Malaria is a cause of iron deficiency in African children.
Nature medicine
Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.
10.1038/s41591-021-01238-4
Maintaining Iron Homeostasis Is the Key Role of Lysosomal Acidity for Cell Proliferation.
Weber Ross A,Yen Frederick S,Nicholson Shirony P V,Alwaseem Hanan,Bayraktar Erol C,Alam Mohammad,Timson Rebecca C,La Konnor,Abu-Remaileh Monther,Molina Henrik,Birsoy Kıvanç
Molecular cell
The lysosome is an acidic multi-functional organelle with roles in macromolecular digestion, nutrient sensing, and signaling. However, why cells require acidic lysosomes to proliferate and which nutrients become limiting under lysosomal dysfunction are unclear. To address this, we performed CRISPR-Cas9-based genetic screens and identified cholesterol biosynthesis and iron uptake as essential metabolic pathways when lysosomal pH is altered. While cholesterol synthesis is only necessary, iron is both necessary and sufficient for cell proliferation under lysosomal dysfunction. Remarkably, iron supplementation restores cell proliferation under both pharmacologic and genetic-mediated lysosomal dysfunction. The rescue was independent of metabolic or signaling changes classically associated with increased lysosomal pH, uncoupling lysosomal function from cell proliferation. Finally, our experiments revealed that lysosomal dysfunction dramatically alters mitochondrial metabolism and hypoxia inducible factor (HIF) signaling due to iron depletion. Altogether, these findings identify iron homeostasis as the key function of lysosomal acidity for cell proliferation.
10.1016/j.molcel.2020.01.003
mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice.
Cell reports
The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor V + V knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.
10.1016/j.celrep.2022.110514
Hap43 Domains Are Required under Iron Starvation but Not Excess.
Skrahina Volha,Brock Matthias,Hube Bernhard,Brunke Sascha
Frontiers in microbiology
Iron availability is a central factor in infections, since iron is a critical micronutrient for all living organisms. The host employs both iron limitation and toxicity strategies to control microbial growth, and successful pathogens are able to tightly coordinate iron homeostasis in response to changing iron levels. As a commensal and opportunistic pathogen, copes with both iron deficiency and excess the precise regulation of iron acquisition, consumption and storage. The transcription factor Hap43 is known to be required for the iron starvation response, while specific domains of its ortholog, HapX, in , were recently shown to regulate iron uptake and consumptions genes under both low and high iron levels. Therefore, we investigated the contribution of Hap43 domains in response to changing iron levels. We found the C-terminus of Hap43 to be essential for the activation of iron uptake genes during iron starvation, whereas, in contrast to , Hap43 was not required in mediating adaptation to iron resistance. These data indicate that the generally conserved metal acquisition systems in fungal pathogens can show individual adaptations to the host environment.
10.3389/fmicb.2017.02388
Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress.
Cell death & disease
MitoNEET (mitochondrial protein containing Asn-Glu-Glu-Thr (NEET) sequence) is a 2Fe-2S cluster-containing integral membrane protein that resides in the mitochondrial outer membrane and participates in a redox-sensitive signaling and Fe-S cluster transfer. Thus, mitoNEET is a key regulator of mitochondrial oxidative capacity and iron homeostasis. Moreover, mitochondrial dysfunction and oxidative stress play critical roles in inflammatory diseases such as sepsis. Increased iron levels mediated by mitochondrial dysfunction lead to oxidative damage and generation of reactive oxygen species (ROS). Increasing evidence suggests that targeting mitoNEET to reverse mitochondrial dysfunction deserves further investigation. However, the role of mitoNEET in inflammatory diseases is unknown. Here, we investigated the mechanism of action and function of mitoNEET during lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Levels of mitoNEET protein increased during microbial or LPS-induced sepsis. Pharmacological inhibition of mitoNEET using mitoNEET ligand-1 (NL-1) decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in animal models of sepsis, as well as LPS-induced inflammatory responses by macrophages in vitro. Inhibition of mitoNEET using NL-1 or mitoNEET shRNA abrogated LPS-induced ROS formation and mitochondrial dysfunction. Furthermore, mitochondrial iron accumulation led to generation of LPS-induced ROS, a process blocked by NL-1 or shRNA. Taken together, these data suggest that mitoNEET could be a key therapeutic molecule that targets mitochondrial dysfunction during inflammatory diseases and sepsis.
10.1038/s41419-022-04586-2
Role of divalent metals in infectious disease susceptibility and outcome.
Weiss G,Carver P L
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
BACKGROUND:Divalent metals play important roles in maintaining metabolism and cellular growth of both eukaryotic hosts and invading microbes. Both metal deficiency and overload can result in abnormal cellular function or damage. Given its central role in host-pathogen interactions, subtle alterations of divalent metal homeostasis can occur in the course of infectious diseases which aim, from the host perspective, either to reduce the availability of respective metals to microbes or to use toxic metal accumulation to eliminate pathogens. AIMS:To provide the reader with background information and clinical data on divalent metal homeostasis in host-pathogen interactions, how this affects the course of infectious disease and whether correction of metal disturbances has shown benefit in infections. SOURCES:An in-depth analysis of PubMed articles related to the topic of this review published in English between 1970 and 2016 was performed. CONTENT:From the microbial perspective, divalent metals are essential for growth and pathogenicity and to mount effective protection against antimicrobial host responses, including toxic radical formation. Microbes have evolved multiple strategies to control their access to divalent metals. From the clinical perspective, alterations of divalent metal levels may result in increased or decreased susceptibility to infection and often occur in response to infections. However, keeping in mind the strategies underlying such alterations, for which the term 'nutritional immunity' was coined, the uncritical correction of such divalent metal imbalances may cause harm to patients. This review addresses the role of the divalent metals iron, selenium, zinc, manganese and copper in infectious diseases from a mechanistic and clinical perspective. IMPLICATIONS:We point out areas of research needed to expand our limited knowledge, hoping to improve the clinical management of patients with infections and to identify promising new targets for treatment by modulation of host or microbe divalent metal metabolism.
10.1016/j.cmi.2017.01.018
Therapeutic Opportunities for Hepcidin in Acute Care Medicine.
Chawla Lakhmir S,Beers-Mulroy Blaire,Tidmarsh George F
Critical care clinics
Iron homeostasis is often disrupted in acute disease with an increase in catalytic free iron leading to the formation of reactive oxygen species and subsequent tissue-specific oxidative damage. This article highlights the potential therapeutic benefit of exogenous hepcidin to prevent and treat iron-induced injury, specifically in the management of infection from enteric gram-negative bacilli or fungi, malaria, sepsis, acute kidney injury, trauma, transfusion, cardiopulmonary bypass surgery, and liver disease.
10.1016/j.ccc.2018.11.014
Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis.
Srinivasan Gayathri,Aitken Jesse D,Zhang Benyue,Carvalho Frederic A,Chassaing Benoit,Shashidharamurthy Rangaiah,Borregaard Niels,Jones Dean P,Gewirtz Andrew T,Vijay-Kumar Matam
Journal of immunology (Baltimore, Md. : 1950)
Various states of inflammation, including sepsis, are associated with hypoferremia, which limits iron availability to pathogens and reduces iron-mediated oxidative stress. Lipocalin 2 (Lcn2; siderocalin, 24p3) plays a central role in iron transport. Accordingly, Lcn2-deficient (Lcn2KO) mice exhibit elevated intracellular labile iron. In this study, we report that LPS induced systemic Lcn2 by 150-fold in wild-type mice at 24 h. Relative to wild-type littermates, Lcn2KO mice were markedly more sensitive to endotoxemia, exhibiting elevated indices of organ damage (transaminasemia, lactate dehydrogenase) and increased mortality. Such exacerbated endotoxemia was associated with substantially increased caspase-3 cleavage and concomitantly elevated immune cell apoptosis. Furthermore, cells from Lcn2KO mice were hyperresponsive to LPS ex vivo, exhibiting elevated cytokine secretion. Additionally, Lcn2KO mice exhibited delayed LPS-induced hypoferremia despite normal hepatic hepcidin expression and displayed decreased levels of the tissue redox state indicators cysteine and glutathione in liver and plasma. Desferroxamine, an iron chelator, significantly protects Lcn2KO mice from LPS-induced toxicity, including mortality, suggesting that Lcn2 may act as an antioxidant in vivo by regulating iron homeostasis. Thus, Lcn2-mediated regulation of labile iron protects the host against sepsis. Its small size and simple structure may make Lcn2 a deployable treatment for sepsis.
10.4049/jimmunol.1200892
The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats.
Scientific reports
Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe/Fe imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe/Fe ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe/Fe ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.
10.1038/s41598-021-03981-7
TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease.
O'Neill Thomas J,Seeholzer Thomas,Gewies Andreas,Gehring Torben,Giesert Florian,Hamp Isabel,Graß Carina,Schmidt Henrik,Kriegsmann Katharina,Tofaute Marie J,Demski Katrin,Poth Tanja,Rosenbaum Marc,Schnalzger Theresa,Ruland Jürgen,Göttlicher Martin,Kriegsmann Mark,Naumann Ronald,Heissmeyer Vigo,Plettenburg Oliver,Wurst Wolfgang,Krappmann Daniel
Science immunology
Balanced control of T cell signaling is critical for adaptive immunity and protection from autoimmunity. By combining genetically engineered mouse models, biochemical analyses and pharmacological interventions, we describe an unexpected dual role of the tumor necrosis factor receptor–associated factor 6 (TRAF6) E3 ligase as both a positive and negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor κB signaling in activated T cells, TRAF6 counteracts basal MALT1 protease activity in resting T cells. In mice, loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is completely reverted by genetic or therapeutic inactivation of MALT1 protease function. Thus, TRAF6 functions as a molecular brake for MALT1 protease in resting T cells and a signaling accelerator for MALT1 scaffolding in activated T cells, revealing that TRAF6 controls T cell activation in a switch-like manner. Our findings have important implications for development and treatment of autoimmune diseases.
10.1126/sciimmunol.abh2095
Iron-sulfur clusters as inhibitors and catalysts of viral replication.
Nature chemistry
A virus hijacks host cellular machineries and metabolites in order to reproduce. In response, the innate immune system activates different processes to fight back. Although many aspects of these processes have been well investigated, the key roles played by iron-sulfur [FeS] clusters, which are among the oldest classes of bio-inorganic cofactors, have barely been considered. Here we discuss how several [FeS] cluster-containing proteins activate, support and modulate the innate immune response to restrict viral infections, and how some of these proteins simultaneously support the replication of viruses. We also propose models of function of some proteins in the innate immune response and argue that [FeS] clusters in many of these proteins act as biological 'fuses' to control the response. We hope this overview helps to inspire future research in the emerging field of bio-inorganic virology/immunology and that such studies may reveal new molecular insight into the links between viral infections and diseases like cancer and neurodegeneration.
10.1038/s41557-021-00882-0
Metabolic Adaptations to Infections at the Organismal Level.
Troha Katia,Ayres Janelle S
Trends in immunology
Metabolic processes occurring during host-microbiota-pathogen interactions can favorably or negatively influence host survival during infection. Defining the metabolic needs of the three players, the mechanisms through which they acquire nutrients, and whether each participant cooperates or competes with each other to meet their own metabolic demands during infection has the potential to reveal new approaches to treat disease. Here, we review topical findings in organismal metabolism and infection and highlight four emerging lines of investigation: how host-microbiota metabolic partnerships protect against infection; competition for glucose between host and pathogen; significance of infection-induced anorexia; and redefinition of the role of iron during infection. We also discuss how these discoveries shape our understanding of infection biology and their likely therapeutic value.
10.1016/j.it.2019.12.001
Iron Acquisition in Mycobacterium tuberculosis.
Chao Alex,Sieminski Paul J,Owens Cedric P,Goulding Celia W
Chemical reviews
The highly contagious disease tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an alarming rate. Like all human pathogens, Mtb requires iron for growth and virulence. Consequently, Mtb iron transport is an emerging drug target. However, the development of anti-TB drugs aimed at these metabolic pathways has been restricted by the dearth of information on Mtb iron acquisition. In this Review, we describe the multiple strategies utilized by Mtb to acquire ferric iron and heme iron. Mtb iron uptake is a complex process, requiring biosynthesis and subsequent export of Mtb siderophores, followed by ferric iron scavenging and ferric-siderophore import into Mtb. Additionally, Mtb possesses two possible heme uptake pathways and an Mtb-specific mechanism of heme degradation that yields iron and novel heme-degradation products. We conclude with perspectives for potential therapeutics that could directly target Mtb heme and iron uptake machineries. We also highlight how hijacking Mtb heme and iron acquisition pathways for drug import may facilitate drug transport through the notoriously impregnable Mtb cell wall.
10.1021/acs.chemrev.8b00285
Regulation of inflammation by the antioxidant haem oxygenase 1.
Nature reviews. Immunology
Haem oxygenase 1 (HO-1), an inducible enzyme responsible for the breakdown of haem, is primarily considered an antioxidant, and has long been overlooked by immunologists. However, research over the past two decades in particular has demonstrated that HO-1 also exhibits numerous anti-inflammatory properties. These emerging immunomodulatory functions have made HO-1 an appealing target for treatment of diseases characterized by high levels of chronic inflammation. In this Review, we present an introduction to HO-1 for immunologists, including an overview of its roles in iron metabolism and antioxidant defence, and the factors which regulate its expression. We discuss the impact of HO-1 induction in specific immune cell populations and provide new insights into the immunomodulation that accompanies haem catabolism, including its relationship to immunometabolism. Furthermore, we highlight the therapeutic potential of HO-1 induction to treat chronic inflammatory and autoimmune diseases, and the issues faced when trying to translate such therapies to the clinic. Finally, we examine a number of alternative, safer strategies that are under investigation to harness the therapeutic potential of HO-1, including the use of phytochemicals, novel HO-1 inducers and carbon monoxide-based therapies.
10.1038/s41577-020-00491-x
Bacterial siderophores in community and host interactions.
Nature reviews. Microbiology
Iron is an essential trace element for most organisms. A common way for bacteria to acquire this nutrient is through the secretion of siderophores, which are secondary metabolites that scavenge iron from environmental stocks and deliver it to cells via specific receptors. While there has been tremendous interest in understanding the molecular basis of siderophore synthesis, uptake and regulation, questions about the ecological and evolutionary consequences of siderophore secretion have only recently received increasing attention. In this Review, we outline how eco-evolutionary questions can complement the mechanistic perspective and help to obtain a more integrated view of siderophores. In particular, we explain how secreted diffusible siderophores can affect other community members, leading to cooperative, exploitative and competitive interactions between individuals. These social interactions in turn can spur co-evolutionary arms races between strains and species, lead to ecological dependencies between them and potentially contribute to the formation of stable communities. In brief, this Review shows that siderophores are much more than just iron carriers: they are important mediators of interactions between members of microbial assemblies and the eukaryotic hosts they inhabit.
10.1038/s41579-019-0284-4
Ironing out mechanisms of iron homeostasis and disorders of iron deficiency.
The Journal of clinical investigation
Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients' symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.
10.1172/JCI148671
Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.
Vlachodimitropoulou Evangelia,Chen Yu-Lin,Garbowski Maciej,Koonyosying Pimpisid,Psaila Bethan,Sola-Visner Martha,Cooper Nichola,Hider Robert,Porter John
Blood
Eltrombopag (ELT) is a thrombopoietin receptor agonist reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β=35). Clinically achievable concentrations (1 µM) progressively mobilized cellular iron from hepatocyte, cardiomyocyte, and pancreatic cell lines, rapidly decreasing intracellular reactive oxygen species (ROS) and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paralleled total cellular iron removal, particularly in hepatocytes. Iron mobilization from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine, or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilization more than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilization by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilization when combined with clinically available chelators.
