage to polyglycolic acid scaffolds. A fibrous outer capsule typically observed in hydrodynamic cultures and characterized by increased cell density and decreased (virtually none) glycosaminoglycan deposition was eliminated when serum concentration was equal to or <0.2% in the presence of hydrodynamic stimuli. Our findings suggest that serum is a requirement in insulin-transferrin-selenium-supplemented cultures in order for constructs to exhibit improved properties in response to hydrodynamic forces, and that mechanical and biochemical stimuli may synergistically modulate tissue properties and morphology through shear-responsive signals.

Alteration of serum concentrations of manganese, iron, ferritin, and transferrin receptor following exposure to welding fumes among career welders.

PubMed

Lu, Ling; Zhang, Long-Lian; Li, G Jane; Guo, Wenrui; Liang, Wannian; Zheng, Wei

2005-03-01

This study was performed to determine airborne manganese levels during welding practice and to establish the relationship between long-term, low-level exposure to manganese and altered serum concentrations of manganese, iron, and proteins associated with iron metabolism in career welders. Ninety-seven welders (average age of 36 years) who have engaged in electric arc weld in a vehicle manufacturer were recruited as the exposed group. Welders worked 7-8h per day with employment duration of 1-33 years. Control subjects consisted of 91 employees (average age of 35 years) in the same factory but not in the welding profession. Ambient manganese levels in welders' breathing zone were the highest inside the vehicle (1.5 +/- 0.7 mg/m3), and the lowest in the center of the workshop (0.2 +/- 0.05 mg/m3). Since the filter size was 0.8 microm, it is possible that these values may be likely an underestimation of the true manganese levels. Serum levels of manganese and iron in welders were about three-fold (p < 0.01) and 1.2-fold (p < 0.01), respectively, higher than those of controls. Serum concentrations of ferritin and transferrin were increased among welders, while serum transferrin receptor levels were significantly decreased in comparison to controls. Linear regression analyses revealed a lack of association between serum levels of manganese and iron. However, serum concentrations of iron and ferritin were positively associated with years of welder experience (p < 0.05). Moreover, serum transferrin receptor levels were inversely associated with serum manganese concentrations (p < 0.05). These findings suggest that exposure to welding fume among welders disturbs serum homeostasis of manganese, iron, and the proteins associated with iron metabolism. Serum manganese may serve as a reasonable biomarker for assessment of recent exposure to airborne manganese.

An innovative pre-targeting strategy for tumor cell specific imaging and therapy

NASA Astrophysics Data System (ADS)

Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

2015-08-01

A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments. Electronic supplementary information (ESI) available: Experimental details, peptide structures, molecular weights, and additional data. See DOI: 10.1039/c5nr03862f

The effects of intravenous, enteral and combined administration of glutamine on malnutrition in sepsis: a randomized clinical trial.

PubMed

Koksal, Guniz Meyancı; Erbabacan, Emre; Tunali, Yusuf; Karaoren, Gulsah; Vehid, Suphi; Oz, Huseyin

2014-01-01

Our aim was to compare the effects of intravenous, enteral, and enteral plus intravenous supplemented glutamine on plasma transferrin, nitrogen balance, and creatinine/height index in septic patients with malnutrition. Blood and urine samples were collected for transferrin, urea and creatinine measurements. Samples, SOFA score and protein-calorie intake values were repeated on days 7 and 15. Patients (n:120) were randomly divided into 4 groups. Group I received 30 g/day IV glutamine, group II received 30 g/day enteral glutamine, group III received 15 g/day IV and 15 g/day enteral glutamine. Group IV received only enteral feeding as a control group. Transferrin levels decreased in group IV (p<0.01 0-7 days, p<0.01 7-15 days, p<0.01 0-15 days). Nitrogen balance levels were highest in group IV when compared with group I (p<0.05, p<0.001), group II (p<0.001), and group III (p<0.05, p<0.001) on days 7-15. Creatinine/height indexes increased in group I (p<0.001), group II (p<0.001), group III (p<0.001), and group IV (p<0.05) on day 15. In group III the creatinine/height index was higher than in groups I and II (p<0.05). In group IV, creatinine/height index was lower than in group I (p<0.01) and group II (p<0.001). Protein-calorie intake in group IV was higher than others on day 7 (p<0.05). SOFA scores of group IV were higher than the other groups on day 15 (p<0.05). This study demonstrated, that combined route of gln supplementation resulted in the most positive outcome to transferrin, creatine/height index and nitrogen balance (on days 7 and 15) during the catabolic phase of septic patients with malnutrition.

Myosin Vb Is Associated with Plasma Membrane Recycling Systems

PubMed Central

Lapierre, Lynne A.; Kumar, Ravindra; Hales, Chadwick M.; Navarre, Jennifer; Bhartur, Sheela G.; Burnette, Jason O.; Provance, D. William; Mercer, John A.; Bähler, Martin; Goldenring, James R.

2001-01-01

Myosin Va is associated with discrete vesicle populations in a number of cell types, but little is known of the function of myosin Vb. Yeast two-hybrid screening of a rabbit parietal cell cDNA library with dominant active Rab11a (Rab11aS20V) identified myosin Vb as an interacting protein for Rab11a, a marker for plasma membrane recycling systems. The isolated clone, corresponding to the carboxyl terminal 60 kDa of the myosin Vb tail, interacted with all members of the Rab11 family (Rab11a, Rab11b, and Rab25). GFP-myosin Vb and endogenous myosin Vb immunoreactivity codistributed with Rab11a in HeLa and Madin-Darby canine kidney (MDCK) cells. As with Rab11a in MDCK cells, the myosin Vb immunoreactivity was dispersed with nocodazole treatment and relocated to the apical corners of cells with taxol treatment. A green fluorescent protein (GFP)-myosin Vb tail chimera overexpressed in HeLa cells retarded transferrin recycling and caused accumulation of transferrin and the transferrin receptor in pericentrosomal vesicles. Expression of the myosin Vb tail chimera in polarized MDCK cells stably expressing the polymeric IgA receptor caused accumulation of basolaterally endocytosed polymeric IgA and the polymeric IgA receptor in the pericentrosomal region. The myosin Vb tail had no effects on transferrin trafficking in polarized MDCK cells. The GFP-myosin Va tail did not colocalize with Rab11a and had no effects on recycling system vesicle distribution in either HeLa or MDCK cells. The results indicate myosin Vb is associated with the plasma membrane recycling system in nonpolarized cells and the apical recycling system in polarized cells. The dominant negative effects of the myosin Vb tail chimera indicate that this unconventional myosin is required for transit out of plasma membrane recycling systems. PMID:11408590

Iron homeostasis and toxicity in retinal degeneration.

PubMed

He, Xining; Hahn, Paul; Iacovelli, Jared; Wong, Robert; King, Chih; Bhisitkul, Robert; Massaro-Giordano, Mina; Dunaief, Joshua L

2007-11-01

Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels buildup with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich's ataxia, and panthothenate kinase-associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age-matched controls. Over the past 10 years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter-1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron-regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron-induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential.

Mouse Polyomavirus Enters Early Endosomes, Requires Their Acidic pH for Productive Infection, and Meets Transferrin Cargo in Rab11-Positive Endosomes

PubMed Central

Liebl, David; Difato, Francesco; Horníková, Lenka; Mannová, Petra; Štokrová, Jitka; Forstová, Jitka

2006-01-01

Mouse polyomavirus (PyV) virions enter cells by internalization into smooth monopinocytic vesicles, which fuse under the cell membrane with larger endosomes. Caveolin-1 was detected on monopinocytic vesicles carrying PyV particles in mouse fibroblasts and epithelial cells (33). Here, we show that PyV can be efficiently internalized by Jurkat cells, which do not express caveolin-1 and lack caveolae, and that overexpression of a caveolin-1 dominant-negative mutant in mouse epithelial cells does not prevent their productive infection. Strong colocalization of VP1 with early endosome antigen 1 (EEA1) and of EEA1 with caveolin-1 in mouse fibroblasts and epithelial cells suggests that the monopinocytic vesicles carrying the virus (and vesicles containing caveolin-1) fuse with EEA1-positive early endosomes. In contrast to SV40, PyV infection is dependent on the acidic pH of endosomes. Bafilomycin A1 abolished PyV infection, and an increase in endosomal pH by NH4Cl markedly reduced its efficiency when drugs were applied during virion transport towards the cell nucleus. The block of acidification resulted in the retention of a fraction of virions in early endosomes. To monitor further trafficking of PyV, we used fluorescent resonance energy transfer (FRET) to determine mutual localization of PyV VP1 with transferrin and Rab11 GTPase at a 2- to 10-nm resolution. Positive FRET between PyV VP1 and transferrin cargo and between PyV VP1 and Rab11 suggests that during later times postinfection (1.5 to 3 h), the virus meets up with transferrin in the Rab11-positive recycling endosome. These results point to a convergence of the virus and the cargo internalized by different pathways in common transitional compartments. PMID:16611921

Evaluation of the Efficiency of the Reticulocyte Hemoglobin Content on Diagnosis for Iron Deficiency Anemia in Chinese Adults.

