Iron Balance Research Articles

Mitochondrial dysfunction in mouse livers depleted of iron chaperone PCBP1

Iron is an essential nutrient that forms cofactors required for the activity of hundreds of cellular proteins. However, iron can be toxic and must be precisely managed. Poly r(C) binding protein 1 (PCBP1) is an essential, multifunctional protein that binds both iron and nucleic acids, regulating the fate of both. As an iron chaperone, PCBP1 binds cytosolic iron and delivers it to iron enzymes for activation and to ferritin for storage. Mice deleted for PCBP1 in the liver exhibit dysregulated iron balance, with lower levels of liver iron stores and iron enzymes, but higher levels of chemically-reactive iron. Unchaperoned iron triggers the formation of reactive oxygen species, leading to lipid peroxidation and ferroptotic cell death. Hepatic PCBP1 deletion produces chronic liver disease in mice, with steatosis, triglyceride accumulation, and elevated plasma ALT levels. Human and mouse models of fatty liver disease are associated with mitochondrial dysfunction. Here we show that, although deletion of PCBP1 does not affect mitochondrial iron balance, it does affect mitochondrial function. PCBP1 deletion affected mitochondrial morphology and reduced levels of respiratory complexes II and IV, oxygen consumption, and ATP production. Depletion of mitochondrial lipids cardiolipin and coenzyme Q, along with reduction of mitochondrial oxygen consumption, were the first manifestations of mitochondrial dysfunction. Although dietary supplementation with vitamin E ameliorated the liver disease in mice with hepatic PCBP1 deletion, supplementation with coenzyme Q was required to fully restore mitochondrial lipids and function. In conclusion, our studies indicate that mitochondrial function can be restored in livers subjected to ongoing oxidative damage from unchaperoned iron by supplementation with coenzyme Q, a mitochondrial lipid essential for respiration that also functions as a lipophilic radical-trapping agent.

Relationship between blood cadmium and iron status among Korean population

BACKGROUND AND AIM: In recent studies for the association between blood Cd and iron deficiency (ID), it was found that ID elevates blood cadmium levels in children, adolescents or adults. But, the previous studies almost only used either serum ferritin or Hemoglobin (Hb) for evaluating ID or iron deficiency anemia (IDA). Blood Cd level according to actual iron status have not been studied. The objective of this study was to investigate the association between Cd and Iron status(normal, negative iron balance, iron deficiency erythropoiesis, IDA) and the risk for high cadmium level depending each iron status using a large-scale nationwide representative sample of the Korean. METHODS: A nationwide cross-sectional study was conducted to examine the relationship between iron status and blood Cd level in 3,366 men and 3,443 women over 10 years of age, using data from the 2010–2012 Korean National Health and Nutrition Examination Survey (KNHANES). We used analysis of variance (ANOVA) or chi-square test to estimate differences in the demographic and biochemical characteristics of participants. Multiple logistic regression models were also used to examine the associations between iron status and high blood Cd level (75th percentile of Cd level in the current sample; 1.37μg/L) RESULTS:Mean values of blood Cd gradually increased in accordance with poor iron status (P-trend0.001). We found that increased risk for high Cd level was associated with poor iron status after adjusting for age, sex, BMI, education, income, cigarette smoking and alcohol consumption. In a sex and menopause stratified analysis, a significant association was stronger only in premenopause women, not in men, menopause women CONCLUSIONS:We found a relationship between poor iron status and blood Cd in a representative population sample of Korean adult. Our results suggested considering the reproductive toxicity of Cd, management for blood Cd level would be necessary in women of childbearing age with poor iron status KEYWORDS: Heavy metals, Environmental epidemiology

Pumping iron in the kidney

Iron balance is tightly controlled to provide adequate amounts of this essential nutrient, but to limit the adverse effects of excess iron. Key mediators of systemic iron homeostasis are the iron regulatory hormone hepcidin and its receptor, the iron export protein ferroportin. A new study by Mohammad etal. demonstrates the functional role of the hepcidin-ferroportin axis in the kidney, and how this contributes to kidney iron levels and the systemic iron economy.