10.1182/blood-2016-10-740241
Iron deficiency, elevated erythropoietin, fibroblast growth factor 23, and mortality in the general population of the Netherlands: A cohort study.
Eisenga Michele F,De Jong Maarten A,Van der Meer Peter,Leaf David E,Huls Gerwin,Nolte Ilja M,Gaillard Carlo A J M,Bakker Stephan J L,De Borst Martin H
PLoS medicine
BACKGROUND:Emerging data in chronic kidney disease (CKD) patients suggest that iron deficiency and higher circulating levels of erythropoietin (EPO) stimulate the expression and concomitant cleavage of the osteocyte-derived, phosphate-regulating hormone fibroblast growth factor 23 (FGF23), a risk factor for premature mortality. To date, clinical implications of iron deficiency and high EPO levels in the general population, and the potential downstream role of FGF23, are unclear. Therefore, we aimed to determine the associations between iron deficiency and higher EPO levels with mortality, and the potential mediating role of FGF23, in a cohort of community-dwelling subjects. METHODS AND FINDINGS:We analyzed 6,544 community-dwelling subjects (age 53 ± 12 years; 50% males) who participated in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study-a prospective population-based cohort study, of which we used the second survey (2001-2003)-and follow-up was performed for a median of 8 years. We measured circulating parameters of iron status, EPO levels, and plasma total FGF23 levels. Our primary outcome was all-cause mortality. In multivariable linear regression analyses, ferritin (ß = -0.43), transferrin saturation (TSAT) (ß = -0.17), hepcidin (ß = -0.36), soluble transferrin receptor (sTfR; ß = 0.33), and EPO (ß = 0.28) were associated with FGF23 level, independent of potential confounders. During median (interquartile range [IQR]) follow-up of 8.2 (7.7-8.8) years, 379 (6%) subjects died. In multivariable Cox regression analyses, lower levels of TSAT (hazard ratio [HR] per 1 standard deviation [SD], 0.84; 95% confidence interval [CI], 0.75-0.95; P = 0.004) and higher levels of sTfR (HR, 1.15; 95% CI 1.03-1.28; P = 0.01), EPO (HR, 1.17; 95% CI 1.05-1.29; P = 0.004), and FGF23 (HR, 1.20; 95% CI 1.10-1.32; P < 0.001) were each significantly associated with an increased risk of death, independent of potential confounders. Adjustment for FGF23 levels markedly attenuated the associations of TSAT (HR, 0.89; 95% CI 0.78-1.01; P = 0.06), sTfR (HR, 1.08; 95% CI 0.96-1.20; P = 0.19), and EPO (HR, 1.10; 95% CI 0.99-1.22; P = 0.08) with mortality. FGF23 remained associated with mortality (HR, 1.15; 95% CI 1.04-1.27; P = 0.008) after adjustment for TSAT, sTfR, and EPO levels. Mediation analysis indicated that FGF23 explained 31% of the association between TSAT and mortality; similarly, FGF23 explained 32% of the association between sTfR and mortality and 48% of the association between EPO and mortality (indirect effect P < 0.05 for all analyses). The main limitations of this study were the observational study design and the absence of data on intact FGF23 (iFGF23), precluding us from discerning whether the current results are attributable to an increase in iFGF23 or in C-terminal FGF23 fragments. CONCLUSIONS AND RELEVANCE:In this study, we found that functional iron deficiency and higher EPO levels were each associated with an increased risk of death in the general population. Our findings suggest that FGF23 could be involved in the association between functional iron deficiency and increased EPO levels and death. Investigation of strategies aimed at correcting iron deficiency and reducing FGF23 levels is warranted.
10.1371/journal.pmed.1002818
A randomized trial of blood donor iron repletion on red cell quality for transfusion and donor cognition and well-being.
Blood
Although altruistic regular blood donors are vital for the blood supply, many become iron deficient from donation-induced iron loss. The effects of blood donation-induced iron deficiency on red cell transfusion quality or donor cognition are unknown. In this double-blind, randomized trial, adult iron-deficient blood donors (n = 79; ferritin < 15 μg/L and zinc protoporphyrin >60 μMol/mol heme) who met donation qualifications were enrolled. A first standard blood donation was followed by the gold-standard measure for red cell storage quality: a 51-chromium posttransfusion red cell recovery study. Donors were then randomized to intravenous iron repletion (1 g low-molecular-weight iron dextran) or placebo. A second donation ∼5 months later was followed by another recovery study. Primary outcome was the within-subject change in posttransfusion recovery. The primary outcome measure of an ancillary study reported here was the National Institutes of Health Toolbox-derived uncorrected standard Cognition Fluid Composite Score. Overall, 983 donors were screened; 110 were iron-deficient, and of these, 39 were randomized to iron repletion and 40 to placebo. Red cell storage quality was unchanged by iron repletion: mean change in posttransfusion recovery was 1.6% (95% confidence interval -0.5 to 3.8) and -0.4% (-2.0 to 1.2) with and without iron, respectively. Iron repletion did not affect any cognition or well-being measures. These data provide evidence that current criteria for blood donation preserve red cell transfusion quality for the recipient and protect adult donors from measurable effects of blood donation-induced iron deficiency on cognition. This trial was registered at www.clinicaltrials.gov as NCT02889133 and NCT02990559.
10.1182/blood.2022017288
Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea.
Jang Jun Ho,Kim Youjin,Park Silvia,Kim Kihyun,Kim Seok Jin,Kim Won Seog,Jung Chul Won,Lee Jeeyun,Lee Se-Hoon
PLoS medicine
BACKGROUND:Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. METHODS AND FINDINGS:We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. CONCLUSIONS:Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. TRIAL REGISTRATION:Clinicaltrials.gov NCT02599012.
10.1371/journal.pmed.1003091
Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for transcatheter aortic valve implantation: results of the IIISAS randomised trial.
European journal of heart failure
AIMS:The aim of this trial was to evaluate whether intravenous iron could provide benefit beyond transcatheter aortic valve implantation (TAVI) in iron-deficient patients with severe aortic stenosis. METHODS AND RESULTS:In this randomised, placebo-controlled, double-blind, single-centre trial, we enrolled patients with severe aortic stenosis and iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with a transferrin saturation <20%) who were evaluated for TAVI. Patients were randomly assigned (1:1) to receive intravenous ferric derisomaltose or placebo ∼3 months before TAVI. The primary endpoint was the between-group, baseline-adjusted 6-min walk distance measured 3 months after TAVI. Secondary outcomes included quality of life, iron stores, hand grip strength, New York Heart Association (NYHA) class, and safety. Between January 2020 and September 2021, we randomised 74 patients to ferric derisomaltose and 75 patients to placebo. The modified intention-to-treat population comprised the 104 patients who completed the 6-min walk test at baseline and 3 months after successful TAVI. Iron stores were restored in 76% of the patients allocated to iron and 13% of the patients allocated to placebo (p < 0.001). There was no difference in the baseline-adjusted 6-min walk distance between the two treatment arms (p = 0.82). The number of serious adverse events, quality of life, hand grip strength, and NYHA class did not differ between the treatment arms. CONCLUSION:Treatment with intravenous iron did not provide clinical benefit beyond TAVI in iron-deficient patients with severe aortic stenosis. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT04206228.
10.1002/ejhf.2557
Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.
Popescu Bogdan F,Frischer Josa M,Webb Samuel M,Tham Mylyne,Adiele Reginald C,Robinson Christopher A,Fitz-Gibbon Patrick D,Weigand Stephen D,Metz Imke,Nehzati Susan,George Graham N,Pickering Ingrid J,Brück Wolfgang,Hametner Simon,Lassmann Hans,Parisi Joseph E,Yong Guo,Lucchinetti Claudia F
Acta neuropathologica
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.
10.1007/s00401-017-1696-8
Prolonged red cell storage before transfusion increases extravascular hemolysis.
Rapido Francesca,Brittenham Gary M,Bandyopadhyay Sheila,La Carpia Francesca,L'Acqua Camilla,McMahon Donald J,Rebbaa Abdelhadi,Wojczyk Boguslaw S,Netterwald Jane,Wang Hangli,Schwartz Joseph,Eisenberger Andrew,Soffing Mark,Yeh Randy,Divgi Chaitanya,Ginzburg Yelena Z,Shaz Beth H,Sheth Sujit,Francis Richard O,Spitalnik Steven L,Hod Eldad A
The Journal of clinical investigation
BACKGROUND:Some countries have limited the maximum allowable storage duration for red cells to 5 weeks before transfusion. In the US, red blood cells can be stored for up to 6 weeks, but randomized trials have not assessed the effects of this final week of storage on clinical outcomes. METHODS:Sixty healthy adult volunteers were randomized to a single standard, autologous, leukoreduced, packed red cell transfusion after 1, 2, 3, 4, 5, or 6 weeks of storage (n = 10 per group). 51-Chromium posttransfusion red cell recovery studies were performed and laboratory parameters measured before and at defined times after transfusion. RESULTS:Extravascular hemolysis after transfusion progressively increased with increasing storage time (P < 0.001 for linear trend in the AUC of serum indirect bilirubin and iron levels). Longer storage duration was associated with decreasing posttransfusion red cell recovery (P = 0.002), decreasing elevations in hematocrit (P = 0.02), and increasing serum ferritin (P < 0.0001). After 6 weeks of refrigerated storage, transfusion was followed by increases in AUC for serum iron (P < 0.01), transferrin saturation (P < 0.001), and nontransferrin-bound iron (P < 0.001) as compared with transfusion after 1 to 5 weeks of storage. CONCLUSIONS:After 6 weeks of refrigerated storage, transfusion of autologous red cells to healthy human volunteers increased extravascular hemolysis, saturated serum transferrin, and produced circulating nontransferrin-bound iron. These outcomes, associated with increased risks of harm, provide evidence that the maximal allowable red cell storage duration should be reduced to the minimum sustainable by the blood supply, with 35 days as an attainable goal.REGISTRATION. ClinicalTrials.gov NCT02087514. FUNDING:NIH grant HL115557 and UL1 TR000040.
10.1172/JCI90837
Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallel-group, open-label, randomised controlled phase 3 trial.
Vanobberghen Fiona,Lweno Omar,Kuemmerle Andrea,Mwebi Kwaba Dennis,Asilia Peter,Issa Amina,Simon Beatus,Mswata Sarah,Schmidlin Sandro,Glass Tracy R,Abdulla Salim,Daubenberger Claudia,Tanner Marcel,Meyer-Monard Sandrine
The Lancet. Global health
BACKGROUND:Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. METHODS:This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 μg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin <100 g/L: 2000 mg in two doses at least 7 days apart). Oral iron treatment consisted of three dried ferrous sulphate tablets of 200 mg containing 60 mg of elementary iron and 5 mg of folic acid every morning. Oral treatment was to be taken for 3 months after haemoglobin normalisation. The primary outcome was haemoglobin normalisation (>115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-to-treat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. FINDINGS:Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. INTERPRETATION:Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting. FUNDING:Vifor Pharma, R Geigy-Stiftung, Freiwillige Akademische Gesellschaft, and Swiss Tropical and Public Health Institute.
10.1016/S2214-109X(20)30448-4
Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity.
Crippa Stefania,Rossella Valeria,Aprile Annamaria,Silvestri Laura,Rivis Silvia,Scaramuzza Samantha,Pirroni Stefania,Avanzini Maria Antonietta,Basso-Ricci Luca,Hernandez Raisa Jofra,Zecca Marco,Marktel Sarah,Ciceri Fabio,Aiuti Alessandro,Ferrari Giuliana,Bernardo Maria Ester
The Journal of clinical investigation
BACKGROUND:The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS:MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS:We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION:Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING:This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente.
10.1172/JCI123191
Low Serum Hepcidin Is Associated With Reduced Short-Term Survival in Adults With Acute Liver Failure.
Spivak Igor,Arora Jyoti,Meinzer Caitlyn,Durkalski-Mauldin Valerie,Lee William M,Trautwein Christian,Fontana Robert J,Strnad Pavel,
Hepatology (Baltimore, Md.)
The liver has an important role in iron homeostasis through the synthesis of the serum transporter transferrin and the iron hormone hepcidin. The aim of this study was to analyze parameters of iron metabolism in a multicenter cohort of adult patients with acute liver failure (ALF) and in an acetaminophen (APAP)-induced ALF mouse model. A representative subset of 121 adults with ALF (including 66 APAP-related patients) had baseline serum samples tested for ferritin, transferrin, iron, and hepcidin. Outcomes at 3 weeks after enrollment were categorized as spontaneous survivor (SS) versus death/transplantation (NSS). Mice were assessed before (controls) and 4 and 18 hours after injection of 300 mg/kg APAP. Patients with ALF as well as APAP-treated mice displayed increased ferritin and diminished serum hepcidin and hepcidin/ferritin ratio. SS had lower iron (29.1% vs. 34.5 µmol/L; P < 0.05) and transferrin saturation (60.9% vs. 79.1%; P < 0.01), but higher hepcidin levels (8.2 vs. 2.7 ng/mL; P < 0.001) and hepcidin/ferritin ratio (0.0047 vs. 0.0009; P < 0.001) than NSS. In a multivariate analysis, a log-transformed hepcidin-containing model displayed similar prognostic power as the established Acute Liver Failure Study Group index (C-statistic 0.87 vs. 0.85) and was better than Model for End-Stage Liver Disease score (C-statistic 0.76). In mice, hepcidin levels inversely correlated with the surrogate of liver injury. Conclusion: Our findings demonstrate that several serum iron parameters significantly associate with 3-week outcomes in adults with ALF. Among them, hepcidin decreases early during experimental APAP-induced ALF, is an independent predictor and might be a useful component of future prognostic scores.
10.1002/hep.30486
Perturbed iron biology in the prefrontal cortex of people with schizophrenia.
Molecular psychiatry
Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.
10.1038/s41380-023-01979-3
Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.
Santos Maria C Ferreira Dos,Anderson Cole P,Neschen Susanne,Zumbrennen-Bullough Kimberly B,Romney Steven J,Kahle-Stephan Melanie,Rathkolb Birgit,Gailus-Durner Valerie,Fuchs Helmut,Wolf Eckhard,Rozman Jan,de Angelis Martin Hrabe,Cai Weiling Maggie,Rajan Malini,Hu Jennifer,Dedon Peter C,Leibold Elizabeth A
Nature communications
Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of tA37 in tRNA to mstA37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes mstA37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2 β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.
10.1038/s41467-019-14004-5
Iron deficiency and red cell indices in patients with heart failure.
Tkaczyszyn Michał,Comín-Colet Josep,Voors Adriaan A,van Veldhuisen Dirk J,Enjuanes Cristina,Moliner-Borja Pedro,Rozentryt Piotr,Poloński Lech,Banasiak Waldemar,Ponikowski Piotr,van der Meer Peter,Jankowska Ewa A
European journal of heart failure
AIMS:To investigate the prevalence of iron deficiency (ID) in heart failure (HF) patients with normal vs. abnormal red cell indices (RCI), the associations between iron parameters and RCI, and prognostic consequences of ID independently of RCI. METHODS AND RESULTS:We analysed clinical data of 1821 patients with HF [mean age 66 ± 13 years; 71% men; New York Heart Association class I/II/III/IV (11%/39%/44%/6%); left ventricular ejection fraction >45%: 19%]. Iron deficiency (ferritin <100 µg/L or ferritin 100-299 µg/L with transferrin saturation <20%) was common irrespective of the presence of anaemia (haemoglobin <12 g/dL in women and <13 g/dL in men) or low RCI, from 75% in anaemic subjects with low mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and MCH concentration (MCHC), to 36% in non-anaemic subjects with MCV, MCH, and MCHC above the lower limit of normal. After adjustment for clinical variables, iron parameters remained independently associated with haemoglobin, MCV, MCH, MCHC, mean reticulocyte haemoglobin content (CHR), and red cell distribution width (RDW). In multivariable Cox proportional hazard regression models there was a trend towards higher mortality in patients with vs. without ID when adjusted for relevant HF prognosticators and MCH or MCHC (but not haemoglobin, CHR or RDW). CONCLUSIONS:Patients with HF should be routinely screened for ID irrespective of the presence of anaemia or abnormal RCI. The detrimental impact of ID on long-term survival in HF is partially independent of RCI.