PubMed

Cai, Jie; Wu, Meng; Ren, Jie; Du, Yali; Long, Zhangbiao; Li, Guoxun; Han, Bing; Yang, Lichen

2017-05-02

Our aim was to evaluate the cut-off value and efficiency of using reticulocyte hemoglobin content as a marker to diagnose iron deficiency anemia in Chinese adults. 140 adults who needed bone marrow aspiration for diagnosis at the hematology department of the Peking Union Medical College Hospital were enrolled according to the inclusive and exclusive criteria. Venous blood samples were collected to detect complete blood count, including hemoglobin, reticulocyte hemoglobin content, hematocrit, mean cellular volume, corpuscular hemoglobin concentration, hemoglobin content, free erythrocyte protoporphyrin; iron indexes of serum ferritin, serum transferrin receptor, and unsaturated iron-binding capacity; and inflammation markers of C-reactive protein and α-acid glycoprotein. Bone marrow samples were obtained for the bone marrow iron staining, which was used as the standard for the evaluation of iron status in this study. Subjects were divided into three groups according to hemoglobin levels and bone marrow iron staining results: the IDA (iron deficiency anemia) group, the NIDA (non-iron deficiency anemia) group, and the control group. The differences of the above-mentioned indexes were compared among the three groups and the effect of inflammation was also considered. The cut-off value of reticulocyte hemoglobin content was determined by receiver operation curves. The IDA group ( n = 56) had significantly lower reticulocyte hemoglobin content, mean cellular volume, corpuscular hemoglobin concentration, hemoglobin content, and serum ferritin; and higher free erythrocyte protoporphyrin, unsaturated iron-binding capacity, and serum transferrin receptor ( p < 0.05) compared with the NIDA group ( n = 38) and control group ( n = 46). Hematocrit, serum ferritin, and unsaturated iron-binding capacity were significantly affected by inflammation while reticulocyte hemoglobin content and other parameters were not. The cut-off value of reticulocyte hemoglobin content for diagnosing iron deficiency anemia was 27.2 pg, with a sensitivity of 87.5% and a specificity of 92.9%. The cut-off values for mean cellular volume, serum ferritin, and serum transferrin receptor were 76.6, 12.9, and 4.89 mg/L, respectively. Reticulocyte hemoglobin content had the largest area under the curve of 0.929, while those for mean cellular volume, serum ferritin, serum transferrin receptor were 0.922, 0.887, and 0.900, respectively. Reticulocyte hemoglobin content has a high sensitivity and specificity in the diagnosis of iron deficiency anemia, and its comprehensive diagnostic efficacy is better than other traditional indicators-such as serum ferritin and serum transferrin receptor.

The effect of empagliflozin on oxidative nucleic acid modifications in patients with type 2 diabetes: protocol for a randomised, double-blinded, placebo-controlled trial

PubMed Central

Larsen, Emil List; Cejvanovic, Vanja; Kjær, Laura Kofoed; Vilsbøll, Tina; Knop, Filip Krag; Rungby, Jørgen; Poulsen, Henrik Enghusen

2017-01-01

Introduction Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). Although glycaemic control reduces microvascular complications, the effect of intensive treatment strategies or individual drugs on macrovascular diseases is still debated. RNA oxidation is associated with increased mortality in patients with T2D. Inspired by animal studies showing effect of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor (empagliflozin) on oxidative stress and a recent trial evaluating empagliflozin that demonstrated improved cardiovascular outcomes in patients with T2D at high risk of cardiovascular events, we hypothesise that empagliflozin lowers oxidative stress. Methods and analysis In this randomised, double-blinded and placebo-controlled study, 34 adult males with T2D will be randomised (1:1) to empagliflozin or placebo once daily for 14 days as add-on to ongoing therapy. The primary endpoints will be changes in 24-hour urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) determined before and after intervention (by ultra-performance liquid chromatography tandem mass-spectrometry). Additionally, fasting levels of malondialdehyde (MDA) will be determined in plasma before and after intervention (by high-performance liquid chromatography). Further, the plasma levels of iron, transferrin, transferrin-saturation, and ferritin are determined to correlate the iron metabolism to the markers of oxidative modifications. Ethics and dissemination The study protocol has been approved by the Regional Committee on Biomedical Research Ethics (approval number H-16017433), the Danish Medicines Agency, and the Danish Data Protection Agency, and will be carried out under the surveillance and guidance of the GCP unit at Bispebjerg Frederiksberg Hospital, University of Copenhagen in compliance with the ICH-GCP guidelines and in accordance with the Declaration of Helsinki. The results of this study will be presented at national and international conferences, and submitted to a peer-reviewed international journal with authorship in accordance with Internation Committee of Medical Journal Editors (ICMJE) Recommendations state. Trial registration Study name: EMPOX; Pre-results: clinicaltrials.gov (NCT02890745). Protocol version 5.1 - August, 2016. PMID:28490557

Monitoring pulmonary vascular permeability using radiolabeled transferrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basran, G.S.; Hardy, J.G.

1988-07-01

A simple, noninvasive technique for monitoring pulmonary vascular permeability in patients in critical care units is discussed. High vascular permeability is observed in patients with clinically defined adult respiratory distress syndrome (ARDS) but not in patients with hydrostatic pulmonary edema or in patients with minor pulmonary insults who are considered to be at risk of developing ARDS. The technique has been used in the field of therapeutics and pharmacology to test the effects of the putative antipermeability agents methylprednisolone and terbutaline sulfate. There appears to be a good correlation between the acute inhibitory effect of either drug on transferrin exudationmore » and patient prognosis. Thus, a byproduct of such drug studies may be an index of survival in patients with established ARDS.« less

Altered receptor trafficking in Huntingtin Interacting Protein 1-transformed cells.

PubMed

Rao, Dinesh S; Bradley, Sarah V; Kumar, Priti D; Hyun, Teresa S; Saint-Dic, Djenann; Oravecz-Wilson, Katherine; Kleer, Celina G; Ross, Theodora S

2003-05-01

The clathrin-associated protein, Huntingtin Interacting Protein 1 (HIP1), is overexpressed in multiple human epithelial tumors. Here, we report that HIP1 is a novel oncoprotein that transforms cells. HIP1-transformed cells, in contrast to RasV12-transformed cells, have dysregulation of multiple receptors involved in clathrin trafficking. Examples include upregulation of the epidermal growth factor receptor (EGFR) and the transferrin receptor. Furthermore, accumulation of transferrin and EGF in the HIP1-transformed cells was increased, and breast tumors that had EGFR expressed also had HIP1 upregulated. Thus, HIP1 overexpression promotes tumor formation and is associated with a general alteration in receptor trafficking. HIP1 is the first endocytic protein to be directly implicated in tumor formation.

Cholesterol-dependent retention of GPI-anchored proteins in endosomes.

PubMed Central

Mayor, S; Sabharanjak, S; Maxfield, F R

1998-01-01

Several cell surface eukaryotic proteins have a glycosylphosphatidylinositol (GPI) modification at the Cterminal end that serves as their sole means of membrane anchoring. Using fluorescently labeled ligands and digital fluorescence microscopy, we show that contrary to the potocytosis model, GPI-anchored proteins are internalized into endosomes that contain markers for both receptor-mediated uptake (e.g. transferrin) and fluid phase endocytosis (e.g. dextrans). This was confirmed by immunogold electron microscopy and the observation that a fluorescent folate derivative bound to the GPI-anchored folate receptor is internalized into the same compartment as co-internalized horseradish peroxidase-transferrin; the folate fluorescence was quenched when cells subsequently were incubated with diaminobenzidine and H2O2. Most of the GPI-anchored proteins are recycled back to the plasma membrane but at a rate that is at least 3-fold slower than C6-NBD-sphingomyelin or recycling receptors. This endocytic retention is regulated by the level of cholesterol in cell membranes; GPI-anchored proteins are recycled back to the cell surface at the same rate as recycling transferrin receptors and C6-NBD-sphingomyelin in cholesterol-depleted cells. Cholesterol-dependent endocytic sorting of GPI-anchored proteins is consistent with the involvement of specialized lipid domains or 'rafts' in endocytic sorting. These results provide an alternative explanation for GPI-requiring functions of some GPI-anchored proteins. PMID:9707422

The acute phase response of cod (Gadus morhua L.): expression of immune response genes.

