Iron Stores Research Articles

Catheter Ablation of Atrial Fibrillation in Infiltrative Cardiomyopathies: A Narrative Review.

Atrial and ventricular arrhythmias are common in patients with Infiltrative heart diseases. This review discusses ablative techniques for arrhythmias in amyloidosis, sarcoidosis, hemochromatosis, and glycogen storage disorders, primarily focusing on atrial fibrillation (AF). A thorough literature review was conducted on the MEDLINE database to synthesize current knowledge and propose future research directions. AF is the most common arrhythmia identified in patients with amyloidosis due to cellular infiltration and atrial dilation. While catheter ablation is associated with a significantly lower rate of all-cause mortality and admission rate, conflicting data exist regarding the higher risk of pericardial effusion, in-hospital mortality, length of stay, and cost of hospitalization. Cardiac sarcoid predisposes AF due to granulomas, atrial dilation, and scarring. Studies demonstrate encouraging outcomes and low recurrence rates in these patients who undergo ablation for AF, with no difference in complications compared to those without sarcoidosis. AF is the most common arrhythmia in hereditary hemochromatosis (HH), secondary to increased myocardial iron stores and elevated oxidative stress, and is primarily managed by chelation. Scant reports regarding ablation are described for HH and glycogen storage disorders. Catheter ablation is a safe and effective modality for the treatment of AF in infiltrative cardiomyopathy. Future large-scale trials are needed to confirm these findings.

Ferritin with methylglyoxal produces reactive oxygen species but remains functional

Iron is necessary for life, but the simultaneous iron-catalyzed formation of reactive oxygen species (ROS) is involved in pathogenesis of many diseases. One of them is diabetes mellitus, a widespread disease with severe long-term complications, including neuropathy, retinopathy, and nephropathy. Much evidence points to methylglyoxal, a potent glycating agent, as the key mediator of diabetic complications. In diabetes, there is also a peculiar dysregulation of iron homeostasis, leading to an expansion of redox-active iron. This in vitro study focuses on the interaction of methylglyoxal with ferritin, which is the main cellular protein for iron storage. Methylglyoxal effectively liberates iron from horse spleen ferritin, as well as synthetic iron cores; in both cases, it is partially mediated by superoxide. The interaction of methylglyoxal with ferritin increases the production of hydrogen peroxide, much above the generation of peroxide by methylglyoxal alone, in an iron-dependent manner. Glycation with methylglyoxal results in structural changes in ferritin. All of these findings can be demonstrated with pathophysiologically relevant (submillimolar) methylglyoxal concentrations. However, the rate of iron release by ascorbate, the ferroxidase activity, or the diameter of gated pores even in intensely glycated ferritin is not altered. In conclusion, although the functional features of ferritin resist alterations due to glycation, the interaction of methylglyoxal with ferritin liberates iron and markedly increases ROS production, both of which could enhance oxidative stress in vivo. Our findings may have implications for the pathogenesis of long-term diabetic complications, as well as for the use of ferritin as a nanocarrier in chemotherapy.

Serum iron and transferrin saturation variation are circadian regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepatic Tfrc expression in mice.

Serum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous ~24-h periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron, transferrin saturation (TSAT), hepatic transferrin receptor (TFR1) gene (Tfrc) expression, and erythropoietic activity exhibit circadian rhythms. Daily oscillations of serum iron, TSAT, hepatic Tfrc expression, and erythropoietic activity are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. Oscillations of serum iron, TSAT, hepatic Tfrc, and erythropoietic activity were ablated when circadian machinery was disrupted in Bmal1 knockout mice. Interestingly, we find that circadian oscillations of erythropoietic activity and hepatic Tfrc expression are maintained in opposing phase, likely allowing for optimized usage and storage of serum iron whilst maintaining adequate serum levels and TSAT. This study provides the first confirmatory evidence that serum iron is circadian regulated, discerns circadian rhythms of TSAT, a widely used clinical marker of iron status, and uncovers liver-specific circadian regulation of TFR1, a major player in cellular iron uptake.