Institutional Usage of Ferric Pyrophosphate Citrate (FPC) Delivered Via Dialysate in Reducing Erythropoiesis Stimulating Agents (ESAs) and IV Iron Cost.

Dialysis patients are often iron deficient due to a multiple factors. Ferric pyrophosphate citrate is a complex iron salt that can be given via dialysate allowing maintenance of hemoglobin (Hgb) concentration and iron balance while reducing the need for IV iron. The purpose of this study is to perform a cost evaluation of FPC and the effect it has on lowering the dose/use of ESAs and IV iron therapy. This study reviewed the same 100 hemodialysis patient's charts before and after the use of FPC. The data points that were collected and analyzed are as follows: hemoglobin, ferritin levels, average weekly ESA dosing, and IV iron replacement therapy dose. Out of 100 patients, there was no statistical difference in the average hemoglobin, ferritin, and iron saturation levels observed in the patients before and after FPC use. The average weekly dose of darbepoetin alfa per patient was 52.74 μg before the FPC group compared to 39.27 μg in the post FPC group (P < .0001). The total dose of ferric gluconate per patient was 3290.01 mg in the before FPC group and 585.60 mg in the post FPC group (P < .0001). The average total iron sucrose dose per patient in the before FPC group was 3097.92 mg versus 1216.67 mg in the post FPC group (P < .1563). When comparing FPC's cost and implementation into both of our outpatient dialysis centers, this yielded a net savings of $296 751.49.

Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study.

Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment.

Abstract 2400: PINK1 is a novel regulator of mitochondria and iron metabolism in colon cancer

Abstract Mitophagy is a cargo-specific autophagic process that recycles damaged mitochondria to promote mitochondrial turnover and cellular health. In particular, PINK and Parkin mediate one of the canonical mitophagy pathways. The mechanisms behind PINK1-Parkin mediated mitophagy is well established, yet its role in cancer remains equivocal. Based on differential gene expression analyses on colon cancer patients, higher PINK1 expressions are correlated with worsened survival. To confirm increased mitophagy in colon cancer cells, we assessed lysosomal proteome under nutrient stress and observed an enrichment of mitochondrial peptides. Then, we generated inducible shRNA knockdown (KD) models for PINK1 in a panel of colon cancer cell lines. Preliminary data suggest loss of PINK1 hinders colon cancer cell growth and induces cell death. We showed that PINK1 KD hinders mitophagy assessed by decreased phospho-ubiquitin, a marker of PINK1 activity. We observed high levels of basal mitophagy in colon cancer cells, and PINK1 KD can efficiently inhibit mitophagy using a fluorescent mitophagy reporter. Interestingly, we demonstrated PINK KD disrupts mitochondria dynamics by decreasing MFN2 protein level, suggesting mitochondrial fusion could be inhibited. In summary, we demonstrated colon cancer cells have high levels of mitophagy and PINK1 KD decreases mitophagy and disrupts mitochondria network. Mitochondria are important organelles that integrates cellular metabolic pathways. With PINK1's role as an overall mitochondrial health sensor, we hypothesized disrupting PINK1 could affect mitochondria metabolism in colon cancer cells. We demonstrated alterations in mitochondrial metabolites as assessed by metabolomics, NAD/NADH imbalance, membrane hyperpolarization, and decreased oxygen consumption rate. It is known that TCA cycle and electron transport chain require iron sulfur clusters (ISC) to maintain proper function. Although the exact quantification of mitochondrial iron fraction is elusive, some studies suggested that mitochondria could harbor up to 20% of cellular iron. These evidences suggest mitochondria play pivotal roles in cellular iron homeostasis. Upon PINK1 KD, we saw an accumulation of cytosolic and mitochondrial iron storage protein, ferritin. Interestingly, we also observed a decrease in ISC-containing ETC proteins upon PINK1 KD. We believe PINK1 could have a non-canonical function in regulating mitochondria iron and play a profound role in regulating cellular iron balance. Overall, these results indicate that PINK1 is essential for maintaining mitochondria metabolism and survival in colon cancers. Here, we showcased that PINK has a unique role in regulating mitochondrial metabolism. In conclusion, the growth and mitochondrial defects we observed from PINK1 KD cells suggest a potential oncogenic role of PINK1 in colorectal cancer that can be targeted for future therapeutic purposes. Citation Format: Brandon Chen, Samantha Devenport, Costas Lyssiotis, Yatrik Shah. PINK1 is a novel regulator of mitochondria and iron metabolism in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2400.

