Iron Transferrin Research Articles

Macrophage-derived extracellular vesicles represent a promising endogenous iron-chelating therapy for iron overload and cardiac injury in myocardial infarction

BackgroundCardiac iron overload and ferroptosis greatly contribute to the poor prognosis of myocardial infarction (MI). Iron chelator is one of the most promising strategies for scavenging excessive iron and alleviating cardiac dysfunction post MI. However, various side effects of existing chemical iron chelators restrict their clinical application, which calls for a more viable and safer approach to protect against iron injury in ischemic hearts.ResultsIn this study, we isolated macrophage-derived extracellular vesicles (EVs) and identified macrophage-derived EVs as a novel endogenous biological chelator for iron. The administration of macrophage-derived EVs effectively reduced iron overload in hypoxia-treated cardiomyocytes and hearts post MI. Moreover, the oxidative stress and ferroptosis induced by excessive iron were considerably suppressed by application of macrophage-derived EVs. Mechanistically, transferrin receptor (TfR), which was inherited from macrophage to the surface of EVs, endowed EVs with the ability to bind to transferrin and remove excess protein-bound iron. EVs with TfR deficiency exhibited a loss of function in preventing MI-induced iron overload and protecting the heart from MI injury. Furthermore, the iron-chelating EVs were ultimately captured and processed by macrophages in the liver.ConclusionsThese results highlight the potential of macrophage-derived EVs as a powerful endogenous candidate for iron chelation therapy, offering a novel and promising therapeutic approach to protect against iron overload-induced injury in MI and other cardiovascular diseases.

Anemia of chronic diseases in the early stages of chronic kidney disease as a risk factor for cardiovascular complications in patients with glomerulonephritis

To determine biomarkers of anemia of chronic disease (ACD) in patients with glomerulonephritis (GN) in the early stages of CKD, to assess their role as risk factors for cardiovascular complications (CVС). Seventy nine patients with GN were studied, among them: 40 with primary сhronic GN (CGN), 39 with secondary forms:19 - GN with ANCA-associated systemic vasculitis, 20 - GN with systemic lupus erythematosus (SLE) at early (all I-II) CKD stages. In all patients, the level of serum C-reactive protein (CRP), hepcidin, interferon γ, and the circulating form of protein Klotho (s-Klotho) were determined. When a relative iron deficiency was detected [transferrin iron saturation coefficient (TSAT) <20%], patients were administered parenterally iron [III] sucrose hydroxide complex (Venofer). The frequency of anemia among patients with systemic diseases is 3.2 times higher than among patients with primary CGN. Patients with anemia (group I; n=43) had higher rates of daily proteinuria (p<0.001), systolic blood pressure (p<0.05), serum levels of interferon γ (p<0.001) and hepcidin (p<0.001) and lower values of eGFR (p<0.05) than patients without anemia (group II; n=36). A strong inverse correlation was noted between the level of hepcidin and the content of iron in serum (r=-0.856; p<0.001), between the level of hemoglobin and the level of interferon γ (r=-0.447; p<0.05), hepcidin (r=-0.459; p<0.05) and CRP (r=-0.453; p<0.05). A significant inverse correlation was found between the level of hemoglobin and CVC risk factors - the value of systolic blood pressure (r=-0.512; p<0.05) and the mass index of the left ventricular myocardium (r=-0.619; p<0.01). At the same time, the contribution of 2 from 6 analyzed factors, hepcidin and eGFR, to the development of ACD was 92.5%, of which 86.6% accounted for hepcidin. A strong direct correlation was also found between a decrease in hemoglobin level and a decrease in the level of s-Klotho protein (r=0.645; p<0.001), a decrease in the level of s-Klotho and an increase in the level of serum hepcidin (r=-0.541; p<0.05). The leading value of anemia (beta -0,29; p=0,04) and depression of the s-Klotho level (beta -0,44; p=0,02) as independent cardiovascular risk factors in this group of patients was confirmed by multivariate analysis. In patients with identified deficiency of iron (n=40), after 3-4 weeks of intravenous administration of venofer, the target level of hemoglobin (Нb>120 g/l) and transferrin saturation with iron (TSAT>20%) were achieved. Among the biomarkers of ACD in patients with immunoinflammatory diseases of the kidneys (primary and secondary СGN), the increase in the serum level of hepcidin is greatest importance. The concomitant to anemia decrease in s-Klotho is a leading risk factor for CVС in CKD. Early correction of ACD with iron supplements makes it possible to achieve target levels of Hb and TSAT and have subsequently a positive effect on the production of s-Klotho and the severity of left ventricular hypertrophia.