10.1002/ejhf.820
Screening, diagnosis and treatment of iron deficiency in chronic heart failure: putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice.
McDonagh Theresa,Damy Thibaud,Doehner Wolfram,Lam Carolyn S P,Sindone Andrew,van der Meer Peter,Cohen-Solal Alain,Kindermann Ingrid,Manito Nicolas,Pfister Otmar,Pohjantähti-Maaroos Hanna,Taylor Jackie,Comin-Colet Josep
European journal of heart failure
Iron deficiency is common in patients with chronic heart failure (CHF) and is associated with reduced exercise performance, impaired health-related quality of life and an increased risk of mortality, irrespective of whether or not anaemia is present. Iron deficiency is a serious but treatable condition. Several randomized controlled clinical trials have demonstrated the ability of intravenous (IV) iron, primarily IV ferric carboxymaltose (FCM), to correct iron deficiency in patients with heart failure with reduced ejection fraction (HFrEF), resulting in improvements in exercise performance, CHF symptoms and health-related quality of life. The importance of addressing the issue of iron deficiency in patients with CHF is reflected in the 2016 European Society of Cardiology (ESC) heart failure guidelines, which recognize iron deficiency as an important co-morbidity, independent of anaemia. These guidelines recommend that all newly diagnosed heart failure patients are routinely tested for iron deficiency and that IV FCM should be considered as a treatment option in symptomatic patients with HFrEF and iron deficiency (serum ferritin < 100 µg/L, or ferritin 100-299 µg/L and transferrin saturation < 20%). Despite these specific recommendations, there is still a lack of practical, easy-to-follow advice on how to diagnose and treat iron deficiency in clinical practice. This article is intended to complement the current 2016 ESC heart failure guidelines by providing practical guidance to all health care professionals relating to the procedures for screening, diagnosis and treatment of iron deficiency in patients with CHF.
10.1002/ejhf.1305
Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function.
Hoes Martijn F,Grote Beverborg Niels,Kijlstra J David,Kuipers Jeroen,Swinkels Dorine W,Giepmans Ben N G,Rodenburg Richard J,van Veldhuisen Dirk J,de Boer Rudolf A,van der Meer Peter
European journal of heart failure
AIMS:Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes. METHODS AND RESULTS:Human embryonic stem cell-derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron-deficient cardiomyocytes, in particular ATP-linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin-bound iron recovered functional and morphological abnormalities within 3 days. CONCLUSION:Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects.
10.1002/ejhf.1154
How can sodium-glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron-deficient? Implications for understanding iron homeostasis in heart failure.
European journal of heart failure
Many patients with heart failure have an iron-deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases in haemoglobin and haematocrit, even in patients who are iron-deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe . By alleviating inflammation and oxidative stress, SGLT2 inhibitors down-regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythrocytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild-to-moderate heart failure are likely to be functional, rather than absolute, that is, they are related to inflammation-mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (i) proteomics analyses of placebo-controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (ii) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events.
10.1002/ejhf.2731
A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia.
Cappellini M Domenica,Viprakasit Vip,Taher Ali T,Georgiev Pencho,Kuo Kevin H M,Coates Thomas,Voskaridou Ersi,Liew Hong-Keng,Pazgal-Kobrowski Idit,Forni G L,Perrotta Silverio,Khelif Abderrahim,Lal Ashutosh,Kattamis Antonis,Vlachaki Efthymia,Origa Raffaella,Aydinok Yesim,Bejaoui Mohamed,Ho P Joy,Chew Lee-Ping,Bee Ping-Chong,Lim Soo-Min,Lu Meng-Yao,Tantiworawit Adisak,Ganeva Penka,Gercheva Liana,Shah Farrukh,Neufeld Ellis J,Thompson Alexis,Laadem Abderrahmane,Shetty Jeevan K,Zou Jun,Zhang Jennie,Miteva Dimana,Zinger Tatiana,Linde Peter G,Sherman Matthew L,Hermine Olivier,Porter John,Piga Antonio,
The New England journal of medicine
BACKGROUND:Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS:In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS:A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS:The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
10.1056/NEJMoa1910182
NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8.
Science advances
Enhancing the intracellular labile iron pool (LIP) represents a powerful, yet untapped strategy for driving ferroptotic death of cancer cells. Here, we show that NRF2 maintains iron homeostasis by controlling HERC2 (E3 ubiquitin ligase for NCOA4 and FBXL5) and VAMP8 (mediates autophagosome-lysosome fusion). knockout cells have low expression, leading to a simultaneous increase in ferritin and NCOA4 and recruitment of apoferritin into the autophagosome. knockout cells also have low expression, which leads to ferritinophagy blockage. Therefore, deletion of results in apoferritin accumulation in the autophagosome, an elevated LIP, and enhanced sensitivity to ferroptosis. Concordantly, NRF2 levels correlate with HERC2 and VAMP8 in human ovarian cancer tissues, as well as ferroptosis resistance in a panel of ovarian cancer cell lines. Last, the feasibility of inhibiting NRF2 to increase the LIP and kill cancer cells via ferroptosis was demonstrated in preclinical models, signifying the impact of NRF2 inhibition in cancer treatment.
10.1126/sciadv.ade9585
Apoferritin Protein Amyloid Fibrils with Tunable Chirality and Polymorphism.
Jurado Rocío,Adamcik Jozef,López-Haro Miguel,González-Vera Juan A,Ruiz-Arias Álvaro,Sánchez-Ferrer Antoni,Cuesta Rafael,Domínguez-Vera José M,Calvino José J,Orte Angel,Mezzenga Raffaele,Gálvez Natividad
Journal of the American Chemical Society
Ferritin, a soluble and highly robust protein with subunits packed into well-defined helices, is a key component of the iron regulatory system in the brain and thus is widely recognized as a crucial protein for iron metabolism, but may also bear possible implications in some neurodegenerative disorders. Here, we present evidence of how human recombinant apoferritin can convert into an unusual structure from its folded native state; that is, amyloid fibrils analogue to those found in pathological disorders such as Alzheimer's and Parkinson's diseases. An extensive combination of advanced microscopy, spectroscopy and scattering techniques concur to reveal that apoferritin fibrils possess a common double stranded twisted ribbon structure which can result in a mesoscopic right-handed chirality. We highlight a direct connection between the chirality and morphology of the resulting amyloid fibrils, and the initial protein subunits composition, advancing our understanding on the possible role of misfolding in some ferritin-related pathologies and posing new bases for the design of chiral 1D functional nanostructures.
10.1021/jacs.8b11418
Distinct gene clusters drive formation of ferrosome organelles in bacteria.
Nature
Cellular iron homeostasis is vital and maintained through tight regulation of iron import, efflux, storage and detoxification. The most common modes of iron storage use proteinaceous compartments, such as ferritins and related proteins. Although lipid-bounded iron compartments have also been described, the basis for their formation and function remains unknown. Here we focus on one such compartment, herein named the 'ferrosome', that was previously observed in the anaerobic bacterium Desulfovibrio magneticus. Using a proteomic approach, we identify three ferrosome-associated (Fez) proteins that are responsible for forming ferrosomes in D. magneticus. Fez proteins are encoded in a putative operon and include FezB, a P-ATPase found in phylogenetically and metabolically diverse species of bacteria and archaea. We show that two other bacterial species, Rhodopseudomonas palustris and Shewanella putrefaciens, make ferrosomes through the action of their six-gene fez operon. Additionally, we find that fez operons are sufficient for ferrosome formation in foreign hosts. Using S. putrefaciens as a model, we show that ferrosomes probably have a role in the anaerobic adaptation to iron starvation. Overall, this work establishes ferrosomes as a new class of iron storage organelles and sets the stage for studying their formation and structure in diverse microorganisms.
10.1038/s41586-022-04741-x
Metabolic Adaptation Establishes Disease Tolerance to Sepsis.
Weis Sebastian,Carlos Ana Rita,Moita Maria Raquel,Singh Sumnima,Blankenhaus Birte,Cardoso Silvia,Larsen Rasmus,Rebelo Sofia,Schäuble Sascha,Del Barrio Laura,Mithieux Gilles,Rajas Fabienne,Lindig Sandro,Bauer Michael,Soares Miguel P
Cell
Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.
10.1016/j.cell.2017.05.031
Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.
Frontiers in immunology
Background:Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. Methods:In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. Results:We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, =-0.587, =0.002; Elderly, =-0.496, =0.012) or transferrin saturation index (Young, =-0.581, =0.002; Elderly, =-0.489, =0.013) were negative in both controls while positive in HIV (=0.464, <0.0001 and =0.421, <0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, =-0.533, =0.006; Elderly, =-0.473, =0.017), was absent in HIV (=0.082; =0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Conclusions:Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.
10.3389/fimmu.2022.977316
Puerarin protects against sepsis-induced myocardial injury through AMPK-mediated ferroptosis signaling.
Aging
OBJECTIVE:Research suggests that Puerarin may protect against sepsis-induced myocardial damage. However, the mechanisms responsible for Puerarin's cardioprotective effect remain largely unclear. In this study, our objective is to investigate the role of Puerarin-induced AMPK-mediated ferroptosis signaling in protecting myocardial injury. METHODS:48 male Sprague-Dawley rats were randomly divided into four groups: control group, LPS group, LPS + Pue group, LPS + Pue + Era (Erastin, ferroptosis activator) group, or LPS + Pue + CC (compound C, AMPK inhibitor) group. During the experiment, cardiac systolic function indexes and myocardial histopathological changes were monitored. The serum levels of myocardial injury marker enzyme, inflammatory response related marker enzyme, and oxidative stress related-marker enzyme were measured with ELISA. Apoptotic cardiomyocytes, the iron content in myocardial tissue, apoptosis-related proteins, AMPK, and ferroptosis-related proteins were determined. RESULTS:Puerarin inhibited the myocardial injury induced by LPS. The cardioprotective effects of Puerarin decreased after adding ferroptosis-activating compound Erastin. The protein expression levels of GPX4 and ferritin were down-regulated, whereas ACSL4, TFR, and heart iron content were up-regulated in LPS + Pue + Era group compared with LPS+Pue group. A significant difference was identified between LPS + Pue + Era group and LPS + Pue group in P-AMPK and T-AMPK levels. Meanwhile, after providing CC, P-AMPK/T-AMPK was significantly reduced, the protein expression levels of GPX4 and ferritin were down-regulated. ACSL4, TFR, and the heart iron content were up-regulated in LPS + Pue + CC group compared to LPS + Pue group. CONCLUSIONS:Puerarin protected against sepsis-induced myocardial injury, and AMPK-mediated ferroptosis signaling played a crucial role in its cardioprotective effect.
10.18632/aging.204033
Iron metabolism and iron disorders revisited in the hepcidin era.
Camaschella Clara,Nai Antonella,Silvestri Laura
Haematologica
Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload. Iron regulatory proteins post-transcriptionally control genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive enterocytes and iron-recycling macrophages. This review emphasizes the most recent findings in iron biology, deregulation of the hepcidin-ferroportin axis in iron disorders and how research results have an impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess leads to iron restriction. Mutations of hemochro-matosis genes result in iron excess by downregulating the liver BMP-SMAD signaling pathway or by causing hepcidin-resistance. In iron-loading anemias, such as β-thalassemia, enhanced albeit ineffective ery-thropoiesis releases erythroferrone, which sequesters BMP receptor ligands, thereby inhibiting hepcidin. In iron-refractory, iron-deficiency ane-mia mutations of the hepcidin inhibitor TMPRSS6 upregulate the BMP-SMAD pathway. Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane-mia of inflammation in the presence of iron-replete macrophages. Our improved understanding of iron homeostasis and its regulation is having an impact on the established schedules of oral iron treatment and the choice of oral intravenous iron in the management of iron deficiency. Moreover it is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.
10.3324/haematol.2019.232124
Iron deficiency.
Lancet (London, England)
Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routinely, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.
10.1016/S0140-6736(20)32594-0
Dysregulation of iron metabolism in cancer stem cells.
Recalcati Stefania,Gammella Elena,Cairo Gaetano
Free radical biology & medicine
Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells endowed with stem-like properties. Importantly, CSCs can survive current standard therapies, resulting in metastatic disease and tumor recurrence. Here we describe the alterations of iron homeostasis occurring in CSCs, which in general are characterized by high intracellular iron content. Importantly, abnormalities of iron metabolism correlate with faster tumor growth and adverse prognosis in cancer patients. In line with the dependence of cancer on iron, we also discuss iron-dependent mechanisms as druggable pathways, as iron chelators have been considered for tumor therapy and new molecules currently proposed and studied as antineoplastic drugs may impinge on iron and its capacity to promote oxidative stress to have therapeutic value in cancer.
10.1016/j.freeradbiomed.2018.07.015
NCOA4 links iron bioavailability to DNA metabolism.
Cell reports
Iron is essential for deoxyribonucleotides production and for enzymes containing an Fe-S cluster involved in DNA replication and repair. How iron bioavailability and DNA metabolism are coordinated remains poorly understood. NCOA4 protein mediates autophagic degradation of ferritin to maintain iron homeostasis and inhibits DNA replication origin activation via hindrance of the MCM2-7 DNA helicase. Here, we show that iron deficiency inhibits DNA replication, parallel to nuclear NCOA4 stabilization. In iron-depleted cells, NCOA4 knockdown leads to unscheduled DNA synthesis, with replication stress, genome instability, and cell death. In mice, NCOA4 genetic inactivation causes defective intestinal regeneration upon dextran sulfate sodium-mediated injury, with DNA damage, defective cell proliferation, and cell death; in intestinal organoids, this is fostered by iron depletion. In summary, we describe a NCOA4-dependent mechanism that coordinates iron bioavailability and DNA replication. This function prevents replication stress, maintains genome integrity, and sustains high rates of cell proliferation during tissue regeneration.
10.1016/j.celrep.2022.111207
Iron Acquisition Systems of Gram-negative Bacterial Pathogens Define TonB-Dependent Pathways to Novel Antibiotics.
Chemical reviews
Iron is an indispensable metabolic cofactor in both pro- and eukaryotes, which engenders a natural competition for the metal between bacterial pathogens and their human or animal hosts. Bacteria secrete siderophores that extract Fe from tissues, fluids, cells, and proteins; the ligand gated porins of the Gram-negative bacterial outer membrane actively acquire the resulting ferric siderophores, as well as other iron-containing molecules like heme. Conversely, eukaryotic hosts combat bacterial iron scavenging by sequestering Fe in binding proteins and ferritin. The variety of iron uptake systems in Gram-negative bacterial pathogens illustrates a range of chemical and biochemical mechanisms that facilitate microbial pathogenesis. This document attempts to summarize and understand these processes, to guide discovery of immunological or chemical interventions that may thwart infectious disease.
10.1021/acs.chemrev.0c01005
Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis.
Das Nupur K,Schwartz Andrew J,Barthel Gabrielle,Inohara Naohiro,Liu Qing,Sankar Amanda,Hill David R,Ma Xiaoya,Lamberg Olivia,Schnizlein Matthew K,Arqués Juan L,Spence Jason R,Nunez Gabriel,Patterson Andrew D,Sun Duxin,Young Vincent B,Shah Yatrik M
Cell metabolism
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
10.1016/j.cmet.2019.10.005
Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.