Hepcidin Downregulation Correlates With Disease Aggressiveness And Immune Infiltration in Liver Cancers.

BackgroundHepcidin is a polypeptide hormone mainly produced by hepatocytes to modulate systemic iron balance. A drastic downregulation of the hepcidin gene was found in liver cancers. However, there is a paucity of information about the clinical significance of hepcidin gene downregulation in liver cancers.MethodsHepcidin expression profiles were assessed using multiple public datasets via several bioinformatics platforms. Clinical and pathological information was utilized to stratify patients for comparison. Patient survival outcomes were evaluated using the Kaplan-Meier plotter, a meta-analysis tool. Tumor immune infiltration was analyzed using the single sample gene set enrichment analysis (ssGSEA) approach on the Cancer Genome Atlas (TCGA) dataset. Hepcidin antagonist Fursultiamine was used to treat liver cancer HepG2 and Huh7 cells together with Sorafenib.ResultsHepcidin gene was predominantly expressed in benign liver tissues but drastically decreased in liver cancer tissues. Hepcidin reduction in liver cancers correlated with risk factors like non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, as well as cancer grade and tumor stage. Hepcidin downregulation was associated with a rapid cancer progression and worse disease-specific survival, especially in patients of the White race without alcohol consumption history. Hepcidin expression in liver cancer tissues positively correlated with the bone morphogenetic protein-6 (BPM6)/interleukin-6 (IL6) cytokines and cytotoxic immune infiltration. Blocking hepcidin action with its antagonist Fursultiamine moderately reduced Sorafenib-induced apoptotic cell death in HepG2 and Huh7 cells.ConclusionHepcidin downregulation in liver cancers correlated with liver cancer risk factors, cancer aggressiveness, cytotoxic immune cell infiltration, and patient survival outcomes. BMP6/IL6 pathway insufficiency is a potential cause of hepcidin downregulation in liver cancers.

Role of Erythropoietin in the Late Anemia of Patients with Chronic Myeloid Leukemia Treated Frontline with Imatinib