Correlation analysis of whole genome sequencing of a pathogenic Escherichia coli strain of Inner Mongolian origin

Anal swabs of 1-month-old Holstein calves with diarrhea were collected from an intensive cattle farm, and a highly pathogenic Escherichia coli strain was obtained by isolation and purification. To study the virulence and resistance genes of pathogenic E.coli that cause diarrhea in calves, a strain of E. coli E12 isolated from calf diarrhea samples was used as experimental material in this experiment, and the virulence of the E12 strain were identified by the mouse infection test, and the whole genome map of the E12 strain were obtained by whole-genome sequencing and analyzed for genome characterization. The results showed that the lethality of strain E12 was 100%, the total length of E12-encoded genes was 4,294,530 bp, Cluster of Orthologous Groups of proteins (COG) annotated to 4,194 functional genes, and the virulence genes of sequenced strain E12 were compared with the virulence genes of sequenced strain E12 from the Virulence Factors of Pathogenic Bacteria (VFDB), which contained a total of 366 virulence genes in sequenced strain E12. The analysis of virulence genes of E12 revealed a total of 52 virulence genes in the iron transferrin system, 56 virulence genes in the secretory system, 41 virulence genes in bacterial toxins, and a total of 217 virulence genes in the Adhesin and Invasins group. The antibiotic resistance genes of sequenced strain E12 were identified through the Antibiotic Resistance Genes Database (ARDB) and Comprehensive Antibiotic Research Database, and it was found that its chromosome and plasmid included a total of 127 antibiotic resistance genes in four classes, and that E12 carried 71 genes related to the antibiotic efflux pumps, 36 genes related to antibiotic inactivation, and 14 antibiotic target alteration and reduced penetration into antibiotics, and 6 antibiotic resistance genes, and the resistance phenotypes were consistent with the genotypes. The pathogenic E. coli that causes diarrhea in calves on this ranch contains a large number of virulence and resistance genes. The results provide a theoretical basis for the prevention and treatment of diarrhea and other diseases caused by E. coli disease.

Plasma and tissue transferrin and ferritin, and gene expression of ferritin, transferrin, and transferrin receptors I and II in channel catfish Ictalurus punctatus fed diets with different concentrations of inorganic or organic iron.

Ferritin, transferrin, and transferrin receptors I and II play a vital role in iron metabolism, health, and indication of iron deficiency anaemia in fish. To evaluate the use of high-iron diets to prevent or reverse channel catfish (Ictalurus punctatus) anaemia of unknown causes, we investigated the expression of these iron-regulatory genes and proteins in channel catfish fed plant-based diets. Catfish fingerlings were fed five diets supplemented with 0 (basal), 125, and 250 mg/kg of either inorganic iron or organic iron for 2 weeks. Ferritin, transferrin, and transferrin receptor I and II mRNA and protein expression levels in fish tissues (liver, intestine, trunk kidney, and head kidney) and plasma were determined. Transferrin (iron transporter) and TfR (I and II) genes were generally highly expressed in fish fed the basal diet compared to those fed the iron-supplemented diets. In contrast, ferritin (iron storage) genes were more expressed in the trunk kidney of fish fed the iron-supplemented diets than in those fed the basal diet. Our results demonstrate that supplementing channel catfish plant-based diets with iron from either organic or inorganic iron sources affected the expression of the iron-regulatory genes and increased body iron status in the fish.