PubMed

Audunsdottir, Sigridur S; Magnadottir, Bergljot; Gisladottir, Berglind; Jonsson, Zophonias O; Bragason, Birkir Th

2012-02-01

An acute phase response (APR) was experimentally induced in Atlantic cod (Gadus morhua L.) by intramuscular injection of turpentine oil. The change in the expression of immune related genes was monitored in the anterior kidney and the spleen over a period of 7 days. The genes examined were two types of pentraxins, apolipoprotein A1 (ApoA-I), the complement component C3, interleukin-1β (IL-1β), transferrin, cathelicidin, and hepcidin. All genes were constitutively expressed in both organs and their expression amplified by the turpentine injection. A pattern of response was observed both with respect to the organ preference and to the timing of a maximum response. The increased gene expression of the pentraxins, ApoA-I and C3 was restricted to the anterior kidney, the gene expression of IL-1β, cathelicidin, and transferrin increased in both organs, while hepcidin gene expression was only significantly increased in the spleen. The pentraxins and ApoA-I appear to be early mediators of APR in cod, possibly stimulating C3 and IL-1β response, while the antimicrobial peptides may play a minor role. The increase in transferrin gene expression in both organs, and apparent indifference to cortisol release associated with the turpentine injection, suggests that this could be a typical acute phase protein in cod. Copyright © 2011 Elsevier Ltd. All rights reserved.

Fabrication of transferrin functionalized gold nanoclusters/graphene oxide nanocomposite for turn-on near-infrared fluorescent bioimaging of cancer cells and small animals.

PubMed

Wang, Yong; Chen, Jia-Tong; Yan, Xiu-Ping

2013-02-19

Transferrin (Tf)-functionalized gold nanoclusters (Tf-AuNCs)/graphene oxide (GO) nanocomposite (Tf-AuNCs/GO) was fabricated as a turn-on near-infrared (NIR) fluorescent probe for bioimaging cancer cells and small animals. A one-step approach was developed to prepare Tf-AuNCs via a biomineralization process with Tf as the template. Tf acted not only as a stabilizer and a reducer but also as a functional ligand for targeting the transferrin receptor (TfR). The prepared Tf-AuNCs gave intense NIR fluorescence that can avoid interference from biological media such as tissue autofluorescence and scattering light. The assembly of Tf-AuNCs and GO gave the Tf-AuNCs/GO nanocomposite, a turn-on NIR fluorescent probe with negligible background fluorescence due to the super fluorescence quenching property of GO. The NIR fluorescence of the Tf-AuNCs/GO nanocomposite was effectively restored in the presence of TfR, due to the specific interaction between Tf and TfR and the competition of TfR with the GO for the Tf in Tf-AuNCs/GO composite. The developed turn-on NIR fluorescence probe offered excellent water solubility, stability, and biocompatibility, and exhibited high specificity to TfR with negligible cytotoxicity. The probe was successfully applied for turn-on fluorescent bioimaging of cancer cells and small animals.

Aging is Associated with Impaired Renal Function, INF-gamma Induced Inflammation and with Alterations in Iron Regulatory Proteins Gene Expression.

PubMed

Costa, Elísio; Fernandes, João; Ribeiro, Sandra; Sereno, José; Garrido, Patrícia; Rocha-Pereira, Petronila; Coimbra, Susana; Catarino, Cristina; Belo, Luís; Bronze-da-Rocha, Elsa; Vala, Helena; Alves, Rui; Reis, Flávio; Santos-Silva, Alice

2014-12-01

Our aim was to contribute to a better understanding of the pathophysiology of anemia in elderly, by studying how aging affects renal function, iron metabolism, erythropoiesis and the inflammatory response, using an experimental animal model. The study was performed in male Wistar, a group of young rats with 2 months age and an old one with 18 months age. Old rats presented a significant higher urea, creatinine, interferon (INF)-gamma, ferritin and soluble transferrin receptor serum levels, as well as increased counts of reticulocytes and RDW. In addition, these rats showed significant lower erythropoietin (EPO) and iron serum levels. Concerning gene expression of iron regulatory proteins, old rats presented significantly higher mRNA levels of hepcidin (Hamp), transferrin (TF), transferrin receptor 2 (TfR2) and hemojuvelin (HJV); divalent metal transporter 1 (DMT1) mRNA levels were significantly higher in duodenal tissue; EPO gene expression was significantly higher in liver and lower in kidney, and the expression of the EPOR was significantly higher in both liver and kidney. Our results showed that aging is associated with impaired renal function, which could be in turn related with the inflammatory process and with a decline in EPO renal production. Moreover, we also propose that aging may be associated with INF-gamma-induced inflammation and with alterations upon iron regulatory proteins gene expression.

Rab15 Effector Protein: A Novel Protein for Receptor Recycling from the Endocytic Recycling CompartmentD⃞

PubMed Central

Strick, David J.; Elferink, Lisa A.

2005-01-01

Sorting endosomes and the endocytic recycling compartment are critical intracellular stores for the rapid recycling of internalized membrane receptors to the cell surface in multiple cell types. However, the molecular mechanisms distinguishing fast receptor recycling from sorting endosomes and slow receptor recycling from the endocytic recycling compartment remain poorly understood. We previously reported that Rab15 differentially regulates transferrin receptor trafficking through sorting endosomes and the endocytic recycling compartment, suggesting a role for distinct Rab15-effector interactions at these endocytic compartments. In this study, we identified the novel protein Rab15 effector protein (REP15) as a binding partner for Rab15-GTP. REP15 is compartment specific, colocalizing with Rab15 and Rab11 on the endocytic recycling compartment but not with Rab15, Rab4, or early endosome antigen 1 on sorting endosomes. REP15 interacts directly with Rab15-GTP but not with Rab5 or Rab11. Consistent with its localization, REP15 overexpression and small interfering RNA-mediated depletion inhibited transferrin receptor recycling from the endocytic recycling compartment, without affecting receptor entry into or recycling from sorting endosomes. Our data identify REP15 as a compartment-specific protein for receptor recycling from the endocytic recycling compartment, highlighting that the rapid and slow modes of transferrin receptor recycling are mechanistically distinct pathways. PMID:16195351

Stable nanoconjugates of transferrin with alloyed quaternary nanocrystals Ag-In-Zn-S as a biological entity for tumor recognition.

PubMed

Matysiak-Brynda, Edyta; Bujak, Piotr; Augustin, Ewa; Kowalczyk, Agata; Mazerska, Zofia; Pron, Adam; Nowicka, Anna M

2018-01-18

One way to limit the negative effects of anti-tumor drugs on healthy cells is targeted therapy employing functionalized drug carriers. Here we present a biocompatible and stable nanoconjugate of transferrin anchored to Ag-In-Zn-S quantum dots modified with 11-mercaptoundecanoic acid (Tf-QD) as a drug carrier versus typical anticancer drug, doxorubicin. Detailed investigations of Tf-QD nanoconjugates without and with doxorubicin by fluorescence studies and cytotoxic measurements showed that the biological activity of both the transferrin and doxorubicin was fully retained in the nanoconjugate. In particular, the intercalation capabilities of free doxorubicin versus ctDNA remained essentially intact upon its binding to the nanoconjugate. In order to evaluate these capabilities, we studied the binding constant of doxorubicin attached to Tf-QDs with ctDNA as well as the binding site size on the ctDNA molecule. The binding constant slightly decreased compared to that of free doxorubicin while the binding site size, describing the number of consecutive DNA lattice residues involved in the binding, increased. It was also demonstrated that the QDs alone and in the form of a nanoconjugate with Tf were not cytotoxic towards human non-small cell lung carcinoma (H460 cell line) and the tumor cell sensitivity of the DOX-Tf-QD nanoconjugate was comparable to that of doxorubicin alone.

Transferrin receptors in human tissues: their distribution and possible clinical relevance.

PubMed

Gatter, K C; Brown, G; Trowbridge, I S; Woolston, R E; Mason, D Y

1983-05-01

The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron.

Transferrin receptors in human tissues: their distribution and possible clinical relevance.

PubMed Central

Gatter, K C; Brown, G; Trowbridge, I S; Woolston, R E; Mason, D Y

1983-01-01

The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron. Images PMID:6302135

Daily propranolol administration reduces persistent injury-associated anemia after severe trauma and chronic stress.

PubMed

Alamo, Ines G; Kannan, Kolenkode B; Bible, Letitia E; Loftus, Tyler J; Ramos, Harry; Efron, Philip A; Mohr, Alicia M

2017-04-01

After severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow (BM) erythroid colony growth, along with decreased iron levels, and elevated erythropoietin (EPO) levels, which are insufficient to promote effective erythropoiesis. The impact of norepinephrine on iron regulators, such as ferroportin, transferrin, and transferrin receptor-1 (TFR-1), is unknown. Using a clinically relevant rodent model of lung contusion (LC), hemorrhagic shock (HS), and chronic stress (CS), we hypothesize that daily propranolol (BB), a nonselective β blocker, restores BM function and improves iron homeostasis. Male Sprague-Dawley rats were subjected to LCHS ± BB and LCHS/CS ± BB. BB was achieved with propranolol (10 mg/kg) daily until the day of sacrifice. Hemoglobin, plasma EPO, plasma hepcidin, BM cellularity and BM erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data are presented as mean ± SD; *p < 0.05 versus untreated counterpart by t test. The addition of CS to LCHS leads to persistent anemia on posttrauma day 7, while the addition of BB improved hemoglobin levels (LCHS/CS: 10.6 ± 0.8 vs. LCHS/CS + BB: 13.9 ± 0.4* g/dL). Daily BB use after LCHS/CS improved BM cellularity, colony-forming units granulocyte, erythrocyte, monocyte megakaryocyte, burst-forming unit erythroid and colony-forming unit erythroid cell colony growth. LCHS/CS + BB significantly reduced plasma EPO levels and increased plasma hepcidin levels on day 7. The addition of CS to LCHS resulted in decreased liver ferroportin expression as well as decreased BM transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators. Daily propranolol administration after LCHS/CS restored BM function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced after LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis.

