Acute Iron Research Articles

Antimicrobial Potency of Nor-Pyochelin Analogues and Their Cation Complexes against Multidrug-Resistant Pathogens.

The opportunistic pathogen Pseudomonas aeruginosa develops increasing resistance toward even the most potent antibiotics. Like other bacteria, the pathogen produces a number of virulence factors including metallophores, which constitute an important group. Pseudomonads produce the iron-chelating metallophore (siderophore) pyochelin, which, in addition to its iron-scavenging ability, is an effector for the transcriptional regulator PchR in its FeIII-bound form (ferripyochelin). In the present study, docking studies predicted a major ferripyochelin binding site in PchR, which prompted the exploration of nor-pyochelin analogues to produce tight binding to PchR, and thereby upregulation of the pyochelin metabolism. In addition, we investigated the effects of using the analogues to bind the antimicrobial cations GaIII and InIII. Selected analogues of nor-pyochelin were synthesized, and their GaIII- and InIII-based complexes were assessed for antimicrobial activity. The results indicate that the GaIII complexes inhibit the pathogens under iron-limited conditions, while the InIII-based systems are more effective in iron-rich media. Several of the GaIII complexes were shown to be highly effective against a multidrug-resistant P. aeruginosa clinical isolate, with minimum inhibitory concentrations (MICs) of ≤1 μg/mL. Similarly, two of the InIII-based systems were particularly effective against the isolate, with an MIC of 8 μg/mL. These results show high promise in comparison with other, traditionally potent antibiotics, as the compounds generally indicated low cytotoxicity toward mammalian cells. Preliminary mechanistic investigations using pseudomonal transposon mutants suggested that the inhibitory effects of the InIII-based systems could be due to acute iron deficiency as a result of InIII-bound bacterioferritin.

Association of Iron Therapy with Mortality in Patients with Acute Myocardial Infarction and Iron Deficiency.

Iron deficiency (ID) is common in patients with acute myocardial infarction (AMI). It is unknown whether patients with AMI combined with ID will benefit from iron supplementation therapy. This study aimed to assess the relationship between iron therapy and mortality in AMI patients. Retrospective analysis was performed in subjects screened from the Medical Information Mart in Intensive Care-IV database. The data were obtained from ICU patients admitted to Beth Israel Deaconess Medical Center between 2008 and 2019. The patients were divided into two groups according to iron treatment exposure. Propensityscorematching(PSM) was performed in the original cohort at a 1:1 ratio. Univariate and multivariate analyses were performed to adjust for confounding factors. The primary outcome was 28-day mortality. A total of 426 patients were included in this study. After 1:1 PSM, 208 patients were analyzed. Iron treatment was associated with a lower risk of 28-day mortality (9 deaths (8.65%) in the iron treatment group vs. 21 deaths (20.19%) in the non-iron treatment group; HR = 0.39; 95% CI = 0.17-0.89; p = 0.025) and in-hospital mortality (4 deaths (3.85%) in the iron treatment group vs. 12 deaths (11.54%) in the non-iron treatment group; OR, 0.15; 95% CI, 0.03-0.74; p = 0.029). Iron treatment was associated with reduced 28-day mortality in patients with AMI combined with ID. Iron treatment had no significant effect on the length of hospitalization or the length of ICU stay. Prospective studies are needed to verify this conclusion.

The oral ferroportin inhibitor vamifeport prevents liver iron overload in a mouse model of hemochromatosis.

Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin-ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the Hfe C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in Hfe C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver Hamp in wild-type mice, which was absent in Hfe C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in Hfe C282Y mice, as well as markedly reducing liver Hamp expression in Hfe C282Y mice, suggesting distinct regulation of liver Hamp expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in Hfe C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the Hfe C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.

Identification of Isoliensinine as a Ferroptosis Suppressor with Iron-Chelating Activity.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.

Ischemic Neuroprotection by Insulin with Down-Regulation of Divalent Metal Transporter 1 (DMT1) Expression and Ferrous Iron-Dependent Cell Death.