Association of Iron Profile with Type 2 Diabetes Mellitus:Review

This minireview assesses the correlation between iron profile levels and type 2 diabetes mellitus. Iron, ferritin, transferrin saturation, and total iron-binding capacity (TIBC) are examples of iron profiles. Every study included in this review shows that type 2 diabetics' blood serum has less iron overall and less iron-binding capacity. Conversely, the same studies' findings showed that individuals with type 2 diabetes had higher levels of ferritin in their blood serum. In terms of transferrin (iron) saturation, a number of studies show that it is rising, while a smaller number shows that it is falling in the blood serum of those who have type 2 diabetes. These investigations led to the conclusion that there is substantial evidence linking the iron profile to type 2 diabetic mellitus (T2DM). Reduced transferrin levels are connected to a lower risk of Type 2 Diabetes Mellitus, but higher serum iron, ferritin, and transferrin saturation are associated with an increased risk. There is also genetic evidence that links elevated systemic iron status to a higher risk of type 2 diabetes.

CORONAVIRUS SARS-COV-2 MODIFIES ANTITUMOR REDOX STATUS OF BLOOD AND INTERCELLULAR MATRIX IN METASTATIC COLORECTAL CANCER PATIENTS (A PILOT STUDY).

The current studies demonstrate that SARS-CoV-2 infection results in increasing complications incidence and the total risk of death in cancer patients. SARS-CoV-2 infection triggers oxidative stress representing one of the major factors of the inflammation contributing to the complicated course of the diseases including cancer. To assess the effect of hypoxia caused by SARS-CoV-2 infection on the redox status of blood in patients with metastatic colorectal cancer (mCRC). 10 patients with SARS-CoV-2, 11 mCRC patients with metachronous liver disease, and 14 mCRC patients with preceding SARS-CoV-2 infection were included in the study. The data on blood biochemistry (C-reactive protein, ferritin, transferrin, and free iron) were analyzed. The levels of superoxide radicals (ROS) in blood cells were determined by electron paramagnetic resonance (EPR) using the spin trap technique. The metalloproteinase activity was measured by polyacrylamide gel zymography with the addition of gelatin as a substrate. In mCRC patients with prior SARS-CoV-2 infection, a 1.26-fold increase in ROS-generating activity of blood neutrophils was observed compared to mCRC patients with no history of SARS-CoV-2 infection. The blood content of C-reactive protein, transferrin, and free iron in mCRC patients with prior SARS-CoV-2 infection increased by 2, 6, and 1.4 times, respectively. The total activity of gelatinases in platelets and neutrophils in the blood of mCRC patients with prior SARS-CoV-2 infection was 1.4 and 1.2 times higher compared to mCRC patients with no history of SARS-CoV-2 infection. mCRC patients with prior COVID-19 have a higher risk of exacerbation of inflammatory reactions. SARS-CoV-2 infection results in redox dіsbalance, which may contribute to the unfavorable course of the disease.

A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice

AbstractIron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are associated with production of α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, a membrane-bound serine protease expressed in hepatocytes, negatively modulates hepcidin production and thus is a key target to prevent iron overload in β-thalassemia. To address safety concerns raised by the suppression of Tmprss6 by antisense oligonucleotides or small interfering RNA, we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2. When administered weekly to Hbbth3/+ mice, RLYB331 induced hepcidin expression, reduced iron loading, prevented the formation of toxic α-chain/heme aggregates, reduced ros oxygen species formation, and improved reticulocytosis and splenomegaly. To increase the effectiveness of RLYB331 in β-thalassemia treatment even further, we administered RLYB331 in combination with RAP-536L, a ligand-trapping protein that contains the extracellular domain of activin receptor type IIB and alleviates anemia by promoting differentiation of late-stage erythroid precursors. RAP-536L alone did not prevent iron overload but significantly reduced apoptosis in the erythroid populations of the bone marrow, normalized red blood cell counts, and improved hemoglobin and hematocrit levels. Interestingly, the association of RLYB331 with RAP-536L entirely reversed the β-thalassemia phenotype in Hbbth3/+ mice and simultaneously corrected iron overload, ineffective erythropoiesis, splenomegaly, and hematological parameters, suggesting that a multifunctional molecule consisting of the fusion of RLYB331 with luspatercept (human version of RAP-536L) would allow administration of a single medication addressing simultaneously the different pathophysiological aspects of β-thalassemia.