Daily propranolol administration reduces persistent injury-associated anemia following severe trauma and chronic stress

PubMed Central

Alamo, Ines G.; Kannan, Kolenkode B.; Bible, Letitia E.; Loftus, Tyler J.; Ramos, Harry; Efron, Philip A.; Mohr, Alicia M.

2017-01-01

Background Following severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow erythroid colony growth, along with decreased iron levels, and elevated erythropoietin (EPO) levels, which are insufficient to promote effective erythropoiesis. The impact of norepinephrine on iron regulators such as ferroportin, transferrin and transferrin receptor-1 (TFR-1) are unknown. Using a clinically relevant rodent model of lung contusion (LC), hemorrhagic shock (HS), and chronic stress (CS), we hypothesize that daily propranolol (BB), a non-selective beta-blocker, restores bone marrow function and improves iron homeostasis. Methods Male Sprague-Dawley rats were subjected to LCHS±BB and LCHS/CS±BB. BB was achieved with propranolol (10mg/kg) daily until the day of sacrifice. Hemoglobin (Hgb), plasma EPO, plasma hepcidin, bone marrow cellularity and bone marrow erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data is presented as mean±SD; *p<0.05 vs. untreated counterpart by t-test. Results The addition of CS to LCHS leads to persistent anemia on post-trauma day 7, while the addition of BB improved Hgb levels (LCHS/CS: 10.6±0.8 vs. LCHS/CS+BB: 13.9±0.4* g/dL). Daily BB use following LCHS/CS improved BM cellularity, CFU-GEMM, BFU-E and CFU-E colony growth. LCHS/CS+BB significantly reduced plasma EPO levels and increased plasma hepcidin levels on day 7. The addition of CS to LCHS resulted in decreased liver ferroportin expression as well as decreased bone marrow transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators. Conclusions Daily propranolol administration following LCHS/CS restored bone marrow function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced following LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis. Level of Evidence Level II, therapeutic study PMID:28099381

Extracellular delivery induced by ultrasound and microbubbles in cells

NASA Astrophysics Data System (ADS)

Hussein, Farah; Antonescu, Costin; Karshafian, Raffi

2017-03-01

Ultrasound and microbubble treatment (USMB) can enhance the intracellular uptake of molecules, which otherwise would be excluded from the cell, through USMB-mediated transient membrane disruption and through enhanced endocytosis. However, the effect of USMB on the outward movement of molecules from cells is not well understood. This study investigates the effects of USMB on the release of molecules from various cellular compartments including cytoplasm, lysosomes, and recycling endosomes. In vitro ARPE-19 (RPE henceforth) cells were loaded with Alexa fluor-labeled transferrin as a marker for recycling endosomes, LAMP-1 antibody was used to detect the fusion of lysosomes with the plasma membrane, GFP-transfected RPE cells were used to examine the release of GFP from the cytoplasm, and 7-AAD was used to assess cell viability. Subsequently, cells were exposed to USMB (106 cells/mL, 300 kPa peak negative pressure, 1 min treatment duration, and 20 µL/mL Definity microbubbles). Following USMB, the release of the fluorescent markers was examined at 1.5, 11.5, and 21.5 minutes from the start of USMB. The mean fluorescent intensity (MFI) of untreated and USMB treated samples were measured using flow cytometry. USMB increased the extracellular delivery of GFP molecules from the cytoplasm; the MFI in USMB treated GFP-transfected RPE cells decreased by 17% in viable cells and this MFI decreased by 70% in non-viable cells. This could be due to diffusion of GFP through the membrane disruptions induced by USMB. Additionally, the MFI of viable cells stained with LAMP-1 antibody increased by 50% and this increase was 15 folds in the non-viable cells indicating lysosome exocytosis as a mechanism for membrane repair. Furthermore, the MFI of cells loaded with fluorescent transferrin decreased by 22% after USMB treatment in viable cells, indicating a significant increase in transferrin recycling to the cell membrane. However, the increased recycling was not statistically significant in the non-viable cells. This indicates that the increase in transferrin recycling was through an active mechanism that was triggered or enhanced by USMB. It was concluded from this study that USMB enhances the release of molecules from the cytoplasm, lysosomes, and recycling endosomes.

Iron homeostasis and toxicity in retinal degeneration

PubMed Central

He, Xining; Hahn, Paul; Iacovelli, Jared; Wong, Robert; King, Chih; Bhisitkul, Robert; Massaro-Giordano, Mina; Dunaief, Joshua L.

2007-01-01

Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels build up with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich’s Ataxia, and panthothenate kinase associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age- matched controls. Over the past ten years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter 1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential. PMID:17921041

Iron toxicity and its possible association with treatment of Cancer: lessons from hemoglobinopathies and rare, transfusion-dependent anemias.

PubMed

Puliyel, Mammen; Mainous, Arch G; Berdoukas, Vasilios; Coates, Thomas D

2015-02-01

Exposure to elevated levels of iron causes tissue damage and organ failure, and increases the risk of cancer. The toxicity of iron is mediated through generation of oxidants. There is also solid evidence indicating that oxidant stress plays a significant role in a variety of human disease states, including malignant transformation. Iron toxicity is the main focus when managing thalassemia. However, the short- and long-term toxicities of iron have not been extensively considered in children and adults treated for malignancy, and only recently have begun to draw oncologists' attention. The treatment of malignancy can markedly increase exposure of patients to elevated toxic iron species without the need for excess iron input from transfusion. This under-recognized exposure likely enhances organ toxicity and may contribute to long-term development of secondary malignancy and organ failure. This review discusses the current understanding of iron metabolism, the mechanisms of production of toxic free iron species in humans, and the relation of the clinical marker, transferrin saturation (TS), to the presence of toxic free iron. We will present epidemiological data showing that high TS is associated with poor outcomes and development of cancer, and that lowering free iron may improve outcomes. Finally, we will discuss the possible relation between some late complications seen in survivors of cancer and those due to iron toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

Iron overload and HFE gene mutations in Czech patients with chronic liver diseases.

PubMed

Dostalikova-Cimburova, Marketa; Kratka, Karolina; Stransky, Jaroslav; Putova, Ivana; Cieslarova, Blanka; Horak, Jiri

2012-01-01

The aim of the study was to identify the prevalence of HFE gene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence of HFE gene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency of HFE gene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence of HFE gene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies of HFE mutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases but {\\it HFE} mutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease.

HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases

PubMed Central

Evangelista, Andreia Silva; de Araújo, Thiago Ferreira; Abrantes-Lemos, Clarice Pires; Deguti, Marta Mitiko; Cançado, Eduardo Luiz Rachid

2015-01-01

Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS) > 45%, and serum ferritin (SF) > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n = 16) were the HFE hereditary hemochromatosis (HFE-HH) group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n = 92). Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population. PMID:25654085

Low prevalence of iron deficiency anemia between 1981 and 2010 in Chilean women of childbearing age.

PubMed

Ríos-Castillo, Israel; Brito, Alex; Olivares, Manuel; López-de Romaña, Daniel; Pizarro, Fernando

2013-01-01

To determine the prevalence of anemia and iron status among Chilean women of childbearing age between 1981 and 2010. Calculation of the prevalence of anemia and iron status was based on multiple cross-sectional iron absorption studies performed in 888 women during this period of time. All studies included measurements of hemoglobin, mean corpuscular volume, zinc protoporphyrin, percentage of transferrin saturation and serum ferritin. Data were grouped by decade (1981-1990, 1991-2000, and 2001-2010). Prevalence of anemia for these decades was 9, 6 and 10%, respectively (p=NS). Iron deficiency anemia was the main cause of anemia in all periods (55, 85 and 75%, respectively; p=NS). A high prevalence of women with normal iron status was observed for all periods (64, 69, and 67, respectively; p=NS). Prevalence of iron deficiency without anemia in 1981-1990, 1991-2000 and 2001-2010 was 7, 20 and 12%, respectively (p<0.05). Finally, prevalence of iron depleted stores was 20, 6 and 10%, respectively (p<0.05). Prevalence of iron deficiency anemia in Chilean women of childbearing age was mild between 1981 and 2010. More than 60% of childbearing age women presented normal iron status in all periods. However, prevalence of iron depleted stores was moderate during 1981-1990, and was mild during 1991-2000 and 2001-2010.