Mitochondria-Targetable Cyclometalated Iridium(III) Complex-Based Luminescence Probe for Monitoring and Assessing Treatment Response of Ferroptosis-Mediated Hepatic Ischemia-Reperfusion Injury.

Ferroptosis plays an essential role in the pathological progression of hepatic ischemia-reperfusion injury (HIRI), which is closely related to iron-dependent lipid peroxidation. Since mitochondria are thought to be the major site of reactive oxygen species (ROS) production and iron storage, monitoring the variations of mitochondrial hypochlorous acid (HClO) (an important member of ROS) has important implications for the assessment of ferroptosis status, as well as the formulation of treatment strategies for HIRI. However, reliable imaging tools for the visualization of mitochondrial HClO and monitoring its dynamic changes in ferroptosis-mediated HIRI are still lacking. Herein, in this work, an HClO-activated near-infrared (NIR) cyclometalated iridium(III) complex-based probe, named NIR-Ir-HClO, was developed for the visual monitoring of the mitochondrial HClO fluxes in ferroptosis-mediated HIRI. The newly prepared probe showed fast response (<30 s), good sensitivity, excellent selectivity, good cell biocompatibility, and satisfactory mitochondrial-targeting performance, making it suitable for accurate monitoring of mitochondrial HClO in living cells. Moreover, visualization of the variations of mitochondrial HClO in ferroptosis-mediated HIRI and monitoring of the treatment response of ferroptosis-mediated HIRI to the ferroptosis inhibitors were achieved for the first time. All these show that probe NIR-Ir-HClO can be utilized as a reliable imaging tool for revealing the pathological mechanism of mitochondrial HClO in ferroptosis-mediated HIRI, as well as for the formulation of new treatment strategies for HIRI.

The efficacy of IV iron in anemic heart failure patients: a systemic review and meta-analysis of randomised controlled trials

Abstract Introduction Iron deficiency in the context of heart failure is a multifaceted concern, where the intricate interplay between diminished iron stores, impaired absorption mechanisms, and reduced recycled iron in the reticuloendothelial system adds a layer of complexity to patient management. Initial attempts to address this issue with oral iron treatments have been questioned due to its poor absorption. Intravenous iron therapy is now preferred, as it has been shown to reduce heart failure hospitalisations and cardiovascular mortality. However, there is a lack of randomised studies specifically focused on heart failure patients, highlighting the need for more targeted investigations. Purpose The aim of this review is to provide reliable evidence from published randomised controlled trials (RCTs) regarding the beneficial effect of IV iron in heart failure patients. Methods We systematically searched PubMed, Web of Science, Scopus, and Cochrane Central, and EMBASE from inception until December 2023. We included randomised controlled trials (RCTs) comparing the effect of IV iron in heart failure patients versus placebo. The primary outcomes were 6MWT mean change, ferritin concentration mean change, transferrin saturation mean change and worsening heart failure. All data were pooled as either Mean difference in the random effect model with the corresponding SD or pooled as RR and 95% CI for dichotomous data. Results Twelve RCTs involving 6800 patients were included in the analysis. The overall effect on the measured primary outcomes was in favour of IV iron in terms of 6MWT mean change (MD= 34.45, 95% CI [ 29.58 to 39.31], P=&amp;lt;0.0001), ferritin concentration mean change (MD= 219.18, 95% CI [ 208.7 to 229.66], P=&amp;lt;0.0001), transferrin saturation mean change (MD= 9.77, 95% CI [ 8.14 to 1.39], P=&amp;lt;0.0001) and worsening heart failure (RR= 0.46, 95% CI [ 0.31 to 0.69], P=0.002). Conclusion The introduction of the IV iron therapy to heart failure patients showed a beneficial effect in terms of the measured haematological and cardiovascular metrics, which include 6MW test mean change, ferritin concentration mean change, and worsening heart failure.6MWT mean changeFerritin mean change