Macdougall Iain C,White Claire,Anker Stefan D,Bhandari Sunil,Farrington Kenneth,Kalra Philip A,McMurray John J V,Murray Heather,Tomson Charles R V,Wheeler David C,Winearls Christopher G,Ford Ian,
The New England journal of medicine
BACKGROUND:Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited. METHODS:In a multicenter, open-label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 μg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 μg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25. RESULTS:A total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, -7539 IU; 95% confidence interval [CI], -9485 to -5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups. CONCLUSIONS:Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25 .).
10.1056/NEJMoa1810742
Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.
Ponikowski Piotr,Kirwan Bridget-Anne,Anker Stefan D,McDonagh Theresa,Dorobantu Maria,Drozdz Jarosław,Fabien Vincent,Filippatos Gerasimos,Göhring Udo Michael,Keren Andre,Khintibidze Irakli,Kragten Hans,Martinez Felipe A,Metra Marco,Milicic Davor,Nicolau José C,Ohlsson Marcus,Parkhomenko Alexander,Pascual-Figal Domingo A,Ruschitzka Frank,Sim David,Skouri Hadi,van der Meer Peter,Lewis Basil S,Comin-Colet Josep,von Haehling Stephan,Cohen-Solal Alain,Danchin Nicolas,Doehner Wolfram,Dargie Henry J,Motro Michael,Butler Javed,Friede Tim,Jensen Klaus H,Pocock Stuart,Jankowska Ewa A,
Lancet (London, England)
BACKGROUND:Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS:AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS:Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION:In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING:Vifor Pharma.
10.1016/S0140-6736(20)32339-4
On Iron Metabolism and Its Regulation.
Vogt Anne-Cathrine S,Arsiwala Tasneem,Mohsen Mona,Vogel Monique,Manolova Vania,Bachmann Martin F
International journal of molecular sciences
Iron is a critical metal for several vital biological processes. Most of the body's iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.
10.3390/ijms22094591
Efficacy and toxicity of intravenous iron in a mouse model of critical care anemia*.
Heming Nicholas,Lettéron Philippe,Driss Fathi,Millot Sarah,El Benna Jamel,Tourret Jérome,Denamur Erick,Montravers Philippe,Beaumont Carole,Lasocki Sigismond
Critical care medicine
OBJECTIVE:Anemia is common in critically ill patients, due to inflammation and blood loss. Anemia can be associated with iron deficiency and low serum hepcidin levels. However, iron administration in this setting remains controversial because of its potential toxicity, including oxidative stress induction and sepsis facilitation. The objective of this work was to determine the efficacy and toxicity of iron administration using a mouse model mimicking critical care anemia as well as a model of acute septicemia. DESIGN:Prospective, randomized, open label controlled animal study. SETTING:University-based research laboratory. SUBJECTS:C57BL/6 and OF1 mice. INTERVENTIONS:Intraperitoneal injection of zymosan inducing generalized inflammation in C57BL/6 mice, followed in our full model by repeated phlebotomies. A dose equivalent to 15 mg/kg of ferric carboxymaltose was injected intravenously on day 5. To assess the toxicity of iron in a septicemia model, OF1 mice were simultaneously injected with iron and different Escherichia coli strains. MEASUREMENTS AND MAIN RESULTS:To investigate the effect of iron on oxidative stress, we measured reactive oxygen species production in the blood using luminol-amplified chemiluminescence and superoxide dismutase 2 messenger RNA levels in the liver. These markers of oxidative stress were increased after iron administration in control mice but not in zymosan-treated mice. Liver catalase messenger RNA levels decreased in iron-treated control mice. Iron administration was not associated with increased mortality in the septicemia model or in the generalized inflammation model. Iron increased hemoglobin levels in mice fed with a low iron diet and subjected to phlebotomies and zymosan 2 wks after treatment administration. CONCLUSIONS:Adverse effects of intravenous iron supplementation by ferric carboxymaltose seem to be minimal in our animal models. Furthermore, iron appears to be effective in correcting anemia, despite inflammation. Studies of efficacy and safety of iron in critically ill patients are warranted.
10.1097/CCM.0b013e31824e6713
Promising applications of red cell distribution width in diagnosis and prognosis of diseases with or without disordered iron metabolism.
Cell biology international
Many indicators, including red cell distribution width (RDW) and iron metabolism, are sensitive to a variety of risk factors, and are associated with the pathological alterations and disease onset. RDW reflects the degree of heterogeneous volumes of peripheral red blood cells (RBCs). It has been well-known that increased RDW indicates iron deficiency anemia, hemolytic anemia, ineffective erythropoiesis, and shorten lifespan of RBCs. Increased RDW is also prevalent in various non-anemic pathological conditions and diseases. We here review the factors affecting RDW, particularly disordered iron metabolism, chronic inflammation, and oxidative stress, and recapitulate the interplays among these factors. Furthermore, we review the application of increased RDW together with disordered iron homeostasis and the deregulations of hepcidin expression and ferritin levels in the diagnoses and prognosis of anemic and nonanemic diseases. RDW is inexpensive and readily available and may be valuable in adding to the diagnosis and monitoring of many pathological conditions. RDW combined with other indicators, for example, hepcidin and ferritin levels, should be utilized more frequently in clinical practice.
10.1002/cbin.12029
Role of iron in cancer.
Salnikow Konstantin
Seminars in cancer biology
Iron is an essential metal for cellular metabolism. The reduced form of iron is a cofactor in numerous redox reactions in the cell and is therefore required for many vital physiological functions. Since iron is an oxidatively active metal, its homeostasis is tightly regulated in healthy cell. Most of iron exists in a protein-bound form, in erythrocytes as the heme compound hemoglobin, and in storage proteins such as ferritin, hemosiderin and myoglobin. Iron also is bound to proteins and non-heme enzymes involved in oxidation-reduction reactions and the transfer of electrons. There is no free iron inside the cell, however a small fraction of loosely bound iron is found in the cytoplasm. This poorly defined pool of ferrous iron is called labile iron pool. Under pathological conditions iron homeostasis may be disrupted at different levels including absorption, systemic transportation, and cellular uptake and storage. Cancer cells display dysregulated iron homeostasis and, for reasons yet poorly understood, require more iron for their metabolism and growth. As a result, in cancer cells labile iron pool is increased, and loosely bound iron catalyzes Fenton reaction and perhaps other reactions that generate reactive oxygen species. Oxygen-derived free radicals produce DNA mutations, damage proteins and lipids resulting in either cell death or cell transformation.
10.1016/j.semcancer.2021.04.001
Revisiting Iron Metabolism, Iron Homeostasis and Iron Deficiency Anemia.
Clinical laboratory
BACKGROUND:Iron deficiency anemia (IDA) is one of the commonest clinical scenarios especially in children, women of childbearing age, and elders. The crux of this review was revisiting iron homeostasis, mechanism of iron absorption, causes, laboratory diagnosis, and management of IDA. METHODS:This narrative review is compiled after a relevant literature search from electronic databases including, but not limited to, Google, Google Scholar, PMC, PubMed, Science Direct, and Scopus. The key words used for searching relevant literature include iron, iron deficiency, iron deficiency anemia, iron metabolism, hepcidin, transferrin, causes of iron deficiency anemia, and laboratory diagnosis of iron deficiency anemia. Reference hema-tology books were also consulted. RESULTS:According to the published literature, about one mg of iron is required daily which equals its loss, although the iron requirement increases in pregnancy and lactating mothers. Dietary non heme iron (oxidized Fe3+) is reduced to the ferrous (Fe2+) form by ferrireductase present in the brush border of duodenal enterocytes. Ferrous iron is absorbed in the brush border of duodenal enterocytes through a carrier protein, divalent metal transporter 1 (DMT1). Heme iron is absorbed by the duodenal enterocytes through a mechanism that is not well understood or a receptor yet to be discovered. Transferrin receptor helps in the internalization of iron in the cells. Hepcidin acts as a gatekeeper and controls iron absorption by enterocytes and macrophages. IDA may be caused by decreased intake of iron, increased iron requirements or loss of iron from the body. CONCLUSIONS:Iron deficiency anemia is the most common nutritional anemia that affects large numbers of people in developed as well as in developing countries. It is estimated that approximately 2 billion people around the world have IDA. Microcytosis with marked reduction in serum iron, decreased % saturation of transferrin, low ferritin, and reduced or even undetectable hepcidin are the laboratory features of IDA. In addition, total iron binding capacity and soluble transferrin receptors increase significantly in IDA. Management of IDA is incomplete if the underlying cause is not ruled out and left untreated.
10.7754/Clin.Lab.2020.200742
Cellular Iron Metabolism and Regulation.
Gao Guofen,Li Jie,Zhang Yating,Chang Yan-Zhong
Advances in experimental medicine and biology
Iron is an essential trace element in the human body, but excess iron is toxic as it contributes to oxidative damage. To keep iron concentration within the optimal physiologic range, iron metabolism at the cellular level and the whole systemic level are tightly regulated. Balance of iron homeostasis depends on the expression levels and activities of iron carriers, iron transporters, and iron regulatory and storage proteins. Divalent metal transporter 1 (DMT1) at the apical membrane of intestinal enterocyte brings in non-heme iron from the diet, whereas ferroportin 1 (FPN1) at the basal membrane exports iron into the circulation. Plasma transferrin (Tf) then carries iron to various tissues and cells. After binding to transferrin receptor 1 (TfR1), the complex is endocytosed into the cell, where iron enters the cytoplasm via DMT1 on the endosomal membrane. Free iron is either utilized in metabolic processes, such as synthesis of hemoglobin and Fe-S cluster, or sequestered in the cytosolic ferritin, serving as a cellular iron store. Excess iron can be exported from the cell via FPN1. The liver-derived peptide hepcidin plays a major regulatory role in controlling FPN1 level in the enterocyte, and thus controls the whole-body iron absorption. Inside the cells, iron regulatory proteins (IRPs) modulate the expressions of DMT1, TfR1, ferritin, and FPN1 via binding to the iron-responsive element (IRE) in their mRNAs. Both the release of hepcidin and the IRP-IRE interaction are coordinated with the fluctuation of the cellular iron level. Therefore, an adequate and steady iron supplement is warranted for the utilization of cells around the body. Investigations on the molecular mechanisms of cellular iron metabolism and regulation could advance the fields of iron physiology and pathophysiology.
10.1007/978-981-13-9589-5_2
Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation.
Barcellini Wilma,Zaninoni Anna,Gregorini Anna I,Soverini Giulia,Duca Lorena,Fattizzo Bruno,Giannotta Juri A,Pedrotti Patrizia,Vercellati Cristina,Marcello Anna P,Fermo Elisa,Bianchi Paola,Cappellini Maria Domenica
British journal of haematology
Iron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non-transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 μg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis-associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ-interferon (IFN-γ) was increased, and both interleukin 6 and IFN-γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.
10.1111/bjh.15811
Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice.
Sivaprakasam Sathish,Ristic Bojana,Mudaliar Nithya,Hamood Abdul N,Colmer-Hamood Jane,Wachtel Mitchell S,Nevels Anna G,Kottapalli Kameswara R,Ganapathy Vadivel
The Biochemical journal
Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon-microbiome interaction and exacerbates the development and progression of colonic inflammation and colon cancer. To test this hypothesis, we examined the progression and severity of colitis and colon cancer in a mouse model of HH (Hfe-/-), and evaluated the potential contributing factors. We found that experimentally induced colitis and colon cancer progressed more robustly in Hfe-/- mice than in wild-type mice. The underlying causes were multifactorial. Hfe-/- colons were leakier with lower proliferation capacity of crypt cells, which impaired wound healing and amplified inflammation-driven tissue injury. The host/microflora axis was also disrupted. Sequencing of fecal 16S RNA revealed profound changes in the colonic microbiome in Hfe-/- mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was an increased number of bacteria adhered onto the mucosal surface of the colonic epithelium in Hfe-/- mice than in wild-type mice. Furthermore, the expression of innate antimicrobial peptides, the first-line of defense against bacteria, was lower in Hfe-/- mouse colon than in wild-type mouse colon; the release of pro-inflammatory cytokines upon inflammatory stimuli was also greater in Hfe-/- mouse colon than in wild-type mouse colon. These data provide evidence that excess iron accumulation in colonic tissue as happens in HH promotes colitis and colon cancer, accompanied with bacterial dysbiosis and loss of function of the intestinal/colonic barrier.
10.1042/BCJ20200392
JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy.
Free radical biology & medicine
Interruption of iron homeostasis is correlated with cell ferroptosis and degenerative diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been reported as a vital mechanism to control cellular iron levels, but its impact on osteoarthritis (OA) pathology and the underline mechanism are unknown. Herein we aimed to investigate the role and regulatory mechanism of NCOA4 in chondrocyte ferroptosis and OA pathogenesis. We demonstrated that NCOA4 was highly expressed in cartilage of patients with OA, aged mice, post-traumatic OA mice, and inflammatory chondrocytes. Importantly, Ncoa4 knockdown inhibited IL-1β-induced chondrocyte ferroptosis and extracellular matrix degradation. Contrarily, overexpression of NCOA4 promoted chondrocyte ferroptosis and the delivery of Ncoa4 adeno-associated virus 9 into knee joint of mice aggravated post-traumatic OA. Mechanistic study revealed that NCOA4 was upregulated in a JNK-JUN signaling-dependent manner in which JUN could directly bind to the promoter of Ncoa4 and initial the transcription of Ncoa4. NCOA4 could interact with ferritin and increase autophagic degradation of ferritin and iron levels, which caused chondrocyte ferroptosis and extracellular matrix degradation. In addition, inhibition of JNK-JUN-NCOA4 axis by SP600125, a specific inhibitor of JNK, attenuated development of post-traumatic OA. This work highlights the role of JNK-JUN-NCOA4 axis and ferritinophagy in chondrocyte ferroptosis and OA pathogenesis, suggesting this axis as a potential target for OA treatment.
10.1016/j.freeradbiomed.2023.03.008
Core Cross-Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages.
Advanced healthcare materials
Iron is an essential co-factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S-ethylsulfonyl-l-cysteine) block, yielding glutathione-responsive core cross-linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild-type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox-responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.
10.1002/adhm.202100385
Potential Mechanisms Underlying the Hepatic-Protective Effects of Danshensu on Iron Overload Mice.
Zhang Yuanyuan,Zhang Gaohua,Liang Yingran,Wang Hongfang,Wang Qian,Zhang Ying,Zhang Xuan,Zhang Jianping,Chu Li
Biological & pharmaceutical bulletin
The purpose of the present study was to investigate the protective effects and the underlying mechanisms of Danshensu on liver injury induced by iron overload. The mouse model was induced by injection of iron dextran intraperitoneally for 14 d. Danshensu significantly ameliorated liver injury by decreasing iron accumulation in the liver, possibly by down-regulating the expression of iron uptake-related proteins: divalent metal ion transporters-1 (DMT-1), transferrin receptor (TfR), and L-type calcium channel α1C subunit. Furthermore, Danshensu alleviated oxidative stress injury through potentiating glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities; Immunohistochemistry results demonstrated that Danshensu reduced the expression of inflammatory cytokines: interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β). Moreover, Danshensu prominently inhibited hepatocyte apoptosis through decreasing Bax and Caspase-3 and increasing Bcl-2 expression levels. The present results suggest that Danshensu possess significant hepatic-protection at least partly through inhibition of iron uptake, oxidative stress, inflammatory, and apoptosis. Therefore, we believe that Danshensu could be used as a promising therapeutic agent for preventing and treating iron overload diseases.
10.1248/bpb.b19-01084
Soluble Transferrin Receptor (sTfR) Identifies Iron Deficiency Anemia (IDA) in Pulmonary Tuberculosis Patients.