NURSE STAFFING AND RENAL ANAEMIA OUTCOMES IN HAEMODIALYSIS CARE.

PubMed

Erlingmark, Julia; Hedström, Mariann; Lindberg, Magnus

2016-09-01

Current trends in renal anaemia management place greater emphasis, and thus increased workload, on the role of the nurse in haemodialysis settings. However, there is little evidence that demonstrates the relationship between nurse staffing and patient outcomes. To describe nurse staffing in haemodialysis settings, its relationship with target levels of renal anaemia management and to describe target level achievement for different ways of organising anaemia management. Cross-sectional audit. Forty (out of 78) haemodialysis centres in Sweden reported quality assurance data. The numbers of bedside registered nurses, licensed nurse assistants and patients undergoing haemodialysis during a predefined morning shift; type of anaemia management and achieved target levels of anaemia management. The mean patient:registered nurse ratio was 2.4 and the mean patient:nurse assistant ratio was 12.8. There were no significant relationships between registered nurse staffing and target level achievement. On average, 45.6% of the patients had haemoglobin within the target levels at centres applying nurse-driven anaemia management, compared with 47.3% at physician-driven centres. These cross-sectional data suggest that renal anaemia outcomes are unrelated to the patient:registered nurse ratio. There is, however, room for improvement in renal anaemia management in the units included in this study, particularly the achievement of target levels of haemoglobin and transferrin saturation. © 2016 European Dialysis and Transplant Nurses Association/European Renal Care Association.

Determining appropriate nutritional interventions for South African children living in informal urban settlements.

PubMed

Coutsoudis, A; Jinabhai, C C; Coovadia, H M; Mametja, L D

1994-09-01

Rapid urbanisation in South Africa has led to the creation of informal shack settlements where the health status of children is in jeopardy; it needs to be monitored so that appropriate intervention strategies can be formulated. Accordingly, the nutritional status of 190 children (3-6 years of age) living in Besters, a typical urban shack settlement north of Durban, was assessed anthropometrically. In addition the following biochemical values were determined: vitamins A and E, calcium, magnesium, phosphorus, albumin, haemoglobin, serum iron and ferritin and percentage of transferrin saturation. Malnutrition was evident in 13% of the children who were underweight (below the National Center for Health Statistics (NCHS) third weight-for-age percentile) and 27% who were stunted (below the NCHS third height-for-age percentile). Concentrations of albumin, calcium, magnesium, phosphorus and vitamin E were close to normal, with no more than 10% of the sample having values outside the normal range. However, 44% of the children had low serum retinol levels (< 20 micrograms/dl) and 21% of the children had anaemia (haemoglobin < 11 micrograms/dl). Significant positive correlations were found between serum retinol and all biochemical indicators of iron status except serum ferritin. This study highlights the fact that nutrient deficiencies are interrelated, particularly protein energy malnutrition and poor vitamin A and iron status. A broad multifaceted comprehensive health intervention programme is therefore required.

Iron uptake and increased intracellular enzyme activity follow host lactoferrin binding by Trichomonas vaginalis receptors

PubMed Central

1984-01-01

Lactoferrin acquisition and iron uptake by pathogenic Trichomonas vaginalis was examined. Saturation binding kinetics were obtained for trichomonads using increasing amounts of radioiodinated lactoferrin, while no significant binding by transferrin under similar conditions was achieved. Only unlabeled lactoferrin successfully and stoichiometrically competed with 125I-labeled lactoferrin binding. Time course studies showed maximal lactoferrin binding by 30 min at 37 degrees C. Data suggest no internalization of bound lactoferrin. The accumulation of radioactivity in supernatants after incubation of T. vaginalis with 125I-labeled lactoferrin and washing in PBS suggested the presence of low affinity sites for this host macromolecule. Scatchard analysis indicated the presence of 90,000 receptors per trichomonad with an apparent Kd of 1.0 microM. Two trichomonad lactoferrin binding proteins were identified by affinity chromatography and immunoprecipitation of receptor-ligand complexes. A 30-fold accumulation of iron was achieved using 59Fe-lactoferrin when compared to the steady state concentration of bound lactoferrin. The activity of pyruvate/ferrodoxin oxidoreductase, an enzyme involved in trichomonal energy metabolism, increased more than sixfold following exposure of the parasites to lactoferrin, demonstrating a biologic response to the receptor-mediated binding of lactoferrin. These data suggest that T. vaginalis possesses specific receptors for biologically relevant host proteins and that these receptors contribute to the metabolic processes of the parasites. PMID:6088662

Intestinal blood loss as an aggravating factor of iron deficiency in infants aged 9 to 12 months fed whole cow's milk.

PubMed

Fernandes, Sandra Maria Rodrigues; de Morais, Mauro Batista; Amancio, Olga Maria Silverio

2008-02-01

To verify the occurrence of occult intestinal blood loss and iron deficiency in infants aged 9 to 12 months. A consecutive sample of 98 infants of the Pediatric Public Health Primary Care Unit in the town of Arapongas, Parana State, Brazil was involved in this cross-sectional study. Dietary history, hemoglobin, serum iron, transferrin saturation, ferritin, and an occult fecal blood loss investigation, by the immune chromatographic method specific for human hemoglobin were performed. Presence of occult intestinal blood occurred in 8/23 of the breast-fed (plus complementary feed) infants and in 30/64 of the infants who were fed with cow's milk (plus complementary feed) (P=0.449). The comparison of body iron indicators in accordance to positive or negative occult fecal blood, did not show any significant difference in the 23 breast-fed infants. Serum ferritin (median=4.2 ng/mL) was significantly lower (P=0.004) in infants who received whole cow's milk and had positive occult fecal blood, than in those infants who received whole cow's milk but were without occult fecal blood (median=12.1 ng/mL). In breast-fed infants with negative occult fecal blood, iron deficiency severity is not greater than in those with positive results. In infants fed whole cow's milk, occult fecal blood loss is an aggravating factor of iron deficiency.

Heritability of Serum Iron Measures in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study

PubMed Central

McLaren, Christine E.; Barton, James C.; Eckfeldt, John H.; McLaren, Gordon D.; Acton, Ronald T.; Adams, Paul C.; Henkin, Leora F.; Gordeuk, Victor R.; Vulpe, Chris D.; Harris, Emily L.; Harrison, Barbara W.; Reiss, Jacob A.; Snively, Beverly M.

2013-01-01

Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation. PMID:20095037

Iron Supplementation Effects on Redox Status following Aseptic Skeletal Muscle Trauma in Adults and Children.

PubMed

Deli, Chariklia K; Fatouros, Ioannis G; Paschalis, Vassilis; Tsiokanos, Athanasios; Georgakouli, Kalliopi; Zalavras, Athanasios; Avloniti, Alexandra; Koutedakis, Yiannis; Jamurtas, Athanasios Z

2017-01-01

Exercise-induced skeletal muscle microtrauma is characterized by loss of muscle cell integrity, marked aseptic inflammatory response, and oxidative stress. We examined if iron supplementation would alter redox status after eccentric exercise. In a randomized, double blind crossover study, that was conducted in two cycles, healthy adults ( n = 14) and children ( n = 11) received daily either 37 mg of elemental iron or placebo for 3 weeks prior to and up to 72 h after an acute eccentric exercise bout. Blood was drawn at baseline, before exercise, and 72 h after exercise for the assessment of iron status, creatine kinase activity (CK), and redox status. Iron supplementation at rest increased iron concentration and transferrin saturation ( p < 0.01). In adults, CK activity increased at 72 h after exercise, while no changes occurred in children. Iron supplementation increased TBARS at 72 h after exercise in both adults and children; no changes occurred under placebo condition. Eccentric exercise decreased bilirubin concentration at 72 h in all groups. Iron supplementation can alter redox responses after muscle-damaging exercise in both adults and children. This could be of great importance not only for healthy exercising individuals, but also in clinical conditions which are characterized by skeletal muscle injury and inflammation, yet iron supplementation is crucial for maintaining iron homeostasis. This study was registered at Clinicaltrials.gov Identifier: NCT02374619.

Phenotypic expression of the HLA-linked iron-loading gene in the Afrikaner population of the western Cape.

PubMed

Meyer, T E; Baynes, R D; Bothwell, T H; Jenkins, T; Ballot, D; Jooste, P L; Green, A; Du Toit, E; Jacobs, P

1988-03-05

A previous study conducted on a group of Afrikaans-speaking subjects in the south-western Cape indicated a high frequency (0.115) of the HLA-linked iron-loading gene which causes idiopathic haemochromatosis. The results of phenotypic and genotypic studies on the first degree relatives of identified homozygotes and heterozygotes are now reported. There was considerable heterogeneity of phenotypic expression in the group of heterozygotes, with overlap between the homozygous and heterozygous subjects. The heterozygous relatives of heterozygous index cases, who had been identified on the basis of a serum ferritin concentration greater than 400 micrograms/l, appeared to have more frequent and more marked abnormalities of iron measurements than the heterozygote relatives of homozygous index cases (serum ferritin value greater than 400 micrograms/l, percentage transferrin saturation greater than 60). This suggests that the screening test was identifying a group of more significantly affected heterozygotes, with biochemical abnormalities that overlapped with the identified homozygotes. The index cases were followed up over a period of 5 years and during this time the 7 subjects diagnosed as heterozygotes showed a progressive increase in serum ferritin concentrations, which suggests some iron accumulation. Individual pedigrees included instances of gene recombination within the major histocompatibility complex, and of probable false-positive genotype assignment. The overall results confirm a high frequency of the gene in this particular community.