Background: The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat 6-OHDA model of Parkinson's disease, where DMT1 involvement is described. According to the regulation of DMT1, previously described as a target gene of NF-kB in the early phase of post-ischemic neurodegeneration, both in vitro and in vivo, and because insulin controls the NFkB signaling with protection from ischemic cell death in rat cardiomyocytes, we evaluated the role of insulin in relation to DMT1 expression and function during ischemic neurodegeneration. Methods: Insulin neuroprotection is evaluated in differentiated human neuroblastoma cells, SK-N-SH, and in primary mouse cortical neurons exposed to oxygen glucose deprivation (OGD) for 8 h or 3 h, respectively, with or without 300 nM insulin. The insulin neuroprotection during OGD was evaluated in both cellular models in terms of cell death, and in SK-N-SH for DMT1 protein expression and acute ferrous iron treatment, performed in acidic conditions, known to promote the maximum DMT1 uptake as a proton co-transporter; and the transactivation of 1B/DMT1 mouse promoter, already known to be responsive to NF-kB, was analyzed in primary mouse cortical neurons. Results: Insulin neuroprotection during OGD was concomitant to the down-regulation of both DMT1 protein expression and 1B/DMT1 mouse promoter transactivation. We also showed the insulin-dependent protection from cell death after acute ferrous iron treatment. In conclusion, although preliminary, this evaluation highlights the peculiar role of DMT1 as a possible pharmacological target, involved in neuroprotection by insulin during in vitro neuronal ischemia and acute ferrous iron uptake.

Recommendations for diagnosis, treatment, and prevention of iron deficiency and iron deficiency anemia.

Iron is an essential nutrient and a constituent of ferroproteins and enzymes crucial for human life. Generally, nonmenstruating individuals preserve iron very efficiently, losing less than 0.1% of their body iron content each day, an amount that is replaced through dietary iron absorption. Most of the iron is in the hemoglobin (Hb) of red blood cells (RBCs); thus, blood loss is the most common cause of acute iron depletion and anemia worldwide, and reduced hemoglobin synthesis and anemia are the most common consequences of low plasma iron concentrations. The term iron deficiency (ID) refers to the reduction of total body iron stores due to impaired nutrition, reduced absorption secondary to gastrointestinal conditions, increased blood loss, and increased needs as in pregnancy. Iron deficiency anemia (IDA) is defined as low Hb or hematocrit associated with microcytic and hypochromic erythrocytes and low RBC count due to iron deficiency. IDA most commonly affects women of reproductive age, the developing fetus, children, patients with chronic and inflammatory diseases, and the elderly. IDA is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39% and 48.1% in developing countries). The diagnosis, management, and treatment of patients with ID and IDA change depending on age and gender and during pregnancy. We herein summarize what is known about the diagnosis, treatment, and prevention of ID and IDA and formulate a specific set of recommendations on this topic.

Diatom Chaetoceros Sp. as an Efficient Biological Antidote in Iron Toxicity: In‐Vitro and In‐Vivo Experiments

AbstractAll living organisms require mineral iron, but excess iron can lead to the production of free radicals and organ damage, such as liver damage in humans. This study investigated the diatom Chaetoceros sp. as an iron adsorbent in iron overload. First, the morphology and chemical composition of the diatom was characterized by spectroscopic and microscopic techniques. It was defined that diatoms have spherical particles with an average size of less than 2.0 μm. The affinity of diatoms for ionic Fe (II) uptake was evaluated. Fe (II) adsorption capacity was determined in vitro in two simulated intestinal and gastric aqueous media with pH values of 7.2 and 1.2. In both media, the diatom acted as a super‐adsorbent of Fe (II), while the highest adsorption occurred in a medium with a pH of 1.2. The correlation of the adsorption isotherm data was well studied with three well‐known equations, Langmuir, Fruindlich, and Redlich‐Peterson. The Langmuir model fitted the adsorption data best. The pseudo‐first‐order reaction model also provided a good fit for the adsorption kinetic data. In the in vivo study, the diatom was administered to iron‐overloaded rats. Biochemical parameters of organ damage and plasma Fe levels were determined at 2 h and 24 h intervals after diatom administration. The results show that diatoms can prevent acute iron poisoning by reducing plasma levels. Diatoms proved to be potent antidote agents in iron overdose conditions.