Iron status in children with acute COVID-19 and paediatric inflammatory multisystem syndrome during infection and after recovery

BackgroundCOVID-19 has significant effects on organ function, particularly on lung function and iron metabolism. Studies have shown increased levels of ferritin, an iron storage protein, in COVID-19 patients, indicating potential changes in iron utilization. Research has focused primarily on adults, with limited studies on paediatric patients and a lack of comparisons with MIS-C patients. This study aimed to assess iron status in paediatric COVID-19 patients using traditional and new biomarkers, soluble transferrin receptors (sTfR) and Reticulocyte hemoglobin equivalent (RET-He), to improve diagnosis and prognosis. Additionally, we sought to compare iron status between acute COVID-19 patients and MIS-C patients and evaluate the relationships among iron dysmetabolism, disease severity, and prognosis in paediatric patients. The study also involved monitoring iron status during and after infection to understand its impact on patient severity and prognosis.MethodsA cohort study involving 49 patients aged 1 month to 18 years was conducted at the isolation department of Mansoura University Children's Hospital. The study included 36 patients with acute COVID-19 and 13 with multisystem inflammatory syndrome of childhood (MIS-C). Diagnosis was based on PCR from a deep nasopharyngeal swab or a positive antibody test. Follow-up of survivors was conducted 3 months after recovery. Blood samples were obtained during infection and at follow-up for CBC, Ret-He, iron kinetics, and sTfR analyses.ResultsSignificant iron deficiency anaemia was observed in all patients during infection, with improvement after 3 months of recovery in survivors. The improvement was more obvious in MIS-C patients, with Hb and iron kinetics not significantly affected by disease severity. The STfR was significantly lower in nonsurvivors than in survivors. The ROC curve showed that a baseline sTfR ≤ 18 nmol/L was a statistically significant difference between nonsurvivors and survivors (area under the curve (AUC) = 0.810, p < .001), with 66.7% sensitivity and 82.5% specificity. Regression analysis revealed that patients with baseline sTfRs ≤ 18 nmol/L were 5.9 times more susceptible to death.ConclusionThis study revealed that COVID-19 in children caused iron deficiency anaemia, which improved within 3 months after recovery. Haemoglobin and sTfRs were identified as reliable indicators of IDA in these patients, unlike iron kinetics and RET-He.

The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression

Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Strength in Numbers - Identifying a Significant Association Between High Serum Ferritin Levels and Newly diagnosed Malignancy in a Large Health Organization Cohort.

Ferritin, an iron storage protein and acute phase reactant, has been implicated in various aspects of human health and disease, including cancer. Previous studies have identified elevated serum ferritin (SF) levels in several cancer types, but a comprehensive examination across different malignancies remains lacking. This study aims to fill this gap by utilizing anonymized data from Maccabi Health Services (MHS), one of Israel's largest health organizations, to explore the association between elevated SF levels and the diagnosis of different malignancies. An extensive dataset from MHS, comprising 2.7 million members, including 1.3 million individuals who underwent SF level testing, was analyzed. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to assess the association between high SF levels and cancer diagnosis. Subgroup analysis was conducted to investigate variations across different malignancies. The analysis revealed a significant association between elevated SF levels and cancer diagnosis among MHS members, with an OR of 1.9 (95% CI 1.71-2.15). Sub- group analysis unveiled differences in the association across malignancy types, with hematological, hepatobiliary and respiratory malignancies more strongly associated with high SF levels. This study provides further support for the link between elevated SF levels and malignancy, leveraging a vast dataset from MHS, underscoring potential utilities of elevated SF levels as a potential indicator for cancer with a variable role among different malignancy types. The identification of elevated SF levels as a potential indicator for underlying malignancy for seemingly-healthy individuals.