Background Late occurrence of moderate/severe anemia in patients with Chronic Myeloid Leukemia (CML) during long-lasting treatment with imatinib has been reported in a sizeable rate and seems to be more common in elderly patients. Treatment of such complication is subjective and the possible role of erythropoietin (EPO) still unclear.Methods To highlight this issue, we revised retrospectively 37 CML patients treated at 10 Institutions in Italy with frontline imatinib for at least 24 months and in stable complete cytogenetic response (CCyR) who developed a late chronic anemia and were treated with EPO. Late chronic anemia was defined as the presence of persistent (> 3 months) and otherwise unexplained (creatinine level < 2 mg/dl, normal iron balance, bilirubin level < 2 mg/dl, folate and Vitamin B12 in the normal range) Hb levels < 11 g/dl which occurred > 6 months from imatinib start. The main clinical features of the patients at diagnosis were as follows: male/female 21/16 (56.8%/43.2%), median age 69.4 years [interquartile range (IQR) 62.7 - 74.8], median Hb 12.2 g/dl (IQR 10.9 - 13.5), median WBC 50.3 x 109/l (IQR 28.7 - 87.2), median PLTS 384 x 109/l (IQR 277 - 645). According to Sokal risk classification, available in 35 patients, 7 (20.0%) were low risk, 24 (68.6%) intermediate risk and 4 (11.4%) high risk.Results Median time from imatinib start to EPO treatment was 44.2 months (IQR 21.6 - 100.2). At baseline of EPO treatment, all patients were in stable CCyR and 31/37 (83.7%) were also in stable MR 3.0. Median Hb value at baseline was 9.9 g/dl (IQR 9.2 - 10.2): four out 37 patients (10.8%) needed packed red cell transfusions before the starting of EPO treatment. Endogenous EPO level at baseline was available in 22 patients, with a median value of 21.5 mU/ml (IQR 13.6 - 35.7). Alpha-EPO (40,000 UI weekly) was employed in 31 cases, beta-EPO (30,000 UI weekly) in 4 cases and darbopoietin (150 mcg/weekly) in 2 patients. On the whole, 29 patients (78.3%) achieved an erythroid response, defined as a stable (> 3 months) increment > 1.5 g/dl of Hb levels, and 8 patients (21.7%) were resistant to treatment: median HB values at different time-points during EPO treatment are reported in the figure 1. Among responding patients, 3 had a relapse of anemia after 8, 24 and 96 months from EPO start, respectively, and stopped EPO, 4 died while in response from CML unrelated causes, 2 stopped EPO while in response: the remaining 20 responding patients are still alive in response and still in treatment with EPO. No EPO-related toxicity was observed. 5-year overall survival from EPO treatment of the entire cohort was 81.0% (95%CI 65.7 - 96.3).Conclusions Results with EPO in the treatment of late chronic anemia which occurs during long-lasting imatinib treatment are encouraging, with a high rate of response and an excellent safety profile: however, larger prospective studies are warranted to define more precisely the role (when to start EPO?, at what dosage?, for how long?) of such an approach in the treatment of this common late complication of prolonged imatinib therapy. [Display omitted] DisclosuresBocchia:Celgene: Other: Travel grant; Novartis: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Galimberti:Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Breccia:Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Pane:Novartis: Honoraria, Speakers Bureau.

Phase I Trial Results of a Solid Dispersion Formulation of Deferasirox with Enhanced Bioavailability Relative to Exjade® and JadenuTM

Chronic iron overload (CIO) is associated with anemias such as thalassemia that require blood transfusions as a chronic therapy. It is a serious and difficult to treat condition that is associated with multiple organ toxicities including of the liver, heart and endocrine glands. Untreated, CIO can lead to organ failure and death.In 2005, the first oral iron chelator, deferasirox (DFX) in the form of a tablet for oral suspension (Exjade®), was approved in the United States for treating CIO. In 2015, a film-coated tablet (JadenuTM) was introduced as a more convenient formulation for patients.Chirnomas, et al at Children's Hospital Boston (Blood, 2009) have previously published on a subgroup of transfusion dependent thalassemia patients in whom failure to achieve negative iron balance is linked to poor absorption of DFX into systemic circulation as compared to a control group that did respond to DFX.DFX is a drug molecule with poor water solubility and large sensitivity to pH. It is practically insoluble in gastric fluid and very slightly soluble in intestinal fluid. These molecular traits of DFX likely contribute to its food effect and more importantly could lead to poor absorption of the drug in some patients (e.g., patients with more acidic GI tracts and/or on high doses).Solid dispersion technology has been successfully used to address drug solubility challenges in a number of cases (e.g., ritonavir, etravirine, everolimus, ivacaftor). However, DFX as a molecule has a high melting temperature and poor solubility in organic solvents which together have precluded the use of traditional solid dispersion technology. A solid dispersion tablet formulation of deferasirox (DST-0509) was developed using a novel solid dispersion technology (KinetiSol®) that is able to process DFX.DST-0509 was tested in 2 phase I studies, Study 101 and 102. Study 101, a single dose study in healthy volunteers, demonstrated improvements in the bioavailability of DST-0509 compared to Jadenu™ at a dose of 14 mg/kg. Furthermore, DST-0509 is the first deferasirox formulation to show no differences in total absorption between high-fat fed and fasted states.Study 102 was a randomized, single dose, 3-period, 3-sequence crossover, oral bioavailability study of DST-0509 compared to Exjade® and Jadenu™ in fasted healthy volunteers at higher doses (25 - 33 mg/kg). The results showed less variability in Cmax and AUC with DST-0509 versus Exjade®, and meaningfully enhanced absorption versus Exjade® and Jadenu™. See Figure 1., “Comparative Bioavailability of DST-0509 to Exjade® and Jadenu™ in healthy subjects at high doses”.Future studies are planned to see if the enhanced bioavailability seen in these studies translates into superior iron control in patients not achieving target iron control on current deferasirox treatments. [Display omitted] DisclosuresKeen:DisperSol Technologies: Employment, Equity Ownership. Miller:DisperSol Technologies: Employment, Equity Ownership, Patents & Royalties. Tulloch:DisperSol Technologies: Consultancy; Capital Biopharma Consulting: Consultancy, Employment; Faraday Pharmaceuticals: Employment, Equity Ownership.