Iron depletion has different consequences on the growth and survival of Toxoplasma gondii strains

ABSTRACT Toxoplasma gondii is an obligate intracellular parasite responsible for a pathology called toxoplasmosis, which primarily affects immunocompromised individuals and developing foetuses. The parasite can scavenge essential nutrients from its host to support its growth and survival. Among them, iron is one of the most important elements needed to sustain basic cellular functions as it is involved in a number of key metabolic processes, including oxygen transport, redox balance, and electron transport. We evaluated the effects of an iron chelator on the development of several parasite strains and found that they differed in their ability to tolerate iron depletion. The growth of parasites usually associated with a model of acute toxoplasmosis was strongly affected by iron depletion, whereas cystogenic strains were less sensitive as they were able to convert into persisting developmental forms that are associated with the chronic form of the disease. Ultrastructural and biochemical characterization of the impact of iron depletion on parasites also highlighted striking changes in both their metabolism and that of the host, with a marked accumulation of lipid droplets and perturbation of lipid homoeostasis. Overall, our study demonstrates that although acute iron depletion has an important effect on the growth of T. gondii, it has a more profound impact on actively dividing parasites, whereas less metabolically active parasite forms may be able to avoid some of the most detrimental consequences.

Formation of intraneuronal iron deposits following local release from nanostructured silica injected into rat brain parenchyma

Nanostructured materials with controllable properties have been used to cage and release various types of compounds. In the present study, iron-loaded nanostructured sol-gel SiO2–Fe materials were prepared and injected into the rat brain to develop a method for gradual iron delivery into the neurons with the aims to avoid acute iron toxicity and develop an animal model of gradual, metal-induced neurodegeneration. Nanoparticles were prepared by the traditional method of hydrolysis and condensation reactions of tetraethyl orthosilicate at room temperature and subsequent heat treatment at 200 °C. FeSO4 was added in situ during the silica preparation. The resulting materials were characterized by UV-VIS and infrared spectroscopies, X-ray diffraction, and N2 adsorption-desorption. An in vitro ferrous sulfate release test was carried out in artificial cerebrospinal fluid as the release medium showing successful ferrous sulfate loading on nanostructured silica and sustained iron release during the test time of 10 h. Male Wistar rats administered with SiO2–Fe nanoparticles in the substantia nigra pars compacta (SNpc) showed significant intraneuronal increase of iron, in contrast to the animals administered with FeSO4 that showed severe neuronal loss, 72 h post-treatment. Both treatments induced lipid fluorescent product formation in the ventral midbrain, in contrast to iron-free SiO2 and PBS-only injection controls. Circling behavior was evaluated six days after the intranigral microinjection, considered as a behavioral end-point of brain damage. The apomorphine-induced ipsilateral turns in the treated animals presented significant differences in relation to the control groups, with FeSO4 administration leading to a dramatic phenotype, compared to a milder impact in SiO2–Fe administrated animals. Thus, the use of SiO2–Fe nanoparticles represents a slow iron release system useful to model the gradual iron-accumulation process observed in the SNpc of patients with idiopathic Parkinson's disease.

Iron chelation and supplementation: A comparison in the management of inflammatory bowel disease using drosophila

AimsInflammatory Bowel Disease (IBD) is associated with systemic iron deficiency and has been managed with iron supplements which cause adverse side effects. Conversely, some reports highlight iron depletion to ameliorate IBD. The underlying intestinal response and comparative benefit of iron depletion and supplementation in IBD is unknown. The aims of this work were to characterize and compare the effects of iron supplementation and iron depletion in IBD. Main methodsIBD was induced in Drosophila melanogaster using 3 % dextran sodium sulfate (DSS) in diet for 7 days. Using this model, we investigated the impacts of acute iron depletion (using bathophenanthroline disulfonate, BPS) and supplementation (using ferrous sulphate, FS), before and after IBD induction, on gut iron homeostasis, cell death, gut permeability, inflammation, antioxidant defence, antimicrobial response and several fly phenotypes. Key findingsDSS decreased fly mass (p < 0.001), increased gut permeability (p < 0.001) and shortened lifespan (p = 0.035) compared to control. The DSS-fed flies also showed significantly elevated lipid peroxidation (p < 0.001), and the upregulated expression of apoptotic marker- drice (p < 0.001), tight junction protein – bbg (p < 0.001), antimicrobial peptide – dpta (p = 0.002) and proinflammatory cytokine – upd2 (p < 0.001). BPS significantly (p < 0.05) increased fly mass and lifespan, decreased gut permeability, decreased lipid peroxidation and decreased levels of drice, bbg, dpta and upd2 in IBD flies. This iron chelation (using BPS) showed better protection from DSS-induced IBD than iron supplementation (using FS). Preventive and curative interventions, by BPS or FS, also differed in outcomes. SignificanceThis may inform precise management strategies aimed at tackling IBD and its recurrence.