Liver iron stores and effectors of ferroptosis are dependent on age and sex.

Ferroptosis is a form of cell death characterized by a pro-oxidative cellular milieu and iron-dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12- and 24-month-old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non-haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor-1. In female rats, the 24-month-old group had higher contents of thiobarbituric acid reactive substances compared with their 12-month-old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4-hydroxnonenal-modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis.

Plasma sphingomyelin levels were negatively correlated with ferritin levels in splenectomized thalassemia patients

Abstract Beta thalassemia results from decreased production of beta chains due to either mutations or deletions in the beta-globin gene, leading to impaired production of hemoglobin A. Thalassemia patients take frequent blood transfusions to compensate for hemolytic anemia and iron overload. Iron overload is monitored by serum ferritin levels in these patients. Extra-medullary hematopoiesis in beta thalassemia major leads to hypersplenism which often necessitates splenectomy to increase red cell life span and decrease transfusion need. Sphingomyelin is the second most abundant phospholipid in human plasma after phosphatidylcholine. In contrast to the well-defined roles of sphingolipids in cell membranes, their possible physiological role in lipoprotein metabolism has recently gained attention. Increased circulating levels of sphingomyelins and ceramides were observed in obesity, diabetes, and cardiovascular diseases. Although lipid abnormalities such as hypocholesterolemia and relatively increased triglycerides were reported in beta-thalassemia patients, there is no study investigating sphingolipid levels in thalassemia. Therefore, we investigate certain long chain and very long chain sphingomyelins and ceramides in beta-thalassemia patients who are under routine follow-up in our hospital. Thalassemia major patients who applied to the hospital for regular blood transfusion and gave consent were included in the study. Blood samples were obtained before transfusion. Plasma sphingomyelin (C16, C18 and C24) and ceramide (C16, C18, C20, C22, C24) species were measured by triple quadruple LC-ESI-MS/MS (Shimadzu, Japan). D-erythrosphingosine-D9 (Matreya) was used as an internal standard, all other lipid standards were from Avanti. Body iron stores of the patients were monitored by serum ferritin levels. A total of thirty patients were included in the study. All patients typically received regular erythrocyte suspension transfusions every three weeks and continuous oral iron chelation therapy. Twenty of the patients had a previous splenectomy. The mean age was 34.5 ±8.1 years in the splenectomy group and 32.8 ±8 years in the group without splenectomy. Mean ferritin levels were not different between the groups, being 1073.2±563.5 µg/L in splenectomy and 1709 ±1660.4 µg/L in non-splenectomy groups. All measured sphingolipid levels were similar between splenectomy and non-splenectomy groups. When correlation analysis was performed between measured sphingolipid and ferritin levels, significant negative correlations were found between sphingomyelin C16 (r= -0.591 p&amp;lt;0.006) and C18 (r= -0.594 p&amp;lt;0.006) with ferritin levels in the splenectomy group. However, this negative correlation was absent in the non-splenectomy group. In conclusion, we found that iron overload is associated with lower plasma sphingomyelin levels in splenectomized thalassemia patients. We have been working on the lipidomic analysis of the plasma and erythrocytes of thalassemia patients and other hemolytic anemias. The results may further help to get a better picture of lipid metabolism in thalassemia.

Hepcidin levels, markers of iron overload, and liver damage in children with beta-thalassemia major