Mendelian inheritance of anemia due to disturbed iron homeostasis

Genetic disorders that affect proteins involved in maintaining iron balance may lead to Mendelian anemias. They may be classified as defects of intestinal iron absorption, iron transport in the circulation, iron uptake and utilization by maturing erythroid cells, iron recycling by macrophages and systemic regulation of iron homeostasis. All these Mendelian anemias are rare disorders, prevalently recessive, characterized by microcytic and hypochromic red blood cells. Advances in our knowledge of iron metabolism and its systemic regulation on one side have facilitated the identification of novel iron related anemias, while on the other the study of the affected patients and of the corresponding animal models have contributed to our understanding of iron trafficking and regulation.

Direct assessment of body iron balance in women with and without iron supplementation using a long-term isotope dilution method in Benin and Switzerland

Long-term isotopic dilution measurements of body iron may allow quantification of basal body iron balance and iron gains during an iron intervention with higher precision and accuracy than conventional iron indices. We compared body iron balance before, during, and after oral iron supplementation in women in Benin and in Switzerland. In prospective studies, Beninese (n=11) and Swiss (n=10) women previously labeled with stable iron isotopes were followed preintervention for 90-120 d, then received 50-mg iron daily for 90-120 d and were followed postintervention for 90-120 d. We used changes in blood isotopic composition to calculate iron absorption (Feabs), iron loss (Feloss), and net iron balance (Fegain). Compliance with supplementation was>90%. In Benin, during the preintervention, intervention, and postintervention periods, Fe means±SDs were as follows: 1) Feabs: 0.92±1.05, 3.75±2.07, and 0.90±0.93 mg/d; 2) Feloss: 1.46±1.95, 1.58±1.57, and 1.84±1.61 mg/d; and 3) Fegain: -0.55±1.56 mg/d, 2.17±1.81 mg/d, and -0.94±1.13 mg/d. In Switzerland, the corresponding values were: 1) 1.51±0.37, 4.09±1.52, and 0.97±0.41 mg/d; 2) 0.76±1.37, 2.54±1.43, and 2.08±1.05 mg/d; and 3) 0.75±1.37, 1.55±1.75, and -1.11±1.06 mg/d. Inflammation was low in both settings, and isotopically calculated iron balance was comparable to that calculated from changes in conventional iron indices. Without iron supplementation, Beninese women had lower long-term dietary iron absorption and higher iron losses in the preintervention period than Swiss women. During iron supplementation, both groups had high iron absorption and similar iron gains. However, there was a 3-fold increase in iron losses in the Swiss women during the supplementation and postintervention period compared with the preintervention period. Body iron isotope dilution is a promising new method for quantifying long-term body iron balance and for assessing the impact of iron interventions. The studies were registered at clinicaltrials.gov as NCT02979080 and NCT02979132, respectively.