Case-Based Virtual Escape Rooms: Using Feedback to Change Online Platforms.

Introduction Virtual escape rooms (VERs) have provided education in healthcare settings. VERs were developed to provide medical education related to pediatric toxicology. This study explores simulation technologies, specifically portals to create and host VERs, including Google Sites, a website-building platform, and Articulate 360, an e-learning platform. The design objective was to create an engaging educational tool using a VER on two pediatric toxicology scenarios. Methods Case-based VERs were developed on Google Sites and Articulate 360. The cases focused on organophosphate toxicity and acute iron toxicity. Google Sites technology was used to build the organophosphate toxicity case, which was implemented and piloted with emergency medicine (EM) trainees in India and workshop participants at the International Pediatric Simulation Symposia and Workshops (IPSSW) in 2022. The iron toxicity case was developed using Articulate 360 and piloted at IPSSW in 2023. Feedback was collected as a survey from participants. Questions focused on using VERs as an engaging educational model, benefits, areas for improvement, and future participation in VERs. Following the study, a focus group meeting was held with facilitators and developers and subsequently analyzed. Results Evaluations from participants and a focus group provided data demonstrating both platforms' utility. Participants completed surveys after each VER. Overall, 84.2% of respondents (n=60) from EM training programs in India, 90.9% of respondents (n=11) from IPSSW in 2022, and 100% of respondents (n=23) from IPSSW in 2023 agreed or strongly agreed that this was an engaging education model. Conclusion Different platforms may be used to develop engaging VERs for gamification in education. This study found that VERs based on pediatric toxicology scenarios created on Google Sites and Articulate 360 are engaging educational tools for distance learning. Simulation technologies have benefits and disadvantages for Google Sites and Articulate 360. Simulation developers and educators should consider time, funding, technological needs, and participant feedback when deciding which portal to choose when building a VER.

Association between sex and efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency: an AFFIRM-AHF subgroup analysis

Abstract Background/Introduction Heart failure (HF) pathophysiology, clinical presentation and treatment response is known to differ between males and females (1). In the AFFIRM-AHF trial, intravenous (IV) ferric carboxymaltose (FCM) reduced the risk of HF hospitalisations and improved quality of life vs placebo in patients with iron deficiency who had stabilised following an acute HF (AHF) episode (2,3); the effect of sex on outcomes with iron-repletion therapy in these high-risk patients has not been fully explored. Purpose To investigate the interaction between sex and the effects of FCM vs placebo on clinical outcomes in the AFFIRM-AHF population. Methods In AFFIRM-AHF, patients with left ventricular ejection fraction &amp;lt;50% and iron deficiency (defined as serum ferritin &amp;lt;100 ng/mL, or 100–299 ng/mL if transferrin saturation is &amp;lt;20%) who had stabilised following recent hospitalisation for AHF were randomised 1:1 to receive IV FCM or placebo for up to 24 weeks.2 The primary endpoint was a composite of total HF hospitalisations and cardiovascular (CV) death up to Week 52; secondary endpoints are listed in the Figure.2 In this prespecified analysis, AFFIRM-AHF patients were stratified into male and female subgroups and the interaction between sex and clinical outcomes with FCM vs placebo was explored. Results Of the 1108 patients included in the AFFIRM-AHF full analysis set, 614 (FCM: 314; placebo: 300) were male and 494 (FCM: 244; placebo: 250) were female. At baseline, a New York Heart Association functional class of III and above was more common in females (59.0%) than in males (48.4%). For the primary endpoint, the adjusted annualised event rate per 100 patient-years with FCM vs placebo was 53.3 vs 83.3 in males (rate ratio [RR] 0.64; 95% confidence interval [CI] 0.46–0.89) and 63.1 vs 60.3 in females (RR 1.05; 95% CI 0.72–1.53) (Figure). For all secondary endpoints except time to CV death, effect sizes in male and female subgroups were similar to those for the primary endpoint. The interaction between sex and treatment effect was non-significant for the primary endpoint (P-interaction=0.054) but reached significance for the secondary endpoints of total CV hospitalisations and CV death (P-interaction=0.024) and time to first HF hospitalisation or CV death (P-interaction=0.043). Conclusion(s) The results of this exploratory subgroup analysis suggest that iron deficiency treatment with IV FCM following an AHF episode may be more effective in males than in females; this may be related to baseline differences between sex subgroups, beyond the factors adjusted for in this analysis.Figure

Are We Diagnosing and Managing Diabetes in Patients with Sickle Cell Disorders Accurately?