Background Thalassemia is a hemoglobin synthesis disorder that causes patients to need lifelong blood transfusions, leading to iron overload and alter organ function, including the liver. Hepcidin, produced by the liver, plays a role in iron homeostasis and should be increased in excess iron stores. However, the level decreases in thalassemia due to some factors, such as ineffective erythropoiesis and liver damage. Recent publications revealed that hepcidin could be associated with iron overload and also a marker of liver diseases. Objective To analyse the correlation between hepcidin level, markers of iron overload, and liver damage in beta-thalassemia major. Methods This cross-sectional study included all ?-thalassemia major age 2-18 years admitted to Dr. Mohammad Hoesin Hospital, Palembang, South Sumatera, who underwent blood transfusions from March to August 2022. We measured the level of iron overload markers, hepcidin, liver function test (LFT), and performed liver ultrasonography (USG). Results Of 97 subjects, median hepcidin level was 10.01 ng/mL and 68% of the subjects showed a decrease. The iron overload parameters were evaluated from serum iron levels (P=0.13), ferritin levels (P=0.90), and transferrin saturation (P=0.29) and 24.7% had abnormal liver USG findings. Spearman’s correlation revealed that only direct bilirubin (DB) (r=0.35; P=0.001) and liver USG (r=0.20; P=0.05) had positive correlations with decreased levels of hepcidin. Also, it had 91.7% sensitivity in predicting liver damage from ultrasound. Conclusion The hepcidin level was not significantly associated with iron overload markers.

Bridging the Knowledge Gap on Iron Deficiency Anemia Among Nursing Students

Background: Iron deficiency anemia (IDA) is a prevalent nutritional disorder characterized by a significant reduction in the body’s iron stores, affecting oxygen transport and leading to various health complications. Specific Background: The understanding of IDA among nursing students is underdeveloped, especially regarding the differences between morning and evening study cohorts. Knowledge Gap: Understanding nursing students' knowledge of IDA is critical for enhancing educational strategies and improving patient care, yet limited studies have assessed this demographic's awareness of the condition and its management. Aims: This study aims to evaluate nursing students' knowledge about IDA and to compare the levels of knowledge between morning and evening students at the College of Nursing, University of Basrah, over a six-month period from November 2023 to March 2024. Results: A descriptive cross-sectional study was conducted involving 145 students (72 morning and 73 evening) who completed a questionnaire. Results indicated that 40.2% of morning students and 53.4% of evening students suffered from iron deficiency. While 86.1% of morning students had prior knowledge of IDA compared to 67.1% of evening students, the mean knowledge levels were deemed good for both groups, with no significant statistical difference between them. Novelty: This research contributes to the existing literature by highlighting knowledge levels of IDA among nursing students in Iraq, revealing that both morning and evening cohorts possess substantial understanding yet exhibit slight discrepancies. Implications: The findings underscore the necessity for targeted educational interventions to bridge the knowledge gap regarding IDA, ultimately enhancing nursing students' competencies in managing this condition in clinical settings. Highlights: IDA Prevalence: 40.2% morning students and 53.4% evening students affected. Knowledge Difference: 86.1% morning vs. 67.1% evening students aware of IDA. Educational Need: Targeted interventions required for improved IDA management in nursing education. Keywords: Iron deficiency anemia, nursing students, knowledge assessment, educational interventions, Iraq

A-159 Re-evaluating Ferritin Cutoffs for the Diagnosis of Iron Deficiency and Iron Deficiency Anemia

Abstract Background Iron deficiency (ID) is the most common nutrient deficiency in the world and iron deficiency anemia (IDA) is estimated to affect 1.24 billion people. Serum ferritin is an iron storage protein commonly used as a biomarker for ID and IDA. The ferritin lower limit of normal (LLN) defined in many clinical laboratories is lower than evidence-based cutoffs and may not detect ID and IDA with adequate sensitivity, particularly when sex-based reference intervals (RIs) are used. This may be due in part to the use of asymptomatic, iron-depleted individuals for RI studies. Recent efforts have been made to increase the LLN for ferritin to at least 30 ng/mL and re-evaluate sex based RIs to improve diagnosis of ID and IDA. In this study, we aimed to investigate LLN ferritin cutoffs for ID and IDA in our patient population. Methods Patient data from June 2022-May 2023 were collected with approval from the Institutional Review Board (IRB), including age, sex, and values for ferritin, iron, transferrin saturation, and hemoglobin. Patients were classified as iron replete (IR), ID, or IDA based on measurements for iron, transferrin saturation, and hemoglobin. IR patients were defined as having iron and transferrin saturation values within current RIs, while those below the cutoff were grouped as ID. ID and IDA were further classified based on hemoglobin values. A range of ferritin concentrations between 1 and 100 ng/mL were used to calculate true and false positive rates (TPR and FPR) and diagnostic accuracy (DA). Receiver operator characteristic (ROC) curve and J index analysis were used to define optimal ferritin cutoffs for ID and IDA. Results Data from 26,455 patients (65% female) were used in this study. Conclusions These findings highlight the need to re-examine ferritin RIs in the context of ID/IDA, especially for those patients assigned female at birth.