MO385THE IMPACT OF SARS-COV-2 INFECTION ON MORTALITY IN CKD PATIENTS – A SINGLE-CENTER PILOT STUDY

Background and AimsSince the beginning of 2019, once COVID-19 pandemic was declared, there is a keen interest in understanding the impact of SARS-CoV-2 infection on chronic kidney disease (CKD) patients, regarding the influence on CKD progression and the suitable therapy options, as most of the indicated medications are contraindicated for a glomerular filtration rate (GFR) below 30 ml/min, and, in addition, there is a little experience in dialyzed patients. The aim of our single-center pilot study is to determine the influence of SARS-CoV-2 infection on CKD patients’ (dialyzed or not) outcome and hospitalization rate.MethodWe evaluated the patients diagnosed with COVID-19, admitted in our Department between October and December 2020. The inclusion criteria were: age > 18 years old, diagnosis of CKD – predialysis and hemodialyzed patients. The exclusion criteria were: patients without pre-existing CKD. All included subjects signed the patients’ consent. To all included patients we performed the following tests: total blood count, erythrocyte sedimentation rate, C-reactive protein, fibrinogen, ferritin, serum free iron, serum creatinine, urea, uric acid, calcemia, total proteins, electrolytes and acid-base balance, urinary exams (including urine culture), coagulation and lipid profile, quantitative D-dimer, IL-6, procalcitonin, and imaging tests (CT, pulmonary Rx, abdominal ultrasonography). The patients were monitored by the infectious disease medical team that adjusted the therapy according to the patients’ lab and imagistic results. The specific treatment for SARS-CoV-2 infection included primary anti-interleukin receptor monoclonal antibody drugs (such as Anakinra, Tocilizumab), corticotherapy (dexamethasone), anti-retroviral therapy (remdesivir, favipiravir) only in hemodialyzed patients or in those presenting an eGFR > 30 mL/min, antibiotics, antifungal drugs, and oxygen-therapy. Usually, anti-interleukin receptor monoclonal antibody consisted in 7 doses, administrated every 48 hours. The dose of all other recommended drugs was adapted according to the patients’ eGFR.ResultsA total of 63 patients were admitted in our Department and were under our care, presenting medium or severe forms of SARS-CoV-2 infection. After applying the inclusion and exclusion criteria, only 38 patients were considered eligible: 21 male patients (mean age 63.52 ± 13.82 years), and 17 female patients (mean age 67.24 ± 12.83 years). 31.57% represented the percentage of death during the hospitalization (due to the severity of the disease, 4 patients died within 24 hours) in patients presenting heterogenous comorbidities, such as diabetes mellitus, hypertension, pre-existing glomerulonephritis and/or oncological pathologies; we also noticed that female gender represented 58.33% of the deceased patients. The mean hospitalization period in the deceased patients was 6.42 ± 5.38 days – 4 ± 3.21 days in female gender, and 9.8 ± 6.30 days in male gender.ConclusionMost of our patients, although diagnosed with medium and severe forms of SARS-CoV-2 infection, presented a favorable evolution, and an adequate response to the specific medication. We observed that most of the deceased cases were female patients, and compared to the male deceased subject, female deceased patients presented a lower period of hospitalization. Therefore, probably female CKD patients with comorbidities and diagnosed with COVID-19 are more predisposed to an unfavorable prognosis. Further and larger clinical trials are necessary to validate the impact of SARS-CoV-2 infection on mortality in CKD patients.

Iron Balance and Iron Nutritional Status in Preterm Infants During the First Four Months of Life.

To determine whether iron absorption occurs in a dose-dependent fashion and/or is a function of iron nutritional status (INS) in preterm infants during the first 4 months of life. Preterm very-low-birth-weight infants (VLBWI) were fed an iron-fortified (0.7 mg/dL) infant formula. Three 48 h balance studies were performed on each infant. INS was determined by serially measuring hemoglobin, mean corpuscular volume (MCV), hematocrit, ferritin, transferrin and transferrin saturation levels. The data were analyzed using ANOVA and stepwise regression. Fifty-four balance studies were performed in 18 infants (birth weight, 1347 ± 201 g; gestation, 30 ± 1.3 weeks; mean ± standard deviation) at 33 ± 1.3, 34 ± 1.2, and 48 ± 0.5 weeks corrected age and weights of 1768 ± 260, 2298 ± 314, 5127 ± 939 g. No relationship was detected between iron intake and absorption. Intake decreased during the study (1.17 ± .08, 1.24 ± 0.11 > 1.1 ± 0.15 mg · kg-1 · day-1) but net (0.32 ± 0.26, 0.36 ± 31 < 0.49 ± .23 mg · kg-1 · day-1) and % (27 ± 22, 29 ± 23 < 46 ± 21) absorption increased (P < 0.01). Serum ferritin, transferrin saturation and MCV fell, while hematocrit and hemoglobin remained stable. No relationship was noted between serum ferritin and iron absorption but transferrin saturation (54%), MCV (7%), and hematocrit (6%) accounted for 67% of the variation in iron absorption (P < 0.001). At intakes of 0.8-1.4 mg · kg-1 · day-1, iron absorption is not dose-dependent nor affected by iron stores. Only when iron delivery to the tissues decreases does absorption increase to meet needs in these otherwise normal and rapidly growing infants.

Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions.

Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)-SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP-SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP-SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.

Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways

Background & aimsIron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe−/− mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe−/− mice influenced the development of NAFLD. MethodsLiver histology was assessed in Hfe−/− mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). ResultsStandard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. ConclusionsOur results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.

Assessment of positive iron balance in end-stage renal disease: Could hepcidin-25 be useful?

The aim of our study was to examine the relationship of hepcidin-25 with red blood cell and reticulocyte indices and to evaluate the diagnostic properties of hepcidin-25 in the assessment of positive iron balance in end-stage renal disease (ESRD) patients. Eighty anemic ESRD patients (hemoglobin<110g/L) were classified as having iron deficiency (ID, N=20), iron sufficiency (IS, N=29), and positive iron balance (PB, N=31) using the conventional biomarkers for iron status evaluation. Hepcidin-25 was determined by a chemiluminescent direct ELISA. Hepcidin-25 was significantly negatively correlated with the proportion of hypochromic erythrocytes (%HYPO) (P=.034) and immature reticulocyte fraction (P=.010) in ID and with the absolute reticulocyte concentration in ID (P=.048) and PB (P=.040). In multivariate models, hepcidin-25 was independently negatively associated with the mean reticulocyte hemoglobin content (CHr; β=-0.493, P=.004) and red blood cell size factor (RSf) (β=-0.334, P=.036) only in the PB group. The best hepcidin-25 value to exclude PB was 66.13µg/L, showing a sensitivity of 61.3%, a specificity of 75.5%, and an AUC of 0.808. Our results suggest that hepcidin-25 levels are independently negatively associated with the iron demand for the most recent erythropoiesis only in PB. Hepcidin-25 performed acceptable in discriminating anemic ESRD patients with positive iron balance and may prove to be a useful additional tool in the evaluation of iron status.

Influence of jarosite precipitation on iron balance in heap bioleaching at Monywa copper mine

Ferric iron is an important oxidant in sulfide ore bioleaching. However, recirculating leach liquors leads to excess iron accumulation, which interferes with leaching kinetics and downstream metal recovery. We developed a method for controlling iron precipitation as jarosite to reduce excess iron in heap bioleaching at Monywa copper mine. Jarosite precipitation was first simulated and then confirmed using batch column tests. From the simulations, the minimum pH values for precipitation of potassium jarosite, hydronium jarosite, and natrojarosite at 25 °C are 1.4, 1.6, and 2.7, respectively; the minimum concentrations of potassium, sulfate, ferric, and sodium ions are 1 mM, 0.54, 1.1, and 3.2 M, respectively, at 25 °C and pH 1.23. Column tests indicate that potassium jarosite precipitation is preferential over natrojarosite. Moreover, decreased acidity (from 12 to 8 g/L), increased temperature (from 30 to 60 °C), and increased potassium ion concentration (from 0 to 5 g/L) increase jarosite precipitation efficiency by 10, 5, and 6 times, respectively. Jarosite precipitation is optimized by increasing the irrigating solution pH to 1.6. This approach is expected to reduce the operating cost of heap bioleaching by minimizing the chemicals needed for neutralization, avoiding the need for tailing pond construction, and increasing copper recovery.

Whole Blood miR-210, miR-122, miR-223 Expression Levels and Their Relationship With Iron Status Parameters and Hypercoagulability Indices in Children With Iron Deficiency Anemia.