Hemochromatosis and Vibrio vulnificus wound infections.

PubMed

Barton, James C; Acton, Ronald T

2009-10-01

There are several reports of persons with hemochromatosis and Vibrio vulnificus primary septicemia, but few accounts of persons with hemochromatosis and V. vulnificus wound infection. A 58-year-old white man developed infection of a forearm injury exposed to seawater in the Gulf of Mexico near the Alabama coast. At age 66, he was diagnosed to have hemochromatosis. Transferrin saturation was 89% and serum ferritin was 4761 pmol/L. HFE genotype was C282Y/C282Y. Serum levels of hepatic enzymes, glucose, IgG, IgA, and IgM, and blood levels of T, B, and natural killer cells were normal. We identified previous reports of only 2 similar cases: a woman from Alabama and a man from northern Australia. Mean age of the 3 subjects was 51 years at diagnosis of infection. Each had elevated serum iron measures or iron overload complications; both men were diagnosed to have hemochromatosis after they developed infection. Each of the 3 had recent exposure of a wound on an extremity to seawater, rapid development of a necrotizing soft tissue infection that required debridement and skin grafting, and positive wound or blood cultures. Each subject survived the infection. V. vulnificus wound infection occurs in some persons with hemochromatosis, but the risk of infection may be small. All patients with V. vulnificus infections should be evaluated for hemochromatosis, iron overload, and liver disorders.

Relationship of Baseline Hemoglobin Level with Serum Ferritin, Postphlebotomy Hemoglobin Changes, and Phlebotomy Requirements among HFE C282Y Homozygotes

PubMed Central

Mousavi, Seyed Ali; Mahmood, Faiza; Aandahl, Astrid; Knutsen, Teresa Risopatron; Llohn, Abid Hussain

2015-01-01

Objectives. We aimed to examine whether baseline hemoglobin levels in C282Y-homozygous patients are related to the degree of serum ferritin (SF) elevation and whether patients with different baseline hemoglobin have different phlebotomy requirements. Methods. A total of 196 patients (124 males and 72 females) who had undergone therapeutic phlebotomy and had SF and both pre- and posttreatment hemoglobin values were included in the study. Results. Bivariate correlation analysis suggested that baseline SF explains approximately 6 to 7% of the variation in baseline hemoglobin. The results also showed that males who had higher (≥150 g/L) baseline hemoglobin levels had a significantly greater reduction in their posttreatment hemoglobin despite requiring fewer phlebotomies to achieve iron depletion than those who had lower (<150 g/L) baseline hemoglobin, regardless of whether baseline SF was below or above 1000 µg/L. There were no significant differences between hemoglobin subgroups regarding baseline and treatment characteristics, except for transferrin saturation between male subgroups with SF above 1000 µg/L. Similar differences were observed when females with higher (≥138 g/L) baseline hemoglobin were compared with those with lower (<138 g/L) baseline hemoglobin. Conclusion. Dividing C282Y-homozygous patients into just two subgroups according to the degree of baseline SF elevation may obscure important subgroup variations. PMID:26380265

Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds.

PubMed

Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Uhr, Manfred; Wagner, Eva-Maria; Gilling, Kate E; Parsons, Chris G; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer; Rammes, Gerhard

2013-07-01

Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.

Creatinine

MedlinePlus

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Toxoplasmosis Testing

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Helicobacter pylori Test

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VMA Test

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Vitamin A Test

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B Vitamins Test

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Celiac Disease Tests

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Plasma Free Metanephrines

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Dengue Fever Testing

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Lactose Tolerance Tests

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Uric Acid Test

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Comprehensive Metabolic Panel

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5-HIAA Test

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Phosphorus Test

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Peritoneal Fluid Analysis

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Serotonin Test

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Throat Culture

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TB Screening Tests

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PTH Test

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Blood Typing

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AMA Test

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Progesterone Test

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Gram Stain

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Additive controlled synthesis of gold nanorods (GNRs) for two-photon luminescence imaging of cancer cells

NASA Astrophysics Data System (ADS)

Zhu, Jing; Yong, Ken-Tye; Roy, Indrajit; Hu, Rui; Ding, Hong; Zhao, Lingling; Swihart, Mark T.; He, Guang S.; Cui, Yiping; Prasad, Paras N.

2010-07-01

Gold nanorods (GNRs) with a longitudinal surface plasmon resonance peak that is tunable from 600 to 1100 nm have been fabricated in a cetyl trimethylammoniumbromide (CTAB) micellar medium using hydrochloric acid and silver nitrate as additives to control their shape and size. By manipulating the concentrations of silver nitrate and hydrochloric acid, the aspect ratio of the GNRs was reliably and reproducibly tuned from 2.5 to 8. The GNRs were first coated with polyelectrolyte multilayers and then bioconjugated to transferrin (Tf) to target pancreatic cancer cells. Two-photon imaging excited from the bioconjugated GNRs demonstrated receptor-mediated uptake of the bioconjugates into Panc-1 cells, overexpressing the transferrin receptor (TfR). The bioconjugated GNR formulation exhibited very low toxicity, suggesting that it is biocompatible and potentially suitable for targeted two-photon bioimaging.

Non-HFE haemochromatosis

PubMed Central

Wallace, Daniel F; Subramaniam, V Nathan

2007-01-01

Non-HFE hereditary haemochromatosis (HH) refers to a genetically heterogeneous group of iron overload disorders that are unlinked to mutations in the HFE gene. The four main types of non-HFE HH are caused by mutations in the hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Juvenile haemochromatosis is an autosomal recessive disorder and can be caused by mutations in either hemojuvelin or hepcidin. An adult onset form of HH similar to HFE-HH is caused by homozygosity for mutations in transferrin receptor 2. The autosomal dominant iron overload disorder ferroportin disease is caused by mutations in the iron exporter ferroportin. The clinical characteristics and molecular basis of the various types of non-HFE haemochromatosis are reviewed. The study of these disorders and the molecules involved has been invaluable in improving our understanding of the mechanisms involved in the regulation of iron metabolism. PMID:17729390

Use of Ribosome-Inactivating Proteins from Sambucus for the Construction of Immunotoxins and Conjugates for Cancer Therapy

PubMed Central

Ferreras, José M.; Citores, Lucía; Iglesias, Rosario; Jiménez, Pilar; Girbés, Tomás

2011-01-01

The type 2 ribosome-inactivating proteins (RIPs) isolated from some species belonging to the Sambucus genus, have the characteristic that although being even more active than ricin inhibiting protein synthesis in cell-free extracts, they lack the high toxicity of ricin and related type 2 RIPs to intact cells and animals. This is due to the fact that after internalization, they follow a different intracellular pathway that does not allow them to reach the cytosolic ribosomes. The lack of toxicity of type 2 RIPs from Sambucus make them good candidates as toxic moieties in the construction of immunotoxins and conjugates directed against specific targets. Up to now they have been conjugated with either transferrin or anti-CD105 to target either transferrin receptor- or endoglin-overexpressing cells, respectively. PMID:22069717

Genetically engineered Escherichia coli Nissle 1917 synbiotic counters fructose-induced metabolic syndrome and iron deficiency.

PubMed

Chaudhari, Archana Somabhai; Raghuvanshi, Ruma; Kumar, G Naresh

2017-06-01

Consumption of fructose leads to metabolic syndrome, but it is also known to increase iron absorption. Present study investigates the effect of genetically modified Escherichia coli Nissle 1917 (EcN) synbiotic along with fructose on non-heme iron absorption. Charles foster rats weighing 150-200 g were fed with iron-deficient diet for 2 months. Probiotic treatment of EcN (pqq) and EcN (pqq-glf-mtlK) was given once per week, 10 9  cells after 2 months with fructose in drinking water. Iron levels, blood, and liver parameters for oxidative stress, hyperglycemia, and dyslipidemia were estimated. Transferrin-bound iron levels in the blood decreased significantly after 10 weeks of giving iron-deficient diet. Probiotic treatment of EcN (pqq-glf-mtlK) and fructose together led to the restoration of normal transferrin-bound iron levels and blood and hepatic antioxidant levels as compared to iron-deficient control group. The probiotic also led to the restoration of body weight along with levels of serum and hepatic lipid, blood glucose, and antioxidant in the blood and liver as compared to iron-deficient control group. Restoration of liver injury marker enzymes was also seen. Administration of EcN-producing PQQ and mannitol dehydrogenase enzyme together with fructose led to increase in the transferrin-bound iron levels in the blood and amelioration of consequences of metabolic syndrome caused due to fructose consumption.