Ferritin and Iron Levels Inversely Associated With Lymphoma Risk: A Mendelian Randomization Study.

Current knowledge on iron's role in lymphoma development is very limited, with studies yielding inconsistent findings. To address this gap, we conducted a rigorous two-sample mendelian randomization study, aiming to elucidate the potential associations between iron storage and the risk of developing lymphoma. This study leveraged extensive genetic data derived from a comprehensive genome-wide association study (GWAS) comprising 257,953 individuals. The primary objective was to pinpoint single-nucleotide polymorphisms (SNPs) that are significantly associated with iron storage. Subsequently, this genetic information was analyzed in conjunction with summary-level data pertaining to lymphoma cases and controls, sourced from the IEU open GWAS project, which included a sample size of 3,546 lymphoma cases and 487,257 controls. To evaluate the relationship between iron storage and lymphoma risk, an inverse variance-weighted method with random effects was employed, complemented by rigorous sensitivity analyses. Genetic predisposition to high ferritin and serum iron status was causally associated with lower odds of lymphoma. Ferritin exhibited an odds ratio (OR) of 0.777 (95% confidence interval (CI): 0.628 - 0.961, P = 0.020), indicating 22.3% reduced odds of lymphoma associated with a one standard deviation increase in ferritin levels. Similarly, serum iron demonstrated an OR of 0.776 (95% CI: 0.609 - 0.989, P = 0.040), corresponding to 22.4% decreased odds of lymphoma for a one standard deviation increase in serum iron. This study suggests that individuals with genes linked to higher iron storage levels have a lower risk of developing lymphoma, but further research is necessary before making any clinical recommendations.

Research progress on iron metabolism in the occurrence and development of periodontitis

Iron metabolism refers to the process of absorption, transport, excretion and storage of iron in organisms, including the biological activities of iron ions and iron-binding proteins in cells. Clinical research and animal experiments have shown that iron metabolism is associated with the progress of periodontitis. Iron metabolism not only enhances the proliferation and toxicity of periodontal pathogens, but also activate host immune-inflammatory response mediated by macrophages, neutrophils and lymphocytes. In addition, iron metabolism is also involved in regulating cellular death sensitivity of gingival fibroblasts and osteoblasts and promoting the differentiation of osteoclasts, which plays a regulatory role in the regeneration and repair of periodontal tissue. This article reviews the research progress on the pathogenesis of periodontitis from the perspective of iron metabolism, aiming to provide new ideas for the treatment of periodontitis.

Vitamin C-rich guava consumed with mungbean dal reduces anemia and increases hemoglobin but not iron stores: a randomized controlled trial of food-to-food fortification in Indian children.