Relationship between iron homeostasis and prognosis in patients with heart failure: a retrospective study based on the MIMIC-IV database.

The role of iron homeostasis has become increasingly recognized as a key factor in determining a prognosis of patients with heart failure (HF). Disruptions in iron balance, encompassing deficiency and overload, can affect patient prognosis, and therefore, significantly impact treatment and management strategies. The study investigated possible associations between iron homeostasis-related indicators and long‑term mortality as well as first‑admission mortality in individuals with HF. Data on 3483 HF patients from the MIMIC‑IV database were retrospectively analyzed. The relationship between iron homeostasis-related indicators (ferritin, serum iron, transferrin, and total iron binding capacity [TIBC]) and the first-admission and long-term mortality of HF patients was discerned utilizing the Cox proportional hazards model and the Kaplan-Meier survival analysis. Additionally, the predictive capability of these indicators for patient prognosis was assessed using the receiver operating characteristic curve. Fourth quartile levels of ferritin and serum iron were obviously associated with poor long‑term outcomes in HF patients. Conversely, fourth quartile levels of transferrin and TIBC served as protective factors and were associated with a lower mortality. Additionally, iron homeostasis indicators exhibited a certain predictive value for both long‑term mortality and first‑admission mortality in HF patients. This study underscores a significant association between iron homeostasis indicators and the prognosis of HF patients, providing valuable insights into risk stratification and clinical decision‑making for this population. Future studies should focus on dynamic fluctuations in iron homeostasis and explore interventions to improve the prognosis of HF patients.

Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting.

Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models. Gene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin. TFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice. TfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.

Analysis of iron status after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis.

Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF). While elexacaftor/tezacaftor/ivacaftor (ETI) has shown remarkable improvements in respiratory symptoms in PwCF, the effect of ETI on iron status remains unknown. This study aims to identify the effect of ETI on iron status in PwCF. A single-center retrospective cohort study of 127 adult PwCF was conducted to assess the impact of ETI on iron, ferritin, transferrin levels, and percent saturation of transferrin (PSAT). Data were collected from the electronic medical record from January 2017 to September 2022, encompassing 2 years before and after ETI initiation. The primary outcome was serum iron parameters: iron, ferritin, transferrin, and PSAT levels following ETI treatment. Secondary outcomes analyzed iron supplementation. Univariate and multivariate mixed-effects models were used for the analysis of ETI. After adjusting for covariates, following ETI initiation, the mean iron level increased by 20.24 μg/dL (p < .001), ferritin levels were 31.4% (p < .001) higher, PSAT showed a 5.09 percentage point increase (p < .001), and transferrin levels increased by 2.71 mg/dL (p = .439). Patients with and without iron supplementation experienced a significant increase in iron after ETI (p < .001). ETI is associated with a significant increase in iron, ferritin, and PSAT levels. Patients with and without iron supplementation demonstrated a significant increase in iron. This study shows the benefits of ETI on iron status in PwCF. However, further translational studies are required to understand the impact of ETI on iron absorption and metabolism in PwCF.

Treatment of Congenital Hypotransferrinemia Patients with Human Apotransferrin Resolves Anemia and Reduces Iron Accumulation