MicroRNAs have the potential to regulate systemic and cellular iron homeostasis at multiple points. In iron deficiency anemia (IDA), hypoxia, platelet reactivity, and potentially microRNAs play a role in the development of hypercoagulability. A total of 57 children diagnosed with IDA between October 2016 and October 2017 and 48 healthy children were included in this cross-sectional study. Blood count parameters, serum iron, transferrin saturation, ferritin level, maximum clot firmness (MCF), and clot formation time index, which are indicators of hypercoagulability in rotational thromboelastometry test, of the IDA and control groups obtained in our previous study were recorded. miR-210, miR-122, and miR-223 levels were analyzed. There was no difference in the miR-210, miR-122, and miR-223 levels between the IDA and control groups. Patients with hemoglobin (Hb) <8 g/dL had higher miR-210 levels than patients with Hb>8 g/dL (P<0.05). There was a negative correlation between miR-210 and Hb and ferritin levels, a positive correlation between miR-122 and ferritin levels, and a negative correlation between miR-223 and MCF index. In IDA, there is a close relationship between the severity of anemia and miR-210, and miR-210 expression is slightly increased in those with severe anemia. miR-210 and miR-122 collectively play a role in maintaining the iron balance. The correlation between miR-223, a platelet function regulator, and the MCF index, suggested that miR-223 has a role in the development of hypercoagulability in IDA.

Impact of Low Hemoglobin on Body Composition, Strength, and Redox Status of Older Hemodialysis Patients Following Resistance Training.

IntroductionThe purpose of this study was to: (i) investigate the effect of six months of resistance training (RT) on body composition, muscle strength, hematological patterns, and redox profile in maintenance hemodialysis (HD) patients, and; (ii) evaluate the effects of baseline concentrations of hemoglobin on the RT response.MethodsOne hundred fifty-seven subjects with chronic kidney disease (CKD) were randomly allocated into two groups: Control [CTL, (n = 76)] and RT (n = 81). A first visit was required for anamnesis and anthropometric measurements. Venous blood samples were collected at baseline and after twenty-four weeks of training in all patients for the analysis of clinical and redox balance markers. The RT program spanned six months and consisted of three sets of 8–12 repetitions with a rating of perceived exertion between 5 and 8 for three weekly sessions. Each exercise session was performed in twelve resistance exercises and it least for approximately 40 min.ResultsThe main results demonstrated that RT decreased waist circumference by 3%, and decreased thiobarbituric reactive species (TBARS) by 28%. Moreover, RT increased handgrip strength by 28.4%, fat-free mass by 4.1%, hemoglobin by 5%, iron by 33.4%, glutathione by 121%, and Trolox equivalent antioxidant capacity by 14.2% (p < 0.05). Low hemoglobin concentrations impaired the effect of RT on fat-free mass gain.ConclusionSix months of RT in HD patients improved clinical parameters, such as hemoglobin, iron, body composition, and redox balance, while low hemoglobin concentration impaired exercise-benefits on fat-free mass in patients with CKD. These findings can contribute to a better clinical application of RT in the maintenance of hemodialysis patients.

Interaction mechanism of ferritin protein with chlorogenic acid and iron ion: The structure, iron redox, and polymerization evaluation

Ferritin is an iron-containing protein and functions in the maintenance of iron balance in organisms. Currently the interaction among ferritin, ion iron, and food bioactive compounds is still unclear. In this study, the mechanism underlying the interaction of ferritin, ion iron, and chlorogenic acid was investigated, as well as the effect of chlorogenic acid on the physicochemical properties of ferritin. The results showed that chlorogenic acid could interact with Fe(III) to form chlorogenic acid-Fe(III) complexes, which then bonded with ferritin via hydrogen bonds in the ferritin–chlorogenic acid-Fe(III) complexes. The chlorogenic acid showed a high efficiency in Fe(II) chelation and hydroxyl radical (•OH) capture, and could promote iron oxidation and iron release induced by ferritin. Chlorogenic acid could also effectively reduce the polymerization extent of ferritin induced by Fe(III) and Fe(II). This study elucidates the interactions of multiple components in foodstuffs by using a protein-metal-polyphenol model.