BackgroundAdding vitamin C-rich fruit to staples containing iron could be an effective strategy to improve iron bioavailability and thereby reduce iron-deficiency anemia in children. ObjectiveWe aimed to assess the effect of consuming a mungbean-based meal with or without guava fruit on body iron stores, hemoglobin concentration, and anemia of children as part of a school feeding program. MethodsWe conducted a 7-month randomized, controlled trial with 6 to 10-year-old school children (n=200; 46% anemic, 71% iron-deficient) from a rural community in Haryana, North India. Children were assigned to two treatment groups to daily receive either a meal of mungbean dal only (3.0 mg of iron; vitamin C:iron molar ratio ∼0.5:1), or mungbean dal with fresh guava (3.2 mg of iron; ∼170 mg of vitamin C; molar ratio ∼18:1). Meals were served every school day under supervision. The primary outcome was body iron stores, while concentrations of hemoglobin and other iron indicators were secondary outcomes. ResultsDaily consumption of mungbean dal along with guava did not result in an overall improvement of body iron stores (mean treatment effect: 0.65 mg/kg body weight; 95% CI: −0.34, 1.63; P=0.197). However, compared to children who consumed mungbean dal only, children in the guava group showed a larger increase in hemoglobin concentration (3.7 g/L; 95% CI: 1.6, 5.6; P=0.001), and a larger drop in the prevalence of anemia (−51%; 95% CIs: −74, −10; P= 0.022) and iron-deficiency anemia (−56%, 95% CI: −83, 13; P=0.087). These effects were more pronounced in children who were iron-deficient at study start. ConclusionsAddition of guava to a mungbean-based meal containing a moderate amount of iron increased hemoglobin and reduced anemia but did not provide enough additional absorbed iron to also increase body iron stores. Food-to-food fortification by inclusion of vitamin C rich fruits in iron-containing school meals may help alleviate the burden of anemia in children.This trial was registered at https://clinicaltrials.gov/ct2/show/NCT01191463.

Importance of ferritin research in clinical practice

Serum ferritin (SF) is typically present in serum at concentrations directly related to iron (Fe) storage and is therefore traditionally used as an indicator of Fe levels in body tissues. Reducing its level is the “gold standard” for diagnosing widespread iron deficiency conditions. No less significant is hyperferritinemia — a nonspecific syndrome that occurs when Fe reserves are overloaded, a number of immunoinflammatory, infectious, oncological diseases, liver diseases, etc. In many pathological conditions, the level of SF determines the severity and prognosis of the disease. Ferritin concentrations greater than 1000 ng/mL, regardless of cause, have been shown to be associated with higher mortality. The reason for the increase in the level of SF in liver pathologies (cancer, hepatitis, cirrhosis) is associated with the process of its release from hepatocytes during their destruction. On the other hand, excessive synthesis and/or cellular secretion of ferritin occurs under the influence of various stimuli (cytokines, oxidative stress, hypoxia, oncogenes and growth factors). The interpretation of elevated ferritin values goes far beyond the role of an indicator of replenishment of Fe stores in tissues. Only 10% of cases of hyperferritinemia are associated with iron overload; in most patients, it is defined as the result of the acute phase and a reactive increase in ferritin levels against the background of any disease. The variety of symptoms of iron deficiency syndromes and hyperferritinemia is due to the involvement of many organs and systems, which requires a thorough examination (study of complaints, anamnesis, family and concomitant diseases, as well as the necessary laboratory and instrumental studies) to search for possible causes. Systemic Fe homeostasis must be closely monitored on a regular basis. It is required to comply with the conditions for blood sampling for SF. Reference values for SF concentrations vary depending on the analytical methods used and the population studied. Age and gender play an important role. Given the range of reference values, it is important for a particular patient to focus on the initial level of his ferritin, determined against the background of health and well-being during clinical observation.

Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis

Leukemia inhibitory factor (LIF) is a multifunctional cytokine that plays a crucial role in various biological processes. However, LIF involvement in iron metabolism remains almost unexplored. This study aimed to explore the impact of LIF on systemic iron transportation and its potential role in ferroptosis in osteoblasts. We observed that the Lif-deficient (Lif−/−) mice is characterized by a reduction in bone mass and a decrease in bone mineral density compared with wild-type (WT) mice. Energy-dispersive X-ray spectroscopy revealed a marked increase in iron content on the surface of femurs from Lif−/− mice. Meanwhile, iron stores test lower iron levels in the spleens and higher levels in the femurs of Lif−/− mice. Besides, Lif−/− mice display increased levels of serum iron, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation and serum ferritin relative to WT mice. Hepcidin mRNA expression reduction in the liver of Lif−/− mice. It also holds true in the AML-12 hepatocyte cell line after Lif-knockdown. Immunohistochemistry and RT-PCR revealed elevated ferroportin (FPN) in duodenal cells of Lif−/− mice. Lif-deficiency decreases SLC7A11 levels in osteoblasts. In addition, overexpression of LIF downregulates CD71, DCYTB, and DMT1, thereby reducing iron uptake in iron-overloaded cells. Femur immunohistochemistry (IHC) revealed increased ACSL4 and decreased GPX4 and SLC7A11, indicating an increase in ferroptosis of osteoblasts in Lif−/− mice. Whole-transcriptome sequencing showed gene expression changes after Lif-knockdown, exhibiting a negative correlation with genes involved in long-chain fatty acid transport, mitochondrial organization, and the p38 MAPK signaling pathway. These results demonstrate that Lif-deficiency alter systemic iron metabolism and increases the susceptibility of osteoblasts to ferroptosis.

ATH434, a promising iron-targeting compound for treating iron regulation disorders.

Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4 µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores.

Oral Liposomal Iron Versus Injectable Iron Sucrose for Anemia Treatment in Non-dialysis Chronic Kidney Disease Patients: A Non-inferiority Study.

Introduction Anemia is a prevalent and persistent complication in chronic kidney disease (CKD), particularly in advanced stages, contributing to the deterioration of renal function and diminishing patients' quality of life. Iron supplementation constitutes a cornerstone of anemia management in this population. Among various iron formulations, liposomal iron has emerged as a promising option due to its enhanced efficacy in replenishing iron reserves and improved tolerability. Objective This study aims to assess the comparative effects of intravenous and liposomal oral iron on hemoglobin levels in non-dialysis CKD patients. Additionally, it seeks to evaluate the rate of hemoglobin correction, iron reserve status during treatment, and therapeutic tolerance to these interventions. Materials and methods A randomized controlled trial enrolled CKD patients (stages 3-5, not on dialysis) with iron deficiency anemia (hemoglobin ≤ 12 g/dL, ferritin ≤ 100 ng/mL, transferrin saturation ≤ 25%). Participants were allocated to receive either daily oral liposomal iron (Group OS) at a dosage of 30 mg or intravenous iron-hydroxide sucrose complex weekly (Group IV) for three months. Follow-up extended through the treatment phase and two months post-withdrawal. Results Thirty-one CKD patients were randomized into two groups: 14 received intravenous iron (IV group) and 17 received oral iron (OS group). After excluding four patients, the final cohort comprised 27 individuals (IV group: n=13, OS group: n=14). Both iron treatments resulted in progressive hemoglobin increases, with the IV group showing a mean increase of 14.65% (p=0.049) compared to 4.78% (p=0.003) in the OS group. Secondary analysis revealed significant increases in ferritin levels (p<0.001) and transferrin saturation (TSAT) levels (p=0.031) in the IV group. Post-treatment follow-up demonstrated stable hemoglobin levels in the OS group and a consistent increase in ferritin levels in the IV group. Adverse reactions predominantly included hypotension in the IV group (4 (30.7%)) and constipation in the OS group (4 (28.4%)). Discussion and conclusion Anemia remains a significant challenge in CKD patients. Our study compares oral liposomal iron to injectable iron for anemia treatment, aiming to minimize hospitalizations for iron infusion, preserve venous capital, and mitigate potential harmful side effects. We found oral liposomal iron to be a safe and effective option for correcting anemia in non-dialysis CKD patients, albeit with lower efficacy in replenishing iron stores compared to IV iron. Comparative analysis with similar studies supports the non-inferiority of oral liposomal iron, although IV iron retains superiority in replenishing iron reserves.