Ratnaningsih Tri,Sukirto Novi W,Wahyuningsih Arum Tri
Acta medica Indonesiana
BACKGROUND:iron deficiency in pulmonary tuberculosis (TB) patients may weaken their immune system, causing difficulty in overcoming the infection. Accurate diagnosis of iron deficiency anemia (IDA) in pulmonary TB patients is essential. In order to prove the iron deficient state, diagnosis should focus on inflammatory factors, which could highly affect the outcome of iron status, such as measurement of serum ferritin (SF). Soluble Transferrin Receptor (sTfR) is the best parameter to diagnose iron deficiency in the inflammatory condition. This study aimed to understand the role of sTfR to identify IDA in TB patients. METHODS:cross-sectional study were applied to 3 study groups: anemic pulmonary TB (68 subjects), IDA (7 subjects), and non-anemic pulmonary TB (15 subjects). The test averages and correlations between sTfR, SF, and other hematological parameters were measured and analyzed. RESULTS:significant differences of sTfR were found in the anemic TB group compared to the IDA group and also between the IDA and non-anemic TB groups (p<0.0001). However, there was no significant difference (p>0.05) between TB anemic and non-anemic groups. We also found no significant difference between the TB anemic sub-group with normal levels of sTfR compared with the non-anemic group. There was no significant difference of sTfR levels between sub-group of increasing sTfR and group IDA (p>0.05). However, there was strong correlation between sTfR and SF in the IDA group (r=-0.89; p=0.007). CONCLUSION:the findings suggest verifying the sTfR amount in anemic patients with pulmonary TB suffering from inflammation, so that the iron deficiency could be more accurately identified and properly treated.
[Research progress on the regulation mechanisms of iron metabolism in anemia of chronic disease].
Sheng li xue bao : [Acta physiologica Sinica]
Anemia of chronic disease (ACD), complicated by various chronic inflammatory diseases, is the second most prevalent type of anemia after iron deficiency anemia in the world. ACD significantly reduces the life quality of patients with chronic diseases, and represents an independent poor prognostic factor in certain chronic diseases. A large body of studies has demonstrated that most of anemia is related to abnormal iron metabolism. In the past decade, hepcidin, as a key factor in regulating iron metabolism, has attracted enormous attention due to its important role in the pathogenesis of ACD. This article reviews the research progress on the role and underlying regulatory mechanisms of hepcidin in ACD. We also discuss the potential of hepcidin as an effective therapeutic target for ACD treatment, in order to provide a new maneuver for improving the quality of ACD patients' life.
Modulating NF-κB, MAPK, and PI3K/AKT signaling by ergothioneine attenuates iron overload-induced hepatocellular injury in rats.
Salama Samir A,Omar Hany A
Journal of biochemical and molecular toxicology
The liver is highly susceptible to iron overload-evoked oxidative injury. Ergothioneine is a thio-histidine amino acid that has exhibited strong antioxidant and metal chelating activities. This study aimed at exploring the potential modulating effects of ergothioneine on iron-triggered liver injury. The results showed that ergothioneine inhibited iron-evoked inflammation and apoptosis as demonstrated by a significant reduction in tumor necrosis factor-α and interleukin-6 levels and in caspase-3 activity. Ergothioneine significantly improved liver cell survival as indicated by modulating phosphatidylinositol 3-kinase/protein kinase B signaling. Consistent with reduced necrotic cell death, ergothioneine diminished the iron-evoked histopathological changes and decreased serum activity of the liver enzymes. Mechanistically, ergothioneine reduced nuclear translocation of nuclear factor kappa B p65 and modulated p38 mitogen-activated protein kinase/c-Fos signaling. In addition, it enhanced the liver tissue antioxidant potential and curbed hepatic iron load. Together, these results point out the modulatory effects of ergothioneine on iron-evoked liver cell injury that are possibly mediated via anti-inflammatory, antioxidant, and possible iron chelation capabilities.
10.1002/jbt.22729
Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients.
Molecular biology reports
BACKGROUND:Due to the growing evidence of the importance of iron status in immune responses, the biomarkers of iron metabolism are of interest in novel Coronavirus Disease 2019 (COVID-19). The present prospective study was carried out to compare iron status indicated by levels of ferritin with the levels of two novel biomarkers related to iron homeostasis, hephaestin and hypoxia-inducible factors-1 (HIF-1α) in the serum of patients with COVID-19 in comparison with a control group. METHODS AND RESULTS:Blood samples from 34 COVID-19 patients and from 43 healthy volunteers were collected and the levels of HEPH and HIF-1α were measured by ELISA and compared with levels of serum ferritin. COVID-19 patients had higher serum levels of ferritin than those levels in control group (P < 0.0001). Conversely levels of HIF-1α and HEPH in the COVID-19 group were significantly lower than those of control group (P < 0.0001 for both). An inverse correlation between hephaestin and ferritin as well as between HIF-1α and ferritin was found among all subjects (P < 0.0001), and among COVID-19 patients, but not to statistical significance. CONCLUSION:Levels of hephaestin and HIF-1α were found to be inversely related levels of ferritin across all participants in the study, and to our knowledge this is the first report of hephaestin and HIF-1α as potential markers of iron status. Further studies are needed to corroborate the findings, utilizing a broader range of markers to monitor inflammatory as well as iron status.
10.1007/s11033-022-08221-3
Iron biodistribution profile changes in the rat spleen after administration of high-fat diet or iron supplementation and the role of curcumin.
Awaad Aziz,Abdel Aziz Hekmat Osman
Journal of molecular histology
Curcumin as active metal chelating and antioxidant agent has a potential role in metal reduction and free radicals' neutralization in tissues. Of note, long-term administration of high fat diet (HFD) is considered as a main factor of blood serum iron deficiency. This study aimed to investigate the biodistribution profiles of iron in the spleen after long-term administration of HFD along with iron supplementation. Furthermore, the ameliorative role of curcumin to reduce iron accumulation level and improve the histological abnormalities produced by iron in spleen will be evaluated in the rats. Treated albino rats of this experiment were divided into six groups. Group I was a control group where group II was treated with HFD. Group III and group IV were treated with combination of HFD and curcumin or HFD and iron supplement respectively. Additionally, group V and group VI were treated with combination of HFD, iron supplement and curcumin or curcumin only respectively. Mainly histological analysis was used to investigate iron biodistribution and induced abnormalities in spleen under light microscope. The histochemical specific staining of iron in the spleen showed different biodistribution profiles of iron in the spleen. Administration of the HFD or HFD and iron supplementation increased the iron accumulation in the spleen. Where, curcumin administration with HFD (Group III) or with HFD and iron supplementation (Group V) significantly reduced the iron levels in the spleen. The splenic tissue inflammation, cellular apoptosis and fibrosis produced by higher iron accumulation was ameliorated after administration of curcumin supplementation as shown in the animals treated with HFD/curcumin (Group III) or HFD/iron supplement/curcumin (Group V). This study recommended that, it is preferable to use iron supplementation along with curcumin supplement for less than 4 months to avoid additional iron accumulation in the healthy organs.
10.1007/s10735-021-09986-w
Iron Prevents Hypoxia-Associated Inflammation Through the Regulation of Nuclear Factor-κB in the Intestinal Epithelium.
Simmen Simona,Cosin-Roger Jesus,Melhem Hassan,Maliachovas Nikolaos,Maane Max,Baebler Katharina,Weder Bruce,Maeyashiki Chiaki,Spanaus Katharina,Scharl Michael,de Vallière Cheryl,Zeitz Jonas,Vavricka Stephan R,Hausmann Martin,Rogler Gerhard,Ruiz Pedro A
Cellular and molecular gastroenterology and hepatology
BACKGROUND & AIMS:Hypoxia-associated pathways influence the development of inflammatory bowel disease. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are regulated by iron-dependent hydroxylases. Signals reflecting oxygen tension and iron levels in enterocytes regulate iron metabolism. Conversely, iron availability modulates responses to hypoxia. In the present study we sought to elucidate how iron influences the responses to hypoxia in the intestinal epithelium. METHODS:Human subjects were exposed to hypoxia, and colonic biopsy specimens and serum samples were collected. HT-29, Caco-2, and T84 cells were subjected to normoxia or hypoxia in the presence of iron or the iron chelator deferoxamine. Changes in inflammatory gene expression and signaling were assessed by quantitative polymerase chain reaction and Western blot. Chromatin immunoprecipitation was performed using antibodies against nuclear factor (NF)-κB and primers for the promoter of tumor necrosis factor (TNF) and interleukin (IL)1β. RESULTS:Human subjects presented reduced levels of ferritin in the intestinal epithelium after hypoxia. Hypoxia reduced iron deprivation-associated TNF and IL1β expression in HT-29 cells through the induction of autophagy. Contrarily, hypoxia triggered TNF and IL1β expression, and NF-κB activation in Caco-2 and T84 cells. Iron blocked autophagy in Caco-2 cells, while reducing hypoxia-associated TNF and IL1β expression through the inhibition of NF-κB binding to the promoter of TNF and IL1β. CONCLUSIONS:Hypoxia promotes iron mobilization from the intestinal epithelium. Hypoxia-associated autophagy reduces inflammatory processes in HT-29 cells. In Caco-2 cells, iron uptake is essential to counteract hypoxia-induced inflammation. Iron mobilization into enterocytes may be a vital protective mechanism in the hypoxic inflamed mucosa.
10.1016/j.jcmgh.2018.10.006
Analytical evaluation of serum non-transferrin-bound iron and its relationships with oxidative stress and cardiac load in the general population.
Medicine
ABSTRACT:Excessive iron accumulation provokes toxic effects, especially in the cardiovascular system. Under iron overload, labile free non-transferrin-bound iron (NTBI) can induce cardiovascular damage with increased oxidative stress. However, the significance of NTBI in individuals without iron overload and overt cardiovascular disease has not been investigated. We aimed to examine the distribution of serum NTBI and its relationship with oxidative stress and cardiac load under physiological conditions in the general population.We enrolled individuals undergoing an annual health check-up and measured serum NTBI and derivatives of reactive oxygen metabolites (d-ROM), an oxidative stress marker. In addition, we evaluated serum levels of B-type natriuretic peptide (BNP) to examine cardiac load. We excluded patients with anemia, renal dysfunction, cancer, active inflammatory disease, or a history of cardiovascular disease.A total of 1244 individuals (57.8 ± 11.8 years) were enrolled, all of whom had detectable serum NTBI. d-ROM and BNP showed significant trends across NTBI quartiles. Multivariable regression analysis revealed that serum iron and low-density lipoprotein cholesterol were positively associated with NTBI but that age, d-ROM, and BNP showed an inverse association with this measure. In logistic regression analysis, NTBI was independently associated with a combination of higher levels of both d-ROM and BNP than the upper quartiles after adjustment for possible confounding factors.Serum NTBI concentration is detectable in the general population and shows significant inverse associations with oxidative stress and cardiac load. These findings indicate that serum NTBI in physiological conditions does not necessarily reflect increased oxidative stress, in contrast to the implications of higher levels in states of iron overload or pathological conditions.
10.1097/MD.0000000000024722
Iron homeostasis is altered in response to hypoxia and hypothermic preconditioning in brain glial cells
Turkish journal of medical sciences
Background/aim:Altered iron metabolism is one of the pathophysiological mechanisms occurring during hypoxic injuries in the central nervous system. Proper homeostasis of cellular iron is regulated by iron import, storage, and export proteins that prevent excess iron overload or iron starvation in cells. Therapeutic hypothermia is an approved treatment for hypoxic ischemia in newborns, but the underlying molecular mechanism is still unknown. We studied the effects of hypoxia, preceded with preconditioning, on the iron homeostasis of glial cells, known as a major actor in the inflammatory process during perinatal brain injury. Materials and methods:Primary microglia and astrocytes in culture were exposed to 12 h of hypoxia with or without mild hypothermic preconditioning. The mRNA expression was assessed using qPCR. Iron accumulation was visualized via modified Perl’s histochemistry. Cytokine levels in cell cultures were measured using ELISA. Results:Hypothermic preconditioning enhanced microglial viability, which previously was decreased in both cell types due to hypoxia. Hypoxia increased iron accumulation in the mixed glial cells and in ferritin expression in both microglia and astrocytes. Hypotermic preconditioning decreased the elevated ferritin-light chain expression significantly in microglia. Iron importer proteins, DMT1 and TfR1, both increased their mRNA expression after hypoxia, and hypothermic preconditioning continued to support the elevation of DMT1 in both glial cell types. Ferroportin expression increased as a survival factor of the glial cell following hypoxia. Hypothermic preconditioning supported this increase in both cell types and was especially significant in astrocytes. IL-10 levels were prominently increased in cell culture after hypothermic preconditioning. Conclusion:The data suggest that hypothermic preconditioning affects cellular iron homeostasis by regulating the storage and transfer proteins of iron. Regulation of the cellular iron traffic may prevent glial cells from experiencing the detrimental effects of hypoxia-related inflammation.
10.3906/sag-2003-41
SMAD family member 3 (SMAD3) and SMAD4 repress HIF2α-dependent iron-regulatory genes.
Ma Xiaoya,Das Nupur K,Castillo Cristina,Gourani Ayla,Perekatt Ansu O,Verzi Michael P,Shah Yatrik M
The Journal of biological chemistry
Hypoxia-inducible factor 2α (HIF2α) directly regulates a battery of genes essential for intestinal iron absorption. Interestingly, iron deficiency and overload disorders do not result in increased intestinal expression of glycolytic or angiogenic HIF2α target genes. Similarly, inflammatory and tumor foci can induce a distinct subset of HIF2α target genes These observations indicate that different stimuli activate distinct subsets of HIF2α target genes via mechanisms that remain unclear. Here, we conducted a high-throughput siRNA-based screen to identify genes that regulate HIF2α's transcriptional activity on the promoter of the iron transporter gene (). SMAD family member 3 (SMAD3) and SMAD4 were identified as potential transcriptional repressors. Further analysis revealed that SMAD4 signaling selectively represses iron-absorptive gene promoters but not the inflammatory or glycolytic HIF2α or HIF1α target genes. Moreover, the highly homologous SMAD2 did not alter HIF2α transcriptional activity. During iron deficiency, SMAD3 and SMAD4 expression was significantly decreased via proteasomal degradation, allowing for derepression of iron target genes. Several iron-regulatory genes contain a SMAD-binding element (SBE) in their proximal promoters; however, mutation of the putative SBE on the promoter did not alter the repressive function of SMAD3 or SMAD4. Importantly, the transcription factor forkhead box protein A1 (FOXA1) was critical in SMAD4-induced repression, and DNA binding of SMAD4 was essential for the repression of HIF2α activity, suggesting an indirect repressive mechanism through DNA binding. These results provide mechanistic clues to how HIF signaling can be regulated by different cellular cues.
10.1074/jbc.RA118.005549
[Polarized activation affects iron metabolism in macrophages].
Li Yun-Qin,Liang Li,Gan Zhen-Shun,Tang Xue-You,DU Hua-Hua
Sheng li xue bao : [Acta physiologica Sinica]
The aim of this study was to investigate the effects of polarization program on the ability of macrophages to regulate iron metabolism. M1 and M2 macrophages were propagated in vitro from porcine alveolar macrophages 3D4/2 and polarized by cytokines. The 3D4/2 macrophages were treated with 20 ng/mL interferon gamma (IFN-γ) and 10 ng/mL interleukin-4 (IL-4) combined with 10 ng/mL macrophage colony-stimulating factor (M-CSF) to induce polarization to M1 and M2, respectively. After incubation for 24 h, the expression levels of inflammatory factors and iron-metabolism genes were determined using real-time qPCR, Western bot and immunofluorescence. The M1/M2 macrophages culture media supernatant was collected and used to treat porcine intestinal epithelial cells IPEC-J2. The proliferation ability of IPEC-J2 was detected using CCK-8 assay kit. Following exogenous addition of ammonium ferric citrate (FAC) to M1/M2 macrophages, the phagocytic function of macrophages was detected using fluorescein isothiocyanate-dextran (FITC-dextran) and flow cytometry. The results showed that, compared with control, M1 macrophages had higher mRNA levels of iron storage proteins (ferritin heavy and light polypeptide, i.e. FtH and FtL), hepcidin and lipocalin-2, as well as iron content. Moreover, iron enhanced the ability of M1 macrophages to phagocytize FITC-dextran. There was no significant change in these mRNA expression levels in M2 macrophages, but the mRNA expression levels of ferroportin and transferrin receptor were up-regulated. In addition, the conditioned media supernatant from M2 macrophages promoted cell proliferation of IPEC-J2. These findings indicate that M1 macrophages tend to lock iron in the cell and reduce extracellular iron content, thereby inhibiting the proliferation of extracellular bacteria. While M2 macrophages tend to excrete iron, which contributes to the proliferation of surrounding cells and thus promotes tissue repair.
Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes.
Charlebois Edouard,Pantopoulos Kostas
PloS one
Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP, ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.
10.1371/journal.pone.0253475
Iron Status and Associated Malaria Risk Among African Children.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:It remains unclear whether improving iron status increases malaria risk, and few studies have looked at the effect of host iron status on subsequent malaria infection. We therefore aimed to determine whether a child's iron status influences their subsequent risk of malaria infection in sub-Saharan Africa. METHODS:We assayed iron and inflammatory biomarkers from community-based cohorts of 1309 Kenyan and 1374 Ugandan children aged 0-7 years and conducted prospective surveillance for episodes of malaria. Poisson regression models were fitted to determine the effect of iron status on the incidence rate ratio (IRR) of malaria using longitudinal data covering a period of 6 months. Models were adjusted for age, sex, parasitemia, inflammation, and study site. RESULTS:At baseline, the prevalence of iron deficiency (ID) was 36.9% and 34.6% in Kenyan and Ugandan children, respectively. ID anemia (IDA) affected 23.6% of Kenyan and 17.6% of Ugandan children. Malaria risk was lower in children with ID (IRR, 0.7; 95% confidence interval [CI], 0.6, 0.8; P < .001) and IDA (IRR, 0.7; 95% CI, 0.6, 0.9; P = .006). Low transferrin saturation (<10%) was similarly associated with lower malaria risk (IRR, 0.8; 95% CI, 0.6, 0.9; P = .016). However, variation in hepcidin, soluble transferrin receptors (sTfR), and hemoglobin/anemia was not associated with altered malaria risk. CONCLUSIONS:ID appears to protect against malaria infection in African children when defined using ferritin and transferrin saturation, but not when defined by hepcidin, sTfR, or hemoglobin. Additional research is required to determine causality. CLINICAL TRIALS REGISTRATION:ISRCTN32849447.
10.1093/cid/ciy791
The Interplay between Intracellular Iron Homeostasis and Neuroinflammation in Neurodegenerative Diseases.
Antioxidants (Basel, Switzerland)
Iron is essential for life. Many enzymes require iron for appropriate function. However, dysregulation of intracellular iron homeostasis produces excessive reactive oxygen species (ROS) via the Fenton reaction and causes devastating effects on cells, leading to ferroptosis, an iron-dependent cell death. In order to protect against harmful effects, the intracellular system regulates cellular iron levels through iron regulatory mechanisms, including hepcidin-ferroportin, divalent metal transporter 1 (DMT1)-transferrin, and ferritin-nuclear receptor coactivator 4 (NCOA4). During iron deficiency, DMT1-transferrin and ferritin-NCOA4 systems increase intracellular iron levels via endosomes and ferritinophagy, respectively. In contrast, repleting extracellular iron promotes cellular iron absorption through the hepcidin-ferroportin axis. These processes are regulated by the iron-regulatory protein (IRP)/iron-responsive element (IRE) system and nuclear factor erythroid 2-related factor 2 (Nrf2). Meanwhile, excessive ROS also promotes neuroinflammation by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB forms inflammasomes, inhibits silent information regulator 2-related enzyme 1 (SIRT1), and induces pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β). Furthermore, 4-hydroxy-2,3--nonenal (4-HNE), the end-product of ferroptosis, promotes the inflammatory response by producing amyloid-beta (Aβ) fibrils and neurofibrillary tangles in Alzheimer's disease, and alpha-synuclein aggregation in Parkinson's disease. This interplay shows that intracellular iron homeostasis is vital to maintain inflammatory homeostasis. Here, we review the role of iron homeostasis in inflammation based on recent findings.
10.3390/antiox12040918
Can iron, zinc, copper and selenium status be a prognostic determinant in COVID-19 patients?
Environmental toxicology and pharmacology
In severe COVID-19, the levels of iron (Fe), copper (Cu), zinc (Zn) and selenium (Se), do not only regulate host immune responses, but modify the viral genome, as well. While low serum Fe concentration is an independent risk factor for the increased death rate, Zn controls oxidative stress, synthesis of inflammatory cytokines and viral replication. Therefore, Zn deficiency associates with a worse prognosis. Although Cu exposure inactivates the viral genome and exhibits spike protein dispersal, increase in Cu/Zn due to high serum Cu levels, are correlated with enhanced risk of infections. Se levels are significantly higher in surviving COVID-19 patients. Meanwhile, both Zn and Se suppress the replication of SARS-CoV-2. Since the balance between the deficiency and oversupply of these metals due to a reciprocal relationship, has decisive effect on the prognosis of the SARS-CoV-2 infection, monitoring their concentrations may facilitate improved outcomes for patients suffering from COVID-19.
10.1016/j.etap.2022.103937
The role of iron metabolism in the pathogenesis and treatment of multiple sclerosis.
Frontiers in immunology
Multiple sclerosis is a severe demyelinating disease mediated by cells of the innate and adaptive immune system, especially pathogenic T lymphocytes that produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Although the factors and molecules that drive the genesis of these cells are not completely known, some were discovered and shown to promote the development of such cells, such as dietary factors. In this regard, iron, the most abundant chemical element on Earth, has been implicated in the development of pathogenic T lymphocytes and in MS development its effects on neurons and glia. Therefore, the aim of this paper is to revise the state-of-art regarding the role of iron metabolism in cells of key importance to MS pathophysiology, such as pathogenic CD4 T cells and CNS resident cells. Harnessing the knowledge of iron metabolism may aid in the discovery of new molecular targets and in the development of new drugs that tackle MS and other diseases that share similar pathophysiology.
10.3389/fimmu.2023.1137635
Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis.
Wlazlo Ewa,Mehrad Borna,Morel Laurence,Scindia Yogesh
Frontiers in medicine
Nephritis is a common manifestation of systemic lupus erythematosus, a condition associated with inflammation and iron imbalance. Renal tubules are the work horse of the nephron. They contain a large number of mitochondria that require iron for oxidative phosphorylation, and a tight control of intracellular iron prevents excessive generation of reactive oxygen species. Iron supply to the kidney is dependent on systemic iron availability, which is regulated by the hepcidin-ferroportin axis. Most of the filtered plasma iron is reabsorbed in proximal tubules, a process that is controlled in part by iron regulatory proteins. This review summarizes tubulointerstitial injury in lupus nephritis and current understanding of how renal tubular cells regulate intracellular iron levels, highlighting the role of iron imbalance in the proximal tubules as a driver of tubulointerstitial injury in lupus nephritis. We propose a model based on the dynamic ability of iron to catalyze reactive oxygen species, which can lead to an accumulation of lipid hydroperoxides in proximal tubular epithelial cells. These iron-catalyzed oxidative species can also accentuate protein and autoantibody-induced inflammatory transcription factors leading to matrix, cytokine/chemokine production and immune cell infiltration. This could potentially explain the interplay between increased glomerular permeability and the ensuing tubular injury, tubulointerstitial inflammation and progression to renal failure in LN, and open new avenues of research to develop novel therapies targeting iron metabolism.
10.3389/fmed.2021.643686
[Iron Overload and Immune Inflammatin Are Risk Factors for the Progression of Myelodysplastic Syndrome--Review].
Jia Yan,Chang Chun-Kang
Zhongguo shi yan xue ye xue za zhi
Abstract Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders derived from haematopoietic stem and progenitor cells, also is a common malignant hematological diseases. It is characterized by ineffective bone marrow (BM) haematopoiesis, peripheral blood cytopaenias and a risk of progression to acute myeloid leukaemia. Iron overload is caused from transfusion dependence and ineffective hematopoiesis, which seriously affects the survival and prognosis of MDS patients. The role of immune inflammation in the development of MDS has been widely concerned. Oxidative stress and metabolic disorder caused from iron overload enhance the immune inflammatory response and accelerate the disease progression. Iron overload and immune inflammation are risk factors for the progression of MDS.
10.19746/j.cnki.issn.1009-2137.2020.02.055
When should iron supplementation in dialysis patients be avoided, minimized or withdrawn?
Rostoker Guy
Seminars in dialysis
Parenteral iron is used to restore the body's iron pool before and during erythropoiesis-stimulating agent (ESA) therapy; together these agents form the backbone of anemia management in end-stage renal disease (ESRD) patients undergoing hemodialysis. ESRD patients receiving chronic intravenous iron products, which exceed their blood loss are exposed to an increased risk of positive iron balance. Measurement of the liver iron concentration (LIC) reflects total body iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Recent studies of LIC in hemodialysis patients, measured by quantitative MRI and magnetic susceptometry, have demonstrated a high risk of iron overload in dialysis patients treated with IV iron products at doses advocated by current anemia management guidelines for dialysis patients. Liver iron overload causes increased production of hepcidin and elevated plasma levels, which can activate macrophages of atherosclerotic plaques. This mechanism may explain the results of 3 long-term epidemiological studies which showed the association of excessive IV iron doses with increased risk of cardiovascular morbidity and mortality among hemodialysis patients. A more physiological approach of iron therapy in ESRD is needed. Peritoneal dialysis patients, hemodialysis patients infected with hepatitis C virus, and hemodialysis patients with ferritin above 1000 μg/L without a concomitant inflammatory state, all require specific and cautious iron management. Two recent studies have shown that most hemodialysis patients will benefit from lower maintenance IV iron dosages; their results are applicable to American hemodialysis patients. Novel pharmacometric and economic approaches to iron therapy and anemia management are emerging which are designed to lessen the potential side effects of excessive IV iron while maintaining hemoglobin stability without an increase in ESA dosing.
10.1111/sdi.12732
Incidence of Iron Deficiency and the Role of Intravenous Iron Use in Perioperative Periods.
Țigliș Mirela,Neagu Tiberiu Paul,Niculae Andrei,Lascăr Ioan,Grințescu Ioana Marina
Medicina (Kaunas, Lithuania)
Iron deficiency is a major problem in worldwide populations, being more alarming in surgical patients. In the presence of absolute iron deficiency (depletion of body iron), functional iron deficiency (during intense bone marrow stimulation by endogenous or exogenous factors), or iron sequestration (acute or chronic inflammatory conditions), iron-restricted erythropoiesis can develop. This systemic review was conducted to draw attention to the delicate problem of perioperative anemia, and to provide solutions to optimize the management of anemic surgical patients. Systemic reviews and meta-analyses, clinical studies and trials, case reports and international guidelines were studied, from a database of 50 articles. Bone marrow biopsy, serum ferritin levels, transferrin saturation, the mean corpuscular volume, and mean corpuscular hemoglobin concentration were used in the diagnosis of iron deficiency. There are various intravenous iron formulations, with different pharmacological profiles used for restoring iron. In surgical patients, anemia is an independent risk factor for morbidity and mortality. Therefore, anemia correction should be rapid, with parenteral iron formulations-the oral ones-being inefficient. Various studies showed the safety and efficacy of parenteral iron formulations in correcting hemoglobin levels and decreasing the blood transfusion rate, the overall mortality, the postoperative infections incidence, hospitalization days, and the general costs.
10.3390/medicina56100528
The versatile biochemistry of iron in macrophage effector functions.
Behmoaras Jacques
The FEBS journal
Macrophages are mononuclear phagocytes with remarkable polarization ability that allow them to have tissue-specific functions during development, homeostasis, inflammatory and infectious disease. One particular trophic factor in the tissue environment is iron, which is intimately linked to macrophage effector functions. Macrophages have a well-described role in the control of systemic iron levels, but their activation state is also depending on iron-containing proteins/enzymes. Haemoproteins, dioxygenases and iron-sulphur (Fe-S) enzymes are iron-binding proteins that have bactericidal, metabolic and epigenetic-related functions, essential to shape the context-dependent macrophage polarization. In this review, I describe mainly pro-inflammatory macrophage polarization focussing on the role of iron biochemistry in selected haemoproteins and Fe-S enzymes. I show how iron, as part of haem or Fe-S clusters, participates in the cellular control of pro-inflammatory redox reactions in parallel with its role as enzymatic cofactor. I highlight a possible coordinated regulation of haemoproteins and Fe-S enzymes during classical macrophage activation. Finally, I describe tryptophan and α-ketoglutarate metabolism as two essential effector pathways in macrophages that use diverse iron biochemistry at different enzymatic steps. Through these pathways, I show how iron participates in the regulation of essential metabolites that shape macrophage function.
10.1111/febs.15682
Questions and answers on iron deficiency treatment selection and the use of intravenous iron in routine clinical practice.
Annals of medicine
Iron deficiency is a common cause of morbidity and can arise as a consequence or complication from many diseases. The use of intravenous iron has increased significantly in the last decade, but concerns remain about indications and administration. Modern intravenous iron preparations can facilitate rapid iron repletion in one or two doses, both for absolute iron deficiency and, in the presence of inflammation, functional iron deficiency, where oral iron therapy is ineffective or has not worked. A multidisciplinary team of experts experienced in iron deficiency undertook a consensus review to support healthcare professionals with practical advice on managing iron deficiency in gastrointestinal, renal and cardiac disease, as well as; pregnancy, heavy menstrual bleeding, and surgery. We explain how intravenous iron may work where oral iron has not. We provide context on how and when intravenous iron should be administered, and informed opinion on potential benefits balanced with potential side-effects. We propose how intravenous iron side-effects can be anticipated in terms of what they may be and when they may occur. The aim of this consensus is to provide a practical basis for educating and preparing staff and patients on when and how iron infusions can be administered safely and efficiently. Key messages Iron deficiency treatment selection is driven by several factors, including the presence of inflammation, the time available for iron replenishment, and the anticipated risk of side-effects or intolerance. Intravenous iron preparations are indicated for the treatment of iron deficiency when oral preparations are ineffective or cannot be used, and therefore have applicability in a wide range of clinical contexts, including chronic inflammatory conditions, perioperative settings, and disorders associated with chronic blood loss. Adverse events occurring with intravenous iron can be anticipated according to when they typically occur, which provides a basis for educating and preparing staff and patients on how iron infusions can be administered safely and efficiently.
10.1080/07853890.2020.1867323
Plasma iron controls neutrophil production and function.
Science advances
Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes, or dendritic cells. Neutrophil rebound after anti-Gr-1-induced neutropenia was blunted during hypoferremia but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically stimulated granulopoiesis mediated by granulocyte colony-stimulating factor and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial reactive oxygen species-dependent NETosis associated with chronic inflammation. Notably, antagonizing endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.
10.1126/sciadv.abq5384
Iron Homeostasis in Healthy Kidney and its Role in Acute Kidney Injury.
Scindia PhD Yogesh,Leeds Md Joseph,Swaminathan Md Sundararaman
Seminars in nephrology
Iron is required for key aspects of cellular physiology including mitochondrial function and DNA synthesis and repair. However, free iron is an aberration because of its ability to donate electrons, reduce oxygen, and generate reactive oxygen species. Iron-mediated cell injury or ferroptosis is a central player in the pathogenesis of acute kidney injury. There are several homeostatic proteins and pathways that maintain critical balance in iron homeostasis to allow iron's biologic functions yet avoid ferroptosis. Hepcidin serves as the master regulator of iron homeostasis through its ability to regulate ferroportin-mediated iron export and intracellular H-ferritin levels. Hepcidin is a protective molecule in acute kidney injury. Drugs targeting hepcidin, H-ferritin, and ferroptosis pathways hold great promise to prevent or treat kidney injury. In this review we discuss iron homeostasis under physiological and pathologic conditions and highlight its importance in acute kidney injury.