Introduction Congenital hypotransferrinemia is a very rare inherited and life-threatening disorder (MIM#209300) characterized by systemic iron overload and anemia. The deficiency of serum transferrin leads to inadequate iron supply to erythroid bone marrow, resulting in microcytic hypochromic anemia. This triggers hepcidin downregulation, causing increased iron absorption and production of non-transferrin bound iron (NTBI), leading to iron overload in various organs and tissues. Currently, there is no targeted therapy for this disease. Method In an open-label phase II/III study, four children (age 0-7 years) and one adult (20 years) with congenital hypotransferrinaemia were treated with purified plasma-fractionated human apotransferrin for nearly 10 years. All patients received an initial intravenous dose of 75 mg/kg every 8 weeks for 6 months, followed by 75 mg/kg every 4 weeks for additional 6 months, and in the subsequent years apotransferrin was administered every 4 weeks but the dose was adjusted to 75-150 mg/kg based on clinical judgement of physician according to patient condition. Prior to the start of the study two patients already received replacement therapy, i.e., human apotransferrin or plasma. Serum transferrin and serum iron were determined before every infusion. Primary objective was to investigate the effect of apotransferrin treatment on anemia and iron overload. Hemoglobin, hematocrit, and erythrocytes as markers of anemia were measured every 8 weeks. Iron overload was monitored by measuring serum ferritin every 8 weeks and yearly iron quantification in liver and heart through MRI. Labile Plasma Iron (LPI) was measured before and after infusion (starting after 2 years of treatment). The need for additional treatment for anemia or iron overload was defined as a secondary outcome. Safety and clinical tolerance were evaluated by adverse event surveillance and laboratory measurements. Results Baseline serum transferrin levels were significantly below the normal range in all patients (&amp;lt;10-189 mg/L; normal range: 1800-3500 mg/L). Treatment with human apotransferrin increased serum transferrin and serum iron levels in all patients. Fifteen minutes after the first infusion, transferrin levels ranged from 1340-2415 mg/L, but declined to values just above baseline before the next infusion (dosing interval 8 weeks). During the study period serum transferrin concentrations were affected by dose adjustments; however, trough levels of transferrin remained below the normal range throughout the study (range 200-800 mg/L). Despite subnormal trough levels, apotransferrin infusion led to rapid increase of hemoglobin (Figure 1), hematocrit, and erythrocyte levels up to normal values. The two patients who were already treated before the study, showed normal levels at baseline that were maintained. In all patients hematologic parameters remained stable throughout the study. Ferritin levels were elevated at baseline and decreased to normal ranges in 1.2 to 7.3 years, with a maximum decrease ranging from 82% to 97% of baseline. MRI examinations revealed liver iron overload at baseline which normalized in all patients after apotransferrin treatment, in most cases after 3 to 4 years (Figure 2). No myocardial iron overload was observed at baseline and during the follow-up. Pre-infusion LPI was found in all five patients, however in three patients the values were undetectable on most occasions. Immediately after infusion with apotransferrin, in none of the patients LPI was present anymore. Throughout the study no additional use of plasma/blood products or iron chelators was needed. Apotransferrin infusions were well tolerated. No serious adverse events were reported. No loss of clinical response to treatment was detected over time. Conclusion Treatment with human apotransferrin in patients with congenital hypotransferrinemia demonstrated good long-term clinical efficacy. Apotransferrin infusions increased hematopoiesis, reduced iron overload in organs, and eliminated the need for additional medication. The therapy was well-tolerated and showed good clinical safety. Human apotransferrin holds promise as the mainstay treatment option for congenital hypotransferrinemia.

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial

Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 μmol/L (95% CI 18·6 to 30·6), 20·1 μmol/L (14·8 to 25·3), 11·9 μmol/L (9·2 to 14·7), 22·5 μmol/L (15·9 to 29·1), and 19·0 μmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 μg/L (52·2 to 114.4), 65·5 μg/L (32·1 to 98·9), 62·8 μg/L (33·8 to 91·9), 150·0 μg/L (86·6 to 213.3), and 94·3 μg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. Protagonist Therapeutics.

Non-invasive assessment of normal and impaired iron homeostasis in the brain

Strict iron regulation is essential for normal brain function. The iron homeostasis, determined by the milieu of available iron compounds, is impaired in aging, neurodegenerative diseases and cancer. However, non-invasive assessment of different molecular iron environments implicating brain tissue’s iron homeostasis remains a challenge. We present a magnetic resonance imaging (MRI) technology sensitive to the iron homeostasis of the living brain (the r1-r2* relaxivity). In vitro, our MRI approach reveals the distinct paramagnetic properties of ferritin, transferrin and ferrous iron ions. In the in vivo human brain, we validate our approach against ex vivo iron compounds quantification and gene expression. Our approach varies with the iron mobilization capacity across brain regions and in aging. It reveals brain tumors’ iron homeostasis, and enhances the distinction between tumor tissue and non-pathological tissue without contrast agents. Therefore, our approach may allow for non-invasive research and diagnosis of iron homeostasis in living human brains.