Lime powder treatment reduces urinary excretion of total protein and transferrin but increases uromodulin excretion in patients with urolithiasis.

PubMed

Tosukhowong, Piyaratana; Kulpradit, Pimsuda; Chaiyarit, Sakdithep; Ungjareonwattana, Wattanachai; Kalpongnukul, Nuttiya; Ratchanon, Supoj; Thongboonkerd, Visith

2018-06-01

Our previous study has shown that lime powder (LP) had an inhibitory effect against calcium oxalate stone formation. However, the precise mechanisms underlying such beneficial effect remained unclear. Our present study thus aimed to address the effect of LP on excretory level and compositions of urinary proteins using a proteomics approach. From a total of 80 calcium oxalate stone formers recruited into our 2-year randomized clinical trial of LP effect, 10 patients with comparable age and clinical parameters were selected for this proteomic study. 24-h urine specimens were collected from all subjects, at baseline (before) and after LP treatment for 6 months, and then subjected to quantitative proteomics analysis and subsequent validation by ELISA. Total urinary protein excretion was significantly decreased by LP treatment, but unaffected by placebo. Nanoflow liquid chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS) followed by quantitative analysis revealed 17 proteins whose levels were significantly altered (16 decreased and 1 increased) exclusively by LP treatment. Among these, the decrease of transferrin and increase of uromodulin were validated by ELISA. Moreover, there was a significant correlation between microalbuminuria and urinary transferrin level by Pearson's correlation test. In summary, LP treatment caused significant reduction in total urinary protein excretion and changes in urinary protein compositions that could be linked to stone inhibitory effects and might be relevant mechanisms responsible for the beneficial effects of LP to prevent kidney stone formation and recurrence.

Transferrin-modified liposome promotes α-mangostin to penetrate the blood-brain barrier.

PubMed

Chen, Zhi-Lan; Huang, Man; Wang, Xia-Rong; Fu, Jun; Han, Min; Shen, You-Qing; Xia, Zheng; Gao, Jian-Qing

2016-02-01

α-Mangostin (α-M) is a polyphenolic xanthone that protects and improves the survival of cerebral cortical neurons against Aβ oligomer-induced toxicity in rats. α-M is a potential candidate as a treatment for Alzheimer's disease (AD). However, the efficacy was limited by the poor penetration of the drug through the blood-brain barrier (BBB). In this study, we modified the α-M liposome with transferrin (Tf) and investigated the intracellular distribution of liposomes in bEnd3 cells. In addition, the transport of α-M across the BBB in the Tf(α-M) liposome group was examined. In vitro studies demonstrated that the Tf(α-M) liposome could cross the BBB in the form of an integrated liposome. Results of the in vivo studies on the α-M distribution in the brain demonstrated that the Tf(α-M) liposome improved the brain delivery of α-M. These results indicated that the Tf liposome is a potential carrier of α-M against AD. The use of α-Mangostin (α-M) as a potential agent to treat Alzheimer's disease (AD) has been reported. However, its use is limited by the poor penetration through the blood brain barrier. The delivery of this agent by transferrin-modified liposomes was investigated by the authors in this study. The positive results could point to a better drug delivery system for brain targeting. Copyright © 2015 Elsevier Inc. All rights reserved.

Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

PubMed Central

Faucheux, B A; Nillesse, N; Damier, P; Spik, G; Mouatt-Prigent, A; Pierce, A; Leveugle, B; Kubis, N; Hauw, J J; Agid, Y

1995-01-01

The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease. Images Fig. 1 Fig. 2 PMID:7568181

Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeong, Seung Min, E-mail: smjeong@catholic.ac.kr; Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 137-701; Hwang, Sunsook

2016-03-11

The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derivedmore » ROS are essential for PDAC growth. However, exogenous iron supplement cannot rescue the defects caused by TfR1 knockdown. Moreover, we found that TfR1 expression determines PDAC cells sensitivity to oxidative stress. Together, our findings reveal that TfR1 can contribute to the mitochondrial respiration and ROS production, which have essential roles in growth and survival of pancreatic cancer. - Highlights: • Pancreatic ductal adenocarcinoma (PDAC) exhibits an elevated transferrin receptor (TfR1) expression in comparison with non-transformed pancreatic cells. • TfR1 is required for PDAC growth by regulating mitochondrial respiration and ROS production. • TfR1 functions as a determinant of cell viability to oxidative stress in PDAC cells.« less

Receptor-based differences in human aortic smooth muscle cell membrane stiffness

NASA Technical Reports Server (NTRS)

Huang, H.; Kamm, R. D.; So, P. T.; Lee, R. T.

2001-01-01

Cells respond to mechanical stimuli with diverse molecular responses. The nature of the sensory mechanism involved in mechanotransduction is not known, but integrins may play an important role. The integrins are linked to both the cytoskeleton and extracellular matrix, suggesting that probing cells via integrins should yield different mechanical properties than probing cells via non-cytoskeleton-associated receptors. To test the hypothesis that the mechanical properties of a cell are dependent on the receptor on which the stress is applied, human aortic smooth muscle cells were plated, and magnetic beads, targeted either to the integrins via fibronectin or to the transferrin receptor by use of an IgG antibody, were attached to the cell surface. The resistance of the cell to deformation ("stiffness") was estimated by oscillating the magnetic beads at 1 Hz by use of single-pole magnetic tweezers at 2 different magnitudes. The ratio of bead displacements at different magnitudes was used to explore the mechanical properties of the cells. Cells stressed via the integrins required approximately 10-fold more force to obtain the same bead displacements as the cells stressed via the transferrin receptors. Cells stressed via integrins showed stiffening behavior as the force was increased, whereas this stiffening was significantly less for cells stressed via the transferrin receptor (P<0.001). Mechanical characteristics of vascular smooth muscle cells depend on the receptor by which the stress is applied, with integrin-based linkages demonstrating cell-stiffening behavior.

Identification of five reptile egg whites protein using MALDI-TOF mass spectrometry and LC/MS-MS analysis.

PubMed

Prajanban, Bung-on; Shawsuan, Laoo; Daduang, Sakda; Kommanee, Jintana; Roytrakul, Sittiruk; Dhiravisit, Apisak; Thammasirirak, Sompong

2012-03-16

Proteomics of egg white proteins of five reptile species, namely Siamese crocodile (Crocodylus siamensis), soft-shelled turtle (Trionyx sinensis taiwanese), red-eared slider turtle (Trachemys scripta elegans), hawksbill turtle (Eretmochelys imbricate) and green turtle (Chelonia mydas) were studied by 2D-PAGE using IPG strip pH 4-7 size 7 cm and IPG strip pH 3-10 size 24 cm. The protein spots in the egg white of the five reptile species were identified by MALDI-TOF mass spectrometry and LC/MS-MS analysis. Sequence comparison with the database revealed that reptile egg white contained at least seven protein groups, such as serpine, transferrin precursor/iron binding protein, lysozyme C, teneurin-2 (fragment), interferon-induced GTP-binding protein Mx, succinate dehydrogenase iron-sulfur subunit and olfactory receptor 46. This report confirms that transferrin precursor/iron binding protein is the major component in reptile egg white. In egg white of Siamese crocodile, twenty isoforms of transferrin precursor were found. Iron binding protein was found in four species of turtle. In egg white of soft-shelled turtle, ten isoforms of lysozyme were found. Apart from well-known reptile egg white constituents, this study identified some reptile egg white proteins, such as the teneurin-2 (fragment), the interferon-induced GTP-binding protein Mx, the olfactory receptor 46 and the succinate dehydrogenase iron-sulfur subunit. Copyright © 2012 Elsevier B.V. All rights reserved.