10.1016/j.semnephrol.2018.10.006
Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study.
Hu Yuanlong,Cheng Xiaomeng,Mao Huaiyu,Chen Xianhai,Cui Yue,Qiu Zhanjun
Frontiers in nutrition
Several observational studies showed a significant association between elevated iron status biomarkers levels and sepsis with the unclear direction of causality. A two-sample bidirectional mendelian randomization (MR) study was designed to identify the causal direction between seven iron status traits and sepsis. Seven iron status traits were studied, including serum iron, ferritin, transferrin saturation, transferrin, hemoglobin, erythrocyte count, and reticulocyte count. MR analysis was first performed to estimate the causal effect of iron status on the risk of sepsis and then performed in the opposite direction. The multiplicative random-effects and fixed-effects inverse-variance weighted, weighted median-based method and MR-Egger were applied. MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran's statistic methods were used to assess heterogeneity and pleiotropy. Genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13-1.29, = 3.16 × 10), ferritin (OR = 1.32, 95%CI = 1.07-1.62, =0.009) and transferrin saturation (OR = 1.14, 95%CI = 1.06-1.23, = 5.43 × 10) were associated with an increased risk of sepsis. No significant causal relationships between sepsis and other four iron status biomarkers were observed. This present bidirectional MR analysis suggested the causal association of the high iron status with sepsis susceptibility, while the reverse causality hypothesis did not hold. The levels of transferrin, hemoglobin, erythrocytes, and reticulocytes were not significantly associated with sepsis. Further studies will be required to confirm the potential clinical value of such a prevention and treatment strategy.
10.3389/fnut.2021.747547
Hepcidin Alleviates LPS-Induced ARDS by Regulating the Ferritin-Mediated Suppression of Ferroptosis.
Shock (Augusta, Ga.)
ABSTRACT:The effects of ferroptosis, an iron-dependent cell death, on acute respiratory distress syndrome (ARDS) remain largely elusive. Hepcidin, encoded by the HAMP gene, affects inflammation, and iron homeostasis. The present study aimed to investigate whether hepcidin protects against ferroptosis in lipopolysaccharide (LPS)-induced ARDS. Our results confirmed that ferroptosis aggravated lung inflammation and damage in LPS-induced ARDS. Hepcidin defended against ferroptosis, with results similar to those of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, hepcidin decreased iron uptake, as determined by Transferrin Receptor 1 (TfR1) expression levels, and increased iron storage, based on ferritin heavy chain (FTH) expression. The effects of hepcidin on the A549 cell line were in line with the in vivo results. In addition, we used si-FTH to knock down FTH expression and found that this suppressed the ability of hepcidin to protect against ferroptosis. Collectively, our data suggest that hepcidin inhibits ferroptosis by increasing FTH expression in LPS-induced ARDS; thus, hepcidin may represent a possible treatment targeting ferroptosis.
10.1097/SHK.0000000000001941
Therapeutic iron restriction in sepsis.
Xia Yanfang,Farah Nizam,Maxan Alexander,Zhou Juan,Lehmann Christian
Medical hypotheses
Sepsis represents the systemic immune response to an infection. Mortality of sepsis slightly decreased over the past years, but due to the growing incidence, the absolute number of deaths still increases and belongs to the three most frequent causes of death worldwide. To date, there is no specific treatment for sepsis available yet. Iron is essential to both human beings and microbes and of great significance in many physiological and biochemical processes. Since iron is involved in the bacterial proliferation and immune dysregulation, we hypothesize that restricting host iron levels by application of iron chelators attenuates bacterial growth and improves the detrimental dysregulation of the systemic immune response in sepsis.
10.1016/j.mehy.2016.01.018
Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study).
Grammer Tanja B,Scharnagl Hubert,Dressel Alexander,Kleber Marcus E,Silbernagel Günther,Pilz Stefan,Tomaschitz Andreas,Koenig Wolfgang,Mueller-Myhsok Bertram,März Winfried,Strnad Pavel
Clinical chemistry
BACKGROUND:Anemia has been shown to be a risk factor for coronary artery disease (CAD) and mortality, whereas the role of iron metabolism remains controversial. METHODS:We analyzed iron metabolism and its associations with cardiovascular death and total mortality in patients undergoing coronary angiography with a median follow-up of 9.9 years. Hemoglobin and iron status were determined in 1480 patients with stable CAD and in 682 individuals in whom significant CAD had been excluded by angiography. RESULTS:Multivariate-adjusted hazard ratios (HRs) for total mortality in the lowest quartiles of iron, transferrin saturation, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were 1.22 (95% CI, 0.96-1.60), 1.23 (95% CI, 0.97-1.56), 1.27 (95% CI, 1.02-1.58), 1.26 (95% CI, 0.97-1.65), and 0.99 (95% CI, 0.79-1.24), respectively, compared to the second or third quartile, which served as reference (1.00) because of a J-shaped association. The corresponding HRs for total mortality in the highest quartiles were 1.44 (95% CI, 1.10-1.87), 1.37 (95% CI, 1.05-1.77), 1.17 (95% CI, 0.92-1.50), 1.76 (95% CI, 1.39-2.22), and 0.83 (95% CI, 0.63-1.09). HRs for cardiovascular death were similar. For hepcidin, the adjusted HRs for total mortality and cardiovascular deaths were 0.62 (95% CI, 0.49-0.78) and 0.70 (95% CI, 0.52-0.90) in the highest quartile compared to the lowest one. CONCLUSIONS:In stable patients undergoing angiography, serum iron, transferrin saturation, sTfR, and ferritin had J-shaped associations and hemoglobin only a marginal association with cardiovascular and total mortality. Hepcidin was continuously and inversely related to mortality.
10.1373/clinchem.2018.297242
SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism.
Stem cell reviews and reports
BACKGROUND:SARS-CoV-2 infection causes acute respiratory distress, which may progress to multiorgan failure and death. Severe COVID-19 disease is accompanied by reduced erythrocyte turnover, low hemoglobin levels along with increased total bilirubin and ferritin serum concentrations. Moreover, expansion of erythroid progenitors in peripheral blood together with hypoxia, anemia, and coagulopathies highly correlates with severity and mortality. We demonstrate that SARS-CoV-2 directly infects erythroid precursor cells, impairs hemoglobin homeostasis and aggravates COVID-19 disease. METHODS:Erythroid precursor cells derived from peripheral CD34+ blood stem cells of healthy donors were infected in vitro with SARS-CoV-2 alpha variant and differentiated into red blood cells (RBCs). Hemoglobin and iron metabolism in hospitalized COVID-19 patients and controls were analyzed in plasma-depleted whole blood samples. Raman trapping spectroscopy rapidly identified diseased cells. RESULTS:RBC precursors express ACE2 receptor and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection. qPCR analysis of differentiated RBCs revealed increased HAMP mRNA expression levels, encoding for hepcidin, which inhibits iron uptake. COVID-19 patients showed impaired hemoglobin biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO, and CO-hemoglobin as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low serum iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity in severely ill COVID-19 patients. CONCLUSIONS:Our data identify RBC precursors as a direct target of SARS-CoV-2 and suggest that SARS-CoV-2 induced dysregulation in hemoglobin- and iron-metabolism contributes to the severe systemic course of COVID-19. This opens the door for new diagnostic and therapeutic strategies.
10.1007/s12015-021-10322-8
[Intravenous Iron Substitution in Chronic Disease - in Whom, When and How?]
Biggar Patrick,Langguth Peter,Krayenbühl Pierre-Alexandre,Brandenburg Vincent
Deutsche medizinische Wochenschrift (1946)
In recent years, considerable progress has been made in the detection and treatment of iron deficiency. The results are also relevant for many specialist areas and, in particular, for patients with chronic inflammatory diseases. In daily practice, iron deficiency is often neither identified nor consistently treated.An iron deficiency can - even before anaemia occurs - reduce the quality of life and influence the course of the underlying disease. In patients with chronic diseases , the iron status should be monitored regularly. Especially, the currently available oral iron preparations for these patients are inefficient, because of the limitated tolerability and, furthermore, because of restricted enteral iron uptake due to inflammation. For this reason, various guidelines recommend intravenous iron substitution.
10.1055/a-0810-8596
Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders.
Ryter Stefan W
International journal of molecular sciences
The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases.
10.3390/ijms22115509
Classic and emergent indicators for the assessment of human iron status.
Restrepo-Gallego Mauricio,Díaz Luis E,Rondó Patrícia H C
Critical reviews in food science and nutrition
Iron deficiency is the leading cause of anemia, a significant global public health problem. Different methods exist for assessing iron nutritional status, including laboratory tests that focus on storage, transportation, and iron functional compartment parameters. Classical markers such as bone marrow, serum iron, ferritin, hemoglobin, erythrocyte parameters, transferrin, transferrin receptors, and zinc protoporphyrin are discussed in this review. Additional parameters calculated from these indicators, including transferrin saturation, ferritin index and Thomas plot, and some emergent parameters such as hepcidin, erythroferrone, and low hemoglobin density are also discussed. There is no a single indicator for assessing iron nutritional status. Therefore, the use of more than one indicator may be the best practice to obtain the correct diagnosis, also considering the influence of inflammation/infection on many of these indicators. The constant validation of the current parameters, the improvement of assessment methods, and the identification of new indicators will be the key to refine the assessment of iron nutritional status and the right choice of treatment for its improvement.
10.1080/10408398.2020.1787326
Effect of hepcidin antagonists on anemia during inflammatory disorders.
Sagar Poonam,Angmo Stanzin,Sandhir Rajat,Rishi Vikas,Yadav Hariom,Singhal Nitin Kumar
Pharmacology & therapeutics
Iron is an essential element for the mammalian body however, its homeostasis must be regulated accurately for appropriate physiological functioning. Alterations in physiological iron levels can lead to moderate to severe iron disorders like chronic and acute iron deficiency (anemia) or iron overload. Hepcidin plays an important role in regulating homeostasis between circulating iron and stored iron in the cells as well as the absorption of dietary iron in the intestine. Inflammatory disorders restrict iron absorption from food due to increased circulating levels of hepcidin. Increased production of hepcidin causes ubiquitination of ferroportin (FPN) leading to its degradation, thereby retaining iron in the spleen, duodenal enterocytes, macrophages, and hepatocytes. Hepcidin inhibitors and antagonists play a consequential role to ameliorate inflammation-associated anemia. Many natural and synthesized compounds, able to reduce hepcidin expression during inflammation have been identified in recent years. Few of which are currently at various phases of clinical trial. This article comprises a comprehensive review of therapeutic approaches for the efficient treatment of anemia associated with inflammation. Many strategies have been developed targeting the hepcidin-FPN axis to rectify iron disorders. Hepcidin modulation with siRNAs, antibodies, chemical compounds, and plant extracts provides new insights for developing advanced therapeutics for iron-related disorders. Hepcidin antagonist's treatment has a high potential to improve iron status in patients with iron disorders, but their clinical success needs further recognition along with the identification and application of new therapeutic approaches.
10.1016/j.pharmthera.2021.107877
Emerging Roles of the Iron Chelators in Inflammation.
International journal of molecular sciences
Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.
10.3390/ijms23147977
Metabolic surgery and iron homeostasis.
Benotti Peter N,Wood G Craig,Still Christopher D,Gerhard Glenn S,Rolston David D,Bistrian Bruce R
Obesity reviews : an official journal of the International Association for the Study of Obesity
Iron deficiency and anaemia after metabolic surgery, potentially modifiable nutritional complications, are becoming an increasing cause for concern as prevalence increases with time and there is limited evidence supporting the effectiveness of the current guidelines for prophylactic oral iron supplementation and treatment for deficiency. Abnormalities in iron nutrition predisposing to deficiency are common in severely obese patients, and the low-grade systemic inflammation, also common to these patients, reduces the effectiveness of oral iron supplementation. The surgical procedures result in alterations of foregut anatomy and physiology, which limit iron absorptive capacity and daily food intake. These alterations and the limited effects of oral iron supplementation explain the high prevalence of postoperative iron deficiency and anaemia. This review outlines current mechanisms concerning the pathogenesis of disordered iron nutrition in patients with severe obesity, current gaps in knowledge, and opportunities for quality improvement.
10.1111/obr.12811
A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.
Communications biology
Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
10.1038/s42003-020-01575-z
A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders.
Yiannikourides Andronicos,Latunde-Dada Gladys O
Medicines (Basel, Switzerland)
Iron is a vital trace element for humans, as it plays a crucial role in oxygen transport, oxidative metabolism, cellular proliferation, and many catalytic reactions. To be beneficial, the amount of iron in the human body needs to be maintained within the ideal range. Iron metabolism is one of the most complex processes involving many organs and tissues, the interaction of which is critical for iron homeostasis. No active mechanism for iron excretion exists. Therefore, the amount of iron absorbed by the intestine is tightly controlled to balance the daily losses. The bone marrow is the prime iron consumer in the body, being the site for erythropoiesis, while the reticuloendothelial system is responsible for iron recycling through erythrocyte phagocytosis. The liver has important synthetic, storing, and regulatory functions in iron homeostasis. Among the numerous proteins involved in iron metabolism, hepcidin is a liver-derived peptide hormone, which is the master regulator of iron metabolism. This hormone acts in many target tissues and regulates systemic iron levels through a negative feedback mechanism. Hepcidin synthesis is controlled by several factors such as iron levels, anaemia, infection, inflammation, and erythropoietic activity. In addition to systemic control, iron balance mechanisms also exist at the cellular level and include the interaction between iron-regulatory proteins and iron-responsive elements. Genetic and acquired diseases of the tissues involved in iron metabolism cause a dysregulation of the iron cycle. Consequently, iron deficiency or excess can result, both of which have detrimental effects on the organism.
10.3390/medicines6030085
Regulation of Iron Homeostasis and Related Diseases.
Li Yikun,Huang Xiali,Wang Jingjing,Huang Ruiling,Wan Dan
Mediators of inflammation
The liver is the organ for iron storage and regulation; it senses circulating iron concentrations in the body through the BMP-SMAD pathway and regulates the iron intake from food and erythrocyte recovery into the bloodstream by secreting hepcidin. Under iron deficiency, hypoxia, and hemorrhage, the liver reduces the expression of hepcidin to ensure the erythropoiesis but increases the excretion of hepcidin during infection and inflammation to reduce the usage of iron by pathogens. Excessive iron causes system iron overload; it accumulates in never system and damages neurocyte leading to neurodegenerative diseases such as Parkinson's syndrome. When some gene mutations affect the perception of iron and iron regulation ability in the liver, then they decrease the expression of hepcidin, causing hereditary diseases such as hereditary hemochromatosis. This review summarizes the source and utilization of iron in the body, the liver regulates systemic iron homeostasis by sensing the circulating iron concentration, and the expression of hepcidin regulated by various signaling pathways, thereby understanding the pathogenesis of iron-related diseases.
10.1155/2020/6062094
Iron homeostasis and disorders revisited in the sepsis.