Effects of malnutrition on length of stay in patients hospitalized in an acute psychiatric ward.

Psychiatric patients are considered at risk for malnutrition due to pharmacological treatments, lifestyle habits and the mental illness by itself. Even though metabolic risk factors have been related to worse outcomes in certain conditions, the evidence regarding the nutritional status and its impact on the length of stay in psychiatric inpatients is scarce. This study aims to characterize the nutritional status in acute psychiatric patients, to correlate it with the length of stay, and to find specific potential indicators of malnutrition. Adult patients admitted to the Hospital Clínic of Barcelona acute psychiatric ward throughout a 1-year period were included in this cross-sectional study. Sociodemographic and clinical variables were registered, including length of stay and the nutritional status measured with the CONUT score. Malnutrition was observed in 42.5% of patients. Plasmatic transferrin saturation, protein and iron levels were inversely correlated with length of stay, having low iron levels an association with longer hospitalizations. The length of stay was not influenced by diagnosis or treatment. Negative correlations with the nutritional status were found in: BMI, cholesterol, triglycerides, albumin, total proteins, prealbumin, iron, lymphocytes and zinc levels, and transferrin saturation. The multivariate analysis showed a significant association for cholesterol and zinc levels, lymphocyte count, and BMI. Our results suggest that nutritional status might influence the course of psychiatric admissions. Cholesterol and zinc levels, lymphocyte count, and BMI might be factors strongly associated with malnutrition. This consideration might allow the identification of profiles in which lifestyle interventions could be implemented.

Pathogenetic Effects of Bacteria of the Genus &lt;i&gt;Desulfovibrio&lt;/i&gt;. Experimental Study. Part One: Iron Metabolism

The aim of the work was to study specific systemic effect of sulfate-reducing bacteria of the genus Desulfovibrio on organism systems through creating an experimental model of intragastric bacterial invasion against the background of dysbiotic conditions of rodent gastrointestinal tract. Materials and methods. The experimental study was conducted on Wistar rats. Intestinal dysbiosis was modeled with the help of antibiotics, amoxicillin and metronidazole. Typical strain Desulfovibrio desulfuricans subsp. desulfuricans VKM B-1799T was used as an infectious agent. Results and discussion. As a result of the experiment performed, during the period of acute infection (on day 15 of the experiment), a direct correlation between the concentration of the injected D. desulfuricans VKM B-1799T bacteria suspension and the serum iron level was observed: the higher the infectious agent dose, the lower the serum iron concentration. During the phase of remote effects (day 38 of the experiment), the inverse correlation between the concentrations of D. desulfuricans VKM B-1799T in the intestines of rodents was revealed: when the concentration of the infecting agent increased from 103 CFU/g and higher, the iron level decreased from 43.5 μmol/l to 38.5 μmol/l. When comparing the level of transferrin and unsaturated iron binding capacity (UIBC), an increase in those parameters was observed in all groups of rats both during the period of acute infection and the period of long-term effects, and the percentage of transferrin iron saturation decreased, indicating the occurrence of iron deficiency against the background of exposure to the infectious agent. Intestinal dysbiosis promotes colonization by opportunistic flora, including Desulfovibrio sp. Changes in the iron metabolism markers in experimental animals against the background of D. desulfuricans VKM B-1799T infestation above 103 CFU/g and the ability of this microorganism to bind iron into an unavailable form suggest that the bacteria Desulfovibrio sp. are one of the key etiological factors of iron deficiency anemia.