Introduction: Patients with hemolytic anemias, especially those resulting from severe sickle cell disorders (SCD), may experience increased red blood cell (RBC) turnover, influencing hemoglobin (Hb) glycation rates. The American Diabetes Association (ADA) recommends measuring plasma glucose levels for diabetes mellitus (DM) diagnosis. However, to monitor glycemic control, fructosamine provides a valuable measure of glycated serum protein byproduct, independent of RBC lifespan. It is important to note that G6PD can aggravate anemia and its co-existence with SCDs is reported to vary between 7%-35.83% depending on genotype, ethnicity and location. Despite National Glycohemoglobin Standardization Program's (NSGP) reporting that most chemistry analyzers exhibit no assay interference, Lacy et al. showed that HbA1C systematically underestimated past glycemia in black patients with sickle cell trait. It is hypothesized that numerous SCD patients with DM receive diagnosis and management based on HbA1C. This study seeks to evaluate the management patterns and the correlation between Hb and HbA1C in the context of a hemoglobinopathy, aiming to enhance patient care standards. Methods: We identified 61 adult sickle cell disorder patients who also had a diagnosis of type 2 DM or prediabetes between January 2019 and May 2023. Patients with acute blood loss events (with or without transfusions), iron deficiency, hyperbilirubinemia, liver or renal disease, HIV infection on antiretroviral therapy, and those receiving Vit A/C supplementation were excluded from the study, as these conditions are known to impact the HbA1C levels. HbA1C testing at our institution was formerly done using Siemens Dimension Vista 500/1500 analyzer until it was switched to Abbott Alinity-c in October 2022. According to NGSP, there are no reports of assay interference in patients with Sickle Cell Disease (SCD) for either of these chemistry analyzers. Descriptive statistics were utilized to report data as means and percentages. Pearson correlation coefficient was used to assess the relationship between Hb and HbA1C values. Results: Mean age of the study participants was 52.59 years (SD 15.56) with a female predominance (53/61, 86.89%). All patients were of African American descent. The study included 49/61 (80.33%) patients with sickle cell trait, 3/61 (4.92%) with HbSC, 2/61 (3.28%) with HbSS, and 1/61 (1.64%) with HbS β+thal genotype. None of the patients had documented evidence of G6PD testing. Initially, all 61 patients had been diagnosed with DM or prediabetes via HbA1C. Only 3/61 (4.92%) patients had a fructosamine test documented in chart. The mean and median HbA1c values were 7.57% and 6.70% respectively (SD 2.07%). Among the participants, 53/61 (86.89%) patients were actively undergoing treatment for DM or prediabetes. There was a negative correlation (r = -0.142) between average Hb (at diagnosis) and HbA1C (at diagnosis) values (p = 0.286) (Figure 1). Conclusions: None of the patients in our study had evidence of G6PD testing. All patients with SCD and DM or prediabetes were initially diagnosed and managed using HbA1C. Only 3/61 patients had documentation of a fructosamine test. In the context of SCD, there was a poor correlation between Hb and HbA1C. The HbA1C test can either overpredict or underpredict DM in SCD patients due to assay interference (Siemens DCA Vantage analyzer is known to overpredict and is commonly used for point-of-care testing in an office setting) or hemoglobinopathy, respectively. Marked discrepancies between plasma glucose levels and measured HbA1C should prompt alternate diagnostic testing. It is recommended to use fasting blood glucose or oral glucose tolerance test to diagnose DM and prediabetes in patients with SCD. The reported cost difference between these tests is not significant. Fructosamine levels remain unaffected by hemoglobinopathies and can thus be used to monitor DM in patients with SCD.

HMGB1 induces hepcidin upregulation in astrocytes and causes an acute iron surge and subsequent ferroptosis in the postischemic brain