TonB-Dependent Transporters Expressed by Neisseria gonorrhoeae

PubMed Central

Cornelissen, Cynthia Nau; Hollander, Aimee

2011-01-01

Neisseria gonorrhoeae causes the common sexually transmitted infection, gonorrhea. This microorganism is an obligate human pathogen, existing nowhere in nature except in association with humans. For growth and proliferation, N. gonorrhoeae requires iron and must acquire this nutrient from within its host. The gonococcus is well-adapted for growth in diverse niches within the human body because it expresses efficient transport systems enabling use of a diverse array of iron sources. Iron transport systems facilitating the use of transferrin, lactoferrin, and hemoglobin have two components: one TonB-dependent transporter and one lipoprotein. A single component TonB-dependent transporter also allows N. gonorrhoeae to avail itself of iron bound to heterologous siderophores produced by bacteria within the same ecological niche. Other TonB-dependent transporters are encoded by the gonococcus but have not been ascribed specific functions. The best characterized iron transport system expressed by N. gonorrhoeae enables the use of human transferrin as a sole iron source. This review summarizes the molecular mechanisms involved in gonococcal iron acquisition from human transferrin and also reviews what is currently known about the other TonB-dependent transport systems. No vaccine is available to prevent gonococcal infections and our options for treating this disease are compromised by the emergence of antibiotic resistance. Because iron transport systems are critical for the survival of the gonococcus in vivo, the surface-exposed components of these systems are attractive candidates for vaccine development or therapeutic intervention. PMID:21747812

von Willebrand Factor Test

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ADH (Antidiuretic Hormone) Test

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Anti-Müllerian Hormone

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C-Reactive Protein (CRP) Test

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GGT (Gamma-Glutamyl Transferase) Test

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Catecholamines, Plasma and Urine Test

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PT and INR Test

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Pleural Fluid Analysis Test

MedlinePlus

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T3 (Triiodothyronine) Test

MedlinePlus

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Tips on Blood Testing

MedlinePlus

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CEA (Carcinoembryonic Antigen) Test

MedlinePlus

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On Parallelizing Single Dynamic Simulation Using HPC Techniques and APIs of Commercial Software

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diao, Ruisheng; Jin, Shuangshuang; Howell, Frederic

Time-domain simulations are heavily used in today’s planning and operation practices to assess power system transient stability and post-transient voltage/frequency profiles following severe contingencies to comply with industry standards. Because of the increased modeling complexity, it is several times slower than real time for state-of-the-art commercial packages to complete a dynamic simulation for a large-scale model. With the growing stochastic behavior introduced by emerging technologies, power industry has seen a growing need for performing security assessment in real time. This paper presents a parallel implementation framework to speed up a single dynamic simulation by leveraging the existing stability model librarymore » in commercial tools through their application programming interfaces (APIs). Several high performance computing (HPC) techniques are explored such as parallelizing the calculation of generator current injection, identifying fast linear solvers for network solution, and parallelizing data outputs when interacting with APIs in the commercial package, TSAT. The proposed method has been tested on a WECC planning base case with detailed synchronous generator models and exhibits outstanding scalable performance with sufficient accuracy.« less

Ameliorating role of rutin on oxidative stress induced by iron overload in hepatic tissue of rats.

PubMed

Aziza, Samy Ali Hussein; Azab, Mohammed El-Said; El-Shall, Soheir Kamal

2014-08-01

Iron is an essential element that participates in several metabolic activities of cells; however, excess iron is a major cause of iron-induced oxidative stress and several human diseases. Natural flavonoids, as rutin, are well-known antioxidants and could be efficient protective agents. Therefore, the present study was undertaken to evaluate the protective influence of rutin supplementation to improve rat antioxidant systems against IOL-induced hepatic oxidative stress. Sixty male albino rats were randomly divided to three equal groups. The first group, the control, the second group, iron overload group, the third group was used as iron overload+rutin group. Rats received six doses of ferric hydroxide polymaltose (100 mg kg(-1) b.wt.) as one dose every two days, by intraperitoneal injections (IP) and administrated rutin (50 mg kg(-1) b.wt.) as one daily oral dose until the sacrificed day. Blood samples for serum separation and liver tissue specimens were collected three times, after three, four and five weeks from the onset of the experiment. Serum iron profiles total iron, Total Iron Binding Capacity (TIBC), Unsaturated Iron Binding Capacity (UIBC), transferrin (Tf) and Transferrin Saturation% (TS%)}, ferritin, albumin, total Protein, total cholesterol, triacylglycerols levels and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were determined. Moreover, total iron in the liver, L-malondialdehyde (L-MDA), glutathione (GSH), Nitric Oxide (NO) and Total Nucleic Acid (TNA) levels and glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) activities were also determined. The obtained results revealed that, iron overload (IOL) resulted in significant increase in serum iron, TIBC, Tf, TS% and ferritin levels and AST and ALT activities and also increased liver iron, L-MDA and NO levels. Meanwhile, it decreased serum UIBC, total cholesterol, triacylglycerols, albumin, total protein and liver GSH, TNA levels and Gpx, CAT and SOD activities when compared with the control group. Rutin administration to iron-overloaded rats resulted in significant decrease in serum total iron, TIBC, Tf, TS%, ferritin levels and AST and ALT activities and liver total iron, L-MDA and NO levels with significant increases in serum UIBC, albumin, total protein and total cholesterol levels and in liver GSH, CAT and SOD activities compared with the IOL group. This study provides in vivo evidence that rutin administration can improve the antioxidant defense systems against IOL-induced hepatic oxidative stress in rats. This protective effect in liver of iron-loaded rats may be due to both antioxidant and metal chelation activities.

Urine Albumin and Albumin/ Creatinine Ratio

MedlinePlus

... Cancer Therapy Glucose Tests Gonorrhea Testing Gram Stain Growth Hormone Haptoglobin hCG Pregnancy hCG Tumor Marker HDL Cholesterol ... Semen Analysis Serotonin Serum Free Light Chains Sex Hormone Binding Globulin ... Transferrin Receptor Stool Culture Stool Elastase Strep ...

Total Protein and Albumin/Globulin Ratio Test

MedlinePlus

... Cancer Therapy Glucose Tests Gonorrhea Testing Gram Stain Growth Hormone Haptoglobin hCG Pregnancy hCG Tumor Marker HDL Cholesterol ... Semen Analysis Serotonin Serum Free Light Chains Sex Hormone Binding Globulin ... Transferrin Receptor Stool Culture Stool Elastase Strep ...

Association study between four polymorphisms in the HFE, TF and TFR genes and Parkinson's disease in southern Italy.

PubMed

Greco, Valentina; De Marco, Elvira Valeria; Rocca, Francesca Emanuela; Annesi, Ferdinanda; Civitelli, Donatella; Provenzano, Giovanni; Tarantino, Patrizia; Scornaienchi, Vittorio; Pucci, Franco; Salsone, Maria; Novellino, Fabiana; Morelli, Maurizio; Paglionico, Sandra; Gambardella, Antonio; Quattrone, Aldo; Annesi, Grazia

2011-06-01

Iron overload may lead to neurodegenerative disorders such as Parkinson's disease (PD) and alterations of iron-related genes might be involved in the pathogenesis of this disease. The gene of haemochromatosis (HFE) encodes the HFE protein which interacts with the transferrin receptor (TFR), lowering its affinity for iron-bound transferrin (TF). We examined four known polymorphisms, C282Y and H63D in the HFE gene, G258S in the TF gene and S82G in the TFR gene, in 181 sporadic PD patients and 180 controls from Southern Italy to investigate their possible role in susceptibility to PD. No significant differences were found in genotype and allele frequencies between PD and controls for all the polymorphisms studied, suggesting that these variants do not contribute significantly to the risk of PD.

Self-propelled carbon nanotube based microrockets for rapid capture and isolation of circulating tumor cells

NASA Astrophysics Data System (ADS)

Banerjee, Shashwat S.; Jalota-Badhwar, Archana; Zope, Khushbu R.; Todkar, Kiran J.; Mascarenhas, Russel R.; Chate, Govind P.; Khutale, Ganesh V.; Bharde, Atul; Calderon, Marcelo; Khandare, Jayant J.

2015-05-01

Here, we report a non-invasive strategy for isolating cancer cells by autonomously propelled carbon nanotube (CNT) microrockets. H2O2-driven oxygen (O2) bubble-propelled microrockets were synthesized using CNT and Fe3O4 nanoparticles in the inner surface and covalently conjugating transferrin on the outer surface. Results show that self-propellant microrockets can specifically capture cancer cells.Here, we report a non-invasive strategy for isolating cancer cells by autonomously propelled carbon nanotube (CNT) microrockets. H2O2-driven oxygen (O2) bubble-propelled microrockets were synthesized using CNT and Fe3O4 nanoparticles in the inner surface and covalently conjugating transferrin on the outer surface. Results show that self-propellant microrockets can specifically capture cancer cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr01797a

An innovative pre-targeting strategy for tumor cell specific imaging and therapy.

PubMed

Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

2015-09-21

A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the "biotin-avidin" interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.

Anaplastic Thyroid Carcinoma: Current Treatments and Potential New Therapeutic Options with Emphasis on TfR1/CD71

PubMed Central

Salvatorelli, Lucia; Magro, Gaetano

2014-01-01

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers. Actually, ATC is refractory to conventional therapies, including surgery, chemotherapy, radiotherapy, and radioiodine (131I) therapy. Accordingly, genetic and molecular characterizations of ATC have been frequently and periodically reviewed in order to identify potential biological markers exploitable for target therapy. This review briefly focuses on main molecular events that characterize ATC and provides an update about preclinical studies. In addition, the overexpression of transferrin receptor 1 (TfR1/CD71) by neoplastic cells of ATC is emphasized in that it could represent a potential therapeutic target. In this regard, new therapeutic approaches based on the use of monoclonal or recombinant antibodies, or transferrin-gallium-TfR1/CD71 molecular complexes, or lastly small interfering RNAs (siRNAs) are proposed. PMID:25097549

Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse

PubMed Central

Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella

2016-01-01

The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597