Neonatal outcomes from a randomized controlled trial of maternal treatment of iron deficiency anemia with intravenous ferumoxytol vs oral ferrous sulfate

Anemia in pregnancy is common worldwide and has known maternal risks. The relationship between the types of treatment offered for maternal anemia and the effects on the fetus and newborn are largely uninvestigated. This study aimed to investigate whether maternal treatment with intravenous ferumoxytol compared to oral ferrous sulfate results in an increase in neonatal hematologic and iron indices. These analyses were planned secondary outcomes and post hoc analysis from the trial with a primary outcome of change in maternal hemoglobin. A randomized controlled trial including 124 participants with anemia by World Health Organization criteria was performed in which participants were allocated in a 1:1 ratio to either 2 infusions of 510 mg of intravenous ferumoxytol or 325 mg oral ferrous sulfate twice daily. Fetal monitoring was performed during each intravenous iron infusion. Standard univariable statistical techniques were used to compare groups and to investigate associations between maternal and neonatal hemoglobin and iron indices. Cord blood hematological parameters were equivalent between groups. Hemoglobin was 15.7 g/dL vs 15.4 g/dL (P=.6) and hematocrit was 50.5% and 49.2% (P=.4) in those randomized to intravenous ferumoxytol and oral ferrous sulfate, respectively. Iron studies revealed higher cord blood ferritin concentrations in infants of participants treated with intravenous ferumoxytol (294 vs 186, P=.005). There were equivalent iron (158 vs 146, P=.4), transferrin (186 vs 196, P=.4) and total iron binding capacity (246 vs 244, P=1) in neonates of participants receiving intravenous vs oral treatment. There were no effects of the infusions observed on cardiotocography. Gestational age at birth was equivalent between groups. We noted a larger birthweight in neonates of participants treated with intravenous ferumoxytol (3215 g vs 3033 g, P=.09), which was not statistically significant. Post hoc analyses revealed a statistically significant correlation between neonatal ferritin and maternal hemoglobin (P=.006) and neonatal ferritin and maternal ferritin (P=.017) at admission for delivery. Neonates of participants who received intravenous ferumoxytol were born with higher ferritin concentrations in cord blood, at the same gestation with the same birthweight. Participants with higher hemoglobin and ferritin indices delivered infants with higher ferritin concentrations in cord blood.

Effect of iron-fortified jamun leather on the Asunra-induced anemia in Sprague Dawley rats.

Micronutrients such as minerals and vitamins are required in a minute quantity but play a pivotal role in the functioning of the body. Therefore, deficiency in one of them can lead to lethal health conditions. Iron deficiency anaemia is one of the most common micronutrient deficiencies across the world and is affecting women and children. The present study aimed to investigate the anti-anaemic effect of fortified jamun leather on anaemia biomarkers and haematology in anaemic female Sprague Dawley rats. A total of 40 Sprague Dawley rats were used in 4 groups. Iron deficiency anaemia was induced by oral administration of the Asunra drug. The treatments were fed at two dosage levels i.e., 40 and 60% iron-fortified leather. All animals were treated for 60 days and the parameters including biochemical, and histopathology of the kidney and liver were examined. The experiment's findings showed that the group fed with iron-fortified leather (G3) succeeded significantly (P < 0.05) in restoring the serum iron (98.68 ± 2.88 μg/dL), haemoglobin (12.41 ± 0.32 g/dL), ferritin (24.54 ± 1.98 ng/mL) and haematocrit levels (39.30 ± 1.66%) at the end of the 60 days period. Additionally, the treated group's mean values for transferrin and total iron binding capacity were lower than those of the anaemic rats, indicating an improvement in iron levels. The microscopic analysis revealed that treatments had no toxic effects on the kidney and liver tissues, except in the diseased group, which had necrosis and irregular cell structure. Conclusively, iron-fortified jamun leather helped improve iron deficiency biomarkers and imparted a non-toxic effect on tissues in rats.

Ferritin as proinflamatory biomarker of iron metabolism in tuberculosis patients (review)