Dysregulation of brain iron levels causes functional disturbances and damages neurons. Hepcidin (a peptide hormone) plays a principal role in regulating intracellular iron levels by modulating ferroportin (FPN, the only known iron exporter) through triggering its internalization and lysosomal degradation. We observed a significant and rapid iron surge in the cortices of ischemic hemispheres at 3 h after cerebral ischemia (middle cerebral artery occlusion, MCAO) that was maintained until 4 d post-MCAO. We showed upregulation of hepcidin expression in the brain as early as 3 h post-MCAO, mainly in astrocytes, and significant hepcidin accumulation in serum from 6 h post-MCAO, and these inductions were maintained for 1 day and 7 days, respectively. High mobility group box 1 (HMGB1), a prototypic danger-associated molecular pattern, accumulates markedly after transient MCAO and plays critical roles in damage aggravation via its proinflammatory effects. Here, we demonstrated that treatment with recombinant HMGB1 stimulated astrocytes to induce hepcidin expression in a TLR4- and CXCR4-dependent manner. Furthermore, hepcidin-mediated intracellular iron accumulation in neurons was confirmed by an experiment using N-methyl-D-aspartate (NMDA)-conditioned medium-treated primary astrocytes and fresh primary cortical neurons treated with hepcidin-containing astrocyte-conditioned medium. Moreover, HMGB1-mediated local hepcidin upregulation and subsequent local iron surge were found to cause ferroptosis in the postischemic brain, which was suppressed by the functional blocking of HMGB1 using intranasally administered HMGB1 A box or anti-HMGB1 antibody. These findings show that HMGB1 serves as a ferroptosis inducer by upregulating hepcidin in astrocytes and thus aggravates acute damage in the postischemic brain.

Liver Disease and Sickle Cell Disease: Auto-Immune Hepatitis more than a Coincidence; A Systematic Review of the Literature.

In patients with SCD, chronic liver damage is a common manifestation. More than 50% of SCD patients have elevated liver enzymes. Common underlying aetiologies include sickle cell hepatic crisis, viral hepatitis, sickle cell intrahepatic cholestasis and hepatic sequestration in the acute setting, and cholelithiasis and iron overload in the chronic setting. Autoimmune hepatitis (AIH) is a rare disease that appears to occur more commonly in the sickle cell disease (SCD) population than in the general population. There are many schools of thought as to why this is the case, including the phosphatidylserine hypothesis, the heme inflammatory hypothesis, the complement generation hypothesis, and the transfusion alloimmunization hypothesis. Due to the natural history of the two illnesses, SCD is almost always diagnosed first in cases of dual pathology. Symptoms such as jaundice, fatigue, and abdominal pain are common in SCD, as are abnormal liver function tests (LFTs). These abnormalities, attributed to the other more frequent liver involvements in SCD, can lead to delays in AIH diagnosis in this population. Corticosteroids, sometimes with other immunosuppressive agents, such as azathioprine, are the cornerstone of acute AIH treatment. However, corticosteroid use in the SCD population has been shown to carry an increased risk of vaso-occlusive crises, providing a treatment dilemma. The following is a review of AIH in the SCD population, where we explore the pathophysiology behind the association between the two disorders, discuss an approach to investigating abnormal LFTs in SCD, and examine treatment options in this population with co-existing diseases.

Accidental iron poisoning in children – Experience from a teaching institution

Background: Acute iron toxicity is fatal in children resulting from an accidental overdose of maternal iron tablets at home. There is scanty literature on children looking at the profile and outcome. We report a case series of five children presenting after accidental ingestion of iron tablets. Two presented with fulminant hepatic failure at 48 h, and despite supportive management and plasmapheresis in one child, both succumbed to illness. Materials and Methods: This retrospective study was conducted in the pediatric intensive care unit (PICU) of a teaching institution in South India between January 2009 and December 2019. All children with accidental iron poisoning were included in the analysis. Results: During the study period, five children presented to our PICU after accidental iron tablet ingestion. The mean age was 25.8 months [standard deviation (SD): 13.9]. All the children had consumed iron tablets from their pregnant mothers. Two children presenting with liver failure succumbed to illness. Treatment included a standard protocol of gastric lavage and desferrioxamine. Most of them (3/5) received whole bowel irrigation. We did plasmapheresis in one child who presented with fulminant hepatic failure. The majority were discharged alive (3/5). The presence of coagulopathy, acute liver failure, and delayed presentation were associated with high mortality. Conclusion: Accidental iron poisoning is prevalent in children and associated with significant mortality. Parents and caretakers must be counseled by primary care physicians and made aware of the safe storage of iron tablets.

Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis.

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca2+ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCUfl/fl) and conditional MCU knockout (MCUfl/fl-MCM) mice. LV function was reduced by chronic iron loading in MCUfl/fl mice, but not in MCUfl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCUfl/fl cardiomyocytes, but not in MCUfl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCUfl/fl, but not in MCUfl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCUfl/fl hearts. Isolated cardiomyocytes from MCUfl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca2+ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCUfl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCUfl/fl-MCM hearts nor was there a reduction in Ca2+ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction.