Traditional methods of tuberculosis (TB) diagnosis, including sputum microscopy and culture for Mycobacterium tuberculosis detection, are time-consuming or have unsatisfactory sensitivity. However, early diagnosis of TB with high accuracy and sensitivity is very important for disease outcomes and prevention. Therefore, there is an urgent need for new TB diagnostic methods based on TB-associated biomarkers, with rapid availability of results that do not require sputum analysis, are inexpensive, and have high sensitivity and specificity. Objective — to study the mechanisms of ferritin participation in the pathogenesis of tuberculosis basing on the literature data. Materials and methods. 242 literature sources were found in the PubMed system by the query «Ferritin AND Tuberculosis» and 40 of them were selected for further detailed study. Results and discussion. Studies have shown that serum iron and transferrin concentrations are lower and ferritin levels are higher in patients with TB compared to those without TB. These deviations in the concentration of ferritin and transferrin usually normalize after treatment. Lower transferrin levels are associated with both early and late TB progression, and higher ferritin and hepcidin levels are associated with a higher risk of early TB progression in TB contacts. In addition, the status of biomarkers of iron metabolism can be used as an indicator of treatment failure (low ferritin) and mortality (high ferritin). Finally, low levels of transferrin and serum iron, as well as high ferritin concentrations in HIV-infected patients predict an increased risk of TB disease and relapse. Conclusions. Iron metabolism between M. tuberculosis and the host organism is closely related and plays an important role in the pathogenesis of tuberculosis. Parameters of iron metabolism are promising markers of both the course and effectiveness of tuberculosis treatment. In particular, changes in the level of ferritin can be predictors of both the ineffectiveness of tuberculosis treatment and mortality from this disease, so the prognostic value of this marker requires further detailed study.

A Rationally Designed Complex Replenishes the Transferrin Iron Pool Directly and with High Specificity.

Many forms of anemia are caused or complicated by pathologic restriction of iron (Fe). Chronic inflammation and certain genetic mutations decrease the activity of ferroportin, the only Fe-exporter protein, so that endogenously recycled or nutritionally absorbed Fe cannot be exported to the extracellular Fe carrier protein transferrin for delivery to the bone marrow. Diminished ferroportin activity renders anemia correction challenging as Fe administered intravenously or through nutritional supplementation is trafficked through the ferroportin-transferrin axis. Utilizing judicious application of coordination chemistry principles, we designed an Fe complex (Fe-BBG) with solution thermodynamics and Fe dissociation kinetics optimized to replenish the transferrin-Fe pool rapidly, directly, and with precision. Fe-BBG is unreactive under conditions designed to force redox cycling and production of reactive oxygen species. The BBG ligand has a low affinity for divalent metal ions and does not compete for binding of other endogenously present ions including Cu and Zn. Treatment with Fe-BBG confers anemia correction in a mouse model of iron-refractory iron-deficiency anemia. Repeated exposure to Fe-BBG did not cause adverse clinical chemistry changes or trigger the expression of genes related to oxidative stress or inflammation. Fe-BBG represents the first entry in a promising new class of transferrin-targeted Fe replacement drugs.

Studying ferroptosis and iron metabolism pre- and post-radiotherapy treatment in breast cancer patients

BackgroundRadiotherapy (RT) is an important part of the treatment of many tumors. Radiotherapy causes oxidative damage in all cellular compartments, including lipid membrane, on a random basis. Toxic lipid peroxidation accumulation has only lately been linked to a regulated type of cell death known as ferroptosis. Iron is required for ferroptosis sensitization in cells.Aim of the workThis work aimed to study ferroptosis and iron metabolism before and after RT in BC patients. Subjects and methodsEighty participants were included divided into two main groups: group I: 40 BC patients treated with RT. Group II: 40 healthy volunteers’ age and sex matched as control group. Venous blood samples were collected from BC patients (prior to and after RT) and healthy controls. Glutathione (GSH), malondialdehyde (MDA), serum iron levels and % of transferrin saturation were measured by colorimetric technique. Ferritin, ferroportin, and prostaglandin-endoperoxide synthase 2 (PTGS2) levels were assessed by ELISA.ResultsSerum ferroportin, reduced glutathione, and ferritin showed significant decrease after radiotherapy in comparison to before radiotherapy. However, there was significant increase in serum PTGS2, MDA, % of transferrin saturation and iron levels after radiotherapy in comparison to before radiotherapy.ConclusionRadiotherapy induced ferroptosis in breast cancer patients as a new cell death mechanism and PTGS2 is a biomarker of ferroptosis. Iron modulation is a useful approach for the treatment of BC especially if combined with targeted therapy and immune-based therapy. Further studies are warranted to be translated into clinical compounds.