Brain Iron, Transferrin and Ferritin Concentrations Are Altered in Developing Iron-Deficient Rats

To study the iron, transferrin, and ferritin distribution at subcellular levels in response to acute dietary iron deficiency, we tested the hypothesis that early post-weaning iron deficiency can change iron and iron regulatory protein concentrations in rat brain. Male Sprague-Dawley rats were fed diets containing either 2 or 35 µg iron/g for 2, 3 or 4 wk starting at 21 d of age. Brain iron, transferrin and ferritin concentrations in cytosolic and microsomal fractions of either whole brain or pons and cerebellum were then determined. After 14 d of dietary iron restriction, brain iron concentrations were 50% lower in the microsomal fraction and 30% lower in cytosol compared with controls. Brain cytosolic transferrin concentration almost doubled in the same animals. Brain ferritin concentration in fractions from rats fed the iron-deficient diet for 14 d was lower than in controls, but then remained fairly constant. Absolute brain weight and total brain protein contents were unaffected by iron restriction. This study extends previous research by demonstrating that the brain responds to changes in body iron status with a change in transferrin concentration. If the dietary restriction is quite severe, this adaptation is insufficient. This study also notes that brain ferritin decreases with decreasing body iron status, though it was less responsive than nonheme iron in liver. The concept that iron enters the brain through a highly regulated endocytotic process at the blood brain barrier, that undoubtedly involves the regulation of transferrin receptors in capillary endothelial cell, is supported by our observation of elevated transferrin concentrations in brain of iron-deficient rats.

An invertebrate model in examining the effect of acute ferric iron exposure on proprioceptive neurons

Iron is an essential element for plant and animal life and is found in soil, fresh waters and marine waters. The Fe3+ ion is a vital prosthetic group and cofactor to mitochondrial electron transport complexes and numerous proteins involved in normal functioning. Despite its importance to life-sustaining processes, overexposure results in toxicity. For example, ferric iron (Fe3+) accumulation in the mammalian central nervous system is associated with various neurological disorders. Although current literature addresses the long-term effects of Fe3+ overload, fewer studies exist examining the effects of acute exposure. Using the blue crab (Callinectes sapidus), we investigate the effects of acute Fe3+ overload on proprioception within the propodite-dactylopodite (PD) nerve. For proprioceptive studies, 10- and 20-mM ferric chloride and ferric ammonium citrate solutions were used at 5- and 20- min exposure times. Exposure to 20 mM concentrations of ferric chloride and ferric ammonium citrate reduced excitability in proprioceptive neurons. Thus, Fe3+ likely blocks stretch-activated channels or voltage-gated Na+ channels. The depressive effects of Fe3+ are partly reversible following saline washout, indicating cells are not acutely damaged. Gadolinium (GdCl3, 1 and 10 mM) was used to examine the effects of an additional trivalent ion comparator. Gd3+ depressed PD nerve compound action potential amplitude while increasing the compound action potential duration. This study is relevant in demonstrating the dose-dependent effects of acute Fe3+ and Gd3+ exposure on proprioception and provides a model system to further investigate the mechanisms by which metals act on the nervous system.

Assessment of the effect of iron-rich humic substances on hematological parameters in the model of acute posthemorrhagic and iron deficiency anemia

Aim. To assess the effect of iron-rich humic substances on hematological parameters in acute post-hemorrhagic and iron deficiency anemia.Materials and methods. Materials for the study were samples of iron-rich active pharmaceutical ingredients based on humic substances (Fe(III) hydroxide complexes with humic substances and polymaltose): HA-Fe3+, HA-PMFe3+, FA-Fe3+, and FA-PM-Fe3+. The anti-anemic activity of the substances was studied on 53 female Wistar rats of the conventional rat line in the model of acute posthemorrhagic and iron deficiency anemia. Anti-anemic activity was assessed by the hemoglobin level, erythrocyte count, hematocrit, and serum iron level.Results. The studied substances HA-Fe3+ and FA-Fe3+ are the most effective in correcting the consequences of both experimental acute posthemorrhagic anemia and iron deficiency anemia. Their effect is comparable to that of the positive control drug Ferrum Lek.Conclusion. Fe(III) hydroxide complexes stabilized by humic and fulvic acids exhibit anti-anemic activity.