Liu Qinjie,Wu Jie,Zhang Xufei,Wu Xiuwen,Zhao Yun,Ren Jianan
Free radical biology & medicine
Sepsis is a life-threatening condition caused by a dysregulated host-response to inflammation, although it currently lacks a fully elucidated pathobiology. Iron is a crucial trace element that is essential for fundamental processes in both humans and bacteria. During sepsis, iron metabolism is altered, including increased iron transport and uptake into cells and decreased iron export. The intracellular sequestration of iron limits its availability to circulating pathogens, which serves as a conservative strategy against the pathogens. Although iron retention has been showed to have protective protect effects, an increase in labile iron may cause oxidative injury and cell death (e.g., pyroptosis, ferroptosis) as the condition progresses. Moreover, iron disorders are substantial and correlate with the severity of sepsis. This also suggests that iron may be useful as a diagnostic marker for evaluating the severity and predicting the outcome of the disease. Further knowledge about these disorders could help in evaluating how drugs targeting iron homeostasis can be optimally applied to improve the treatment of patients with sepsis. Here, we present a comprehensive review of recent advances in the understanding of iron metabolism, focusing on the regulatory mechanisms and iron-mediated injury in sepsis.
10.1016/j.freeradbiomed.2021.01.025
The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.
10.1016/j.biopha.2021.111228
Intravenous iron supplementation therapy.
Schaefer Benedikt,Meindl Eva,Wagner Sonja,Tilg Herbert,Zoller Heinz
Molecular aspects of medicine
Intravenous infusions of iron have evolved from a poorly effective and dangerous intervention to a safe cornerstone in the treatment of iron deficiency. Modern iron formulations are composite nanoparticles composed of carbohydrate ferric oxy-hydroxides. Iron dextran, iron derisomaltose (formely known as iron isomaltoside 1000), ferric carboxymaltose, ferrumoxytol, iron sucrose and sodium ferric gluconate can be infused at different doses and allow correction of total iron deficit with single or repeated doses in 1-2 weeks depending on the specific formulation. All iron preparations are associated with a risk of severe infusion reactions. In recent prospective clinical trials, the risk of moderate to severe infusion reactions was comparable among all modern preparations affecting <1% of patients. Hence, intravenous iron therapy is reserved for iron deficiency anemia patients with intolerance or unresponsiveness of oral iron. As per European drug label, intravenous iron may also be preferred when rapid correction of the iron deficit is required. In patients with inflammation, iron-deficiency should also be suspected as anemia cause when transferrin saturation is low because serum ferritin can be spuriously normal. The main treatment target for i.v. iron is an improvement of the quality of life, for which hemoglobin is a surrogate marker. An emerging complication affecting 50-74% of patients treated with ferric carboxymaltose in prospective clinical trials is hypophosphatemia - or more accurately the 6H syndrome (hyperphosphaturic hypophosphatemia triggered by high fibroblast growth factor 23 that causes hypovitaminosis D, hypocalcemia and secondary hyperparathyroidism). These biochemical changes can cause severe and potentially irreversible clinical complications, such a bone pain, osteomalacia and fractures. Individual selection of the appropriate iron therapy and evaluation of treatment response are mandatory to safely deliver improved outcome through intravenous iron therapies.
10.1016/j.mam.2020.100862
The Evaluation of Iron Deficiency and Iron Overload
Deutsches Arzteblatt international
BACKGROUND:In the western world, 10-15% of women of child-bearing age suffer from iron-deficiency anemia. Iron overload due to chronic treatment with blood transfusions or hereditary hemochromatosis is much rarer. METHODS:This review is based on pertinent publications retrieved by a selective search on the pathophysiology, clinical features, and diagnostic evaluation of iron deficiency and iron overload. RESULTS:The main causes of iron deficiency are malnutrition and blood loss. Its differential diagnosis includes iron-refractory iron deficiency anemia (IRIDA), a rare congenital disease in which the hepcidin level is pathologically elevated, as well as the more common anemia of chronic disease (anemia of chronic inflammation), in which increased amounts of hepcidin are formed under the influence of interleukin-6 and enteric iron uptake is blocked as a result. Iron overload comes about through long-term transfusion treatment or a congenital disturbance of iron metabolism (hemochromatosis). Its diagnostic evaluation is based on clinical and laboratory findings, imaging studies, and specific mutation analyses. CONCLUSION:Our improving understanding of the molecular pathophysiology of iron metabolism aids in the evaluation of iron deficiency and iron overload and may in future enable treatment not just with iron supplementation or iron chelation, but also with targeted pharmacological modulation of the hepcidin regulatory system.
10.3238/arztebl.m2021.0290
Ferritin - from iron, through inflammation and autoimmunity, to COVID-19.
Journal of autoimmunity
While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.
10.1016/j.jaut.2021.102778
Effects of Tocilizumab on Inflammation and Iron Metabolism in Critically Ill Patients with COVID-19.
Pharmaceutics
COVID-19 produces cytokine-mediated persistent inflammation and is associated with elevated iron stores and low circulating iron. It is believed that central to the pathophysiological mechanism is interleukin 6 and hepcidin. A state of iron overload, termed hyperferritinemia, and inflammatory anemia take place. Both conditions are linked to a worse result in critically ill patients. Blocking the interleukin 6-hepcidin pathway with Tocilizumab could present favorable outcomes. The aim of this study was to evaluate if Tocilizumab influences survival, the occurrence of sepsis, anemia and transfusions in critically ill patients suffering from COVID-19. This prospective observational study focused on levels of interleukin 6, hepcidin and blood iron parameters in patients treated with Tocilizumab. Data were compared before and after therapy as well as between treated and control groups. Results indicate that there is no difference in terms of survival nor in the rate of anemia or sepsis occurrence. Hepcidin was elevated and anemia ensued after treatment, which could indicate alternative pathways. In conclusion, when the classic interleukin 6-hepcidin pathway is blocked, inflammation seems to use alternative routes. Further understanding of these pathways is required and new pharmacological therapies need to be developed to treat persistent inflammation.
10.3390/pharmaceutics15020646
Inflammatory anemia-associated parameters are related to 28-day mortality in patients with sepsis admitted to the ICU: a preliminary observational study.
Jiang Yi,Jiang Feng-Quan,Kong Fang,An Meng-Meng,Jin Bei-Bei,Cao Da,Gong Ping
Annals of intensive care
BACKGROUND:Anemia is one of the most common complications of sepsis. Sepsis-related anemia is associated mainly with inflammation. We aimed to observe the changes in the inflammatory anemia-associated parameters of patients with sepsis in the early stage of intensive care unit (ICU) admission and to evaluate their association with 28-day mortality. METHODS:A total of 198 patients with sepsis were divided into survivor (n = 110) and non-survivor (n = 88) groups on the basis of 28-day survival. Healthy volunteers (n = 20) were enrolled as a control group. Plasma levels of iron, ferritin, erythropoietin (EPO), soluble transferrin receptor (sTfR), hepcidin, interleukin-6 (IL-6), hemoglobin and the red blood cell distribution width (RDW) were measured on days 1, 3 and 7 of ICU admission. Clinical data and laboratory findings were collected, and the Sequential Organ Failure Assessment (SOFA) score was calculated. RESULTS:Patients with sepsis showed significant decreases in hemoglobin, plasma iron and sTfR/log ferritin and significant increases in plasma EPO, sTfR, hepcidin, ferritin and IL-6 on days 1, 3 and 7 of ICU admission compared with healthy volunteers. Hemoglobin was correlated negatively with plasma IL-6 and hepcidin. In patients with sepsis, non-survivors had significantly lower plasma iron, EPO and sTfR/log ferritin, but higher plasma hepcidin, ferritin and IL-6 than survivors on days 1, 3 and 7 of ICU admission. Plasma EPO, hepcidin, ferritin, IL-6, sTfR/log ferritin, the RDW and SOFA score were associated significantly with 28-day mortality but to a varying extent. In particular, in predicting 28-day mortality, plasma hepcidin had an area under the receiver operating curve of 0.808 and 87.3% specificity, which was the highest among the inflammatory anemia-associated parameters tested. CONCLUSIONS:Inflammatory anemia-associated parameters changed significantly in patients with sepsis in the first week of ICU admission. Plasma EPO, hepcidin, ferritin, IL-6, sTfR/log ferritin, the RDW and SOFA score were associated significantly with 28-day mortality. Plasma hepcidin might have a superior predictive value, with high specificity, compared with other inflammatory anemia-associated parameters for 28-day mortality of sepsis patients in the ICU.
10.1186/s13613-019-0542-7
The use of inflammatory markers as a diagnostic and prognostic approach in neonatal calves with septicaemia.
Kirbas Akın,Kandemir Fatih Mehmet,Celebi Demet,Hanedan Basak,Timurkan Mehmet Ozkan
Acta veterinaria Hungarica
The objective of this study was to evaluate the usefulness of inflammatory markers as a diagnostic and prognostic approach in neonatal calves with septicaemia. The study material consisted of 13 neonatal calves with septicaemia (septicaemic calves, SC) and ten healthy neonatal calves (control calves, CC). Blood samples were collected for biochemical, haematological and microbiological analyses. In addition, faecal samples were collected for microbiological and virological analyses. Three of neonatal calves with septicaemia were positive for ( O157 serotype) by microbiological examination, but all neonatal calves with septicaemia were negative for rota- and coronaviruses. By haematological examination, there were no significant differences between SC and CC for white blood cell (WBC) and neutrophil (NEU) counts (P > 0.05). NEU counts were higher on day 0 than on day 15 in SC (P < 0.05). Red blood cell (RBC) counts and packed cell volume (PCV) values were higher on day 0 in the SC than in the CC (P < 0.05). By biochemical analyses, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), procalcitonin (PCT), haptoglobin (Hp), and fibrinogen (Fb) concentrations were higher on day 0 in the SC than in the CC (P < 0.05). After treatment (on day 15), the serum IL-6, PCT, Hp, and Fb concentrations were significantly decreased in the SC compared to the CC (P < 0.05). The serum iron (Fe) concentrations were lower on day 0 in the SC than in the CC (P < 0.05), and were higher on day 15 than on day 0 in the SC (P < 0.05). The study revealed that inflammatory markers could be used for determining the diagnosis and prognosis in neonatal calves with septicaemia.
10.1556/004.2019.037
Serum Ferritin Predicts Neither Organ Dysfunction Nor Mortality in Pediatric Sepsis Due to Tropical Infections.
Williams Vijai,Menon Nisha,Bhatia Prateek,Biswal Manisha,Sreedharanunni Sreejesh,Rawat Amit,Jayashree Muralidharan,Nallasamy Karthi
Frontiers in pediatrics
To evaluate serial ferritin levels measured in the initial 72 h of admission as a biomarker for new and progressive multi organ dysfunction syndrome (NPMODS) and mortality (unfavorable outcomes) in critically ill children with sepsis due to tropical infections. In this prospective observational study from a tertiary care teaching hospital in India, children 3 month to 12 years with a diagnosis of acute febrile illness and any two features suggesting tropical infections [cytopenia (platelet count <1,00,000/cu.mm, total leucocyte count <4,000/cu.mm), hepatomegaly and/or splenomegaly, lymphadenopathy, systemic signs (rash, edema), respiratory distress, and encephalopathy not accounted by localized infection] were eligible for inclusion. Children with known or suspected disorder of iron metabolism were excluded. Primary outcome was to determine the association of serial ferritin levels with mortality and NPMODS. Secondary outcomes included estimation of the prevalence of hyperferritinemia and comparison of risk prediction scores with serial ferritin measurement in predicting unfavorable outcomes. In the 202 children enrolled, diagnosis could be established in 133 (65.8%) children. Scrub typhus and dengue were the most common infections. Median (IQR) ferritin measured at admission ( = 183) and on day 3 ( = 120) of hospital stay were 798 (378, 3,205) μg/L and 429 (213,680) μg/L, respectively. Majority ( = 180, 89.1%) had MODS at admission defined as per International pediatric sepsis consensus conference. NPMODS occurred in 47 (23.3%) children of whom 37 (18.3%) died. Children with three or less organ dysfunctions had lower mortality. Neither admission ferritin values nor the percentage change over 72 h was different between children with favorable and unfavorable outcomes. Pediatric Risk of Mortality (PRISM-III) and daily Pediatric Logistic Organ Dysfunction score (dPELOD2 score) were significantly different in those with unfavorable outcomes. Admission ferritin levels and percentage change in 72 h had poor discriminatory power for mortality with AUC of 0.53 (0.53, 0.67) and 0.50 (0.50, 0.64), respectively. dPELOD2 had the best discriminatory power for mortality with AUC of 0.89 (0.89, 0.95). Serial ferritin estimation predicted neither organ dysfunction nor mortality in pediatric sepsis with tropical infections. dPELOD-2 and PRISM-III predicted unfavorable outcomes better than ferritin. The current diagnostic criteria for MODS overestimated organ dysfunctions in tropical infections and hence may need modification with further validation in this epidemiological cohort.
10.3389/fped.2020.607673
The effect of red blood cell transfusion on iron metabolism in critically ill patients.
Boshuizen Margit,van Hezel Maike E,van Manen Lisa,Straat Marleen,Somsen Yvemarie B O,Spoelstra-de Man Angelique M E,Blumberg Neil,van Bruggen Robin,Juffermans Nicole P
Transfusion
BACKGROUND:Anemia of inflammation (AI) has a high prevalence in critically ill patients. In AI, iron metabolism is altered, as high levels of inflammation-induced hepcidin reduce the amount of iron available for erythropoiesis. AI is treated with red blood cell (RBC) transfusions. The effect of RBC transfusion on iron metabolism during inflammatory processes in adults is unknown. We investigated the effect of RBC transfusion on iron metabolism in critically ill patients. METHODS:In a prospective cohort study in 61 critically ill patients who received 1 RBC unit, levels of iron variables were determined before, directly after, and 24 hours after transfusion in septic and nonseptic patients. RESULTS:Serum iron levels were low and increased after transfusion (p = 0.02). However, RBC transfusion had no effect on transferrin saturation (p = 0.14) and ferritin levels (p = 0.74). Hepcidin levels increased after RBC transfusion (p = 0.01), while interleukin-6 levels decreased (p = 0.03). In septic patients, RBC transfusion induced a decrease in haptoglobin levels compared to baseline, which did not occur in nonseptic patients (p = 0.01). The effect of RBC transfusion on other iron variables did not differ between septic and nonseptic patients. CONCLUSION:Transfusion of a RBC unit transiently increases serum iron levels in intensive care unit patients. The increase in hepcidin levels after transfusion can further decrease iron release from intracellular storage making it available for erythropoiesis. RBC transfusion is associated with a decrease in haptoglobin levels in septic compared to nonseptic patients, but did not affect other markers of hemolysis.
10.1111/trf.15127
Serum Hepcidin-25 Levels Reflect the Presence of Bacteremia in Patients with Systemic Inflammatory Response Syndrome.
Wakakuri Hiroaki,Hyodo Hideya,Ohara Toshihiko,Yasutake Masahiro
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi
BACKGROUND:Hepcidin-25 is a key regulatory hormone of iron homeostasis in humans, and its production is greatly upregulated by inflammation as well as iron overload. The aim of this study was to investigate the pathophysiological role of hepcidin-25 in patients with systemic inflammatory response syndrome (SIRS). METHODS:We enrolled 113 consecutive patients (aged 63.4±21, 50 men, 63 women), with 2 or more SIRS criteria, who were admitted to our department of general medicine between August 1, 2015 and August 31, 2017. We measured complete blood cell count and serum levels of hepcidin-25, iron, iron-binding capacity, ferritin, blood urea nitrogen, creatinine, albumin, and C-reactive protein (CRP) on admission. The patients were divided into 3 group: a bacteremia group (27 patients), a culture-negative bacterial infection group (60 patients), and a non-bacterial infection group (26 patients). RESULTS:Hepcidin-25 levels were found to be comparable in terms of SIRS criteria: 162 [2.8-579], 193 [2.24-409], and 180 [89.2-421] ng/mL in patients with 2, 3, and 4 criteria, respectively (P=0.533). However, hepcidin-25 levels were significantly higher in the bacteremia group (209 [56.7-579] ng/mL) than in either the culture-negative bacterial infection group (168 [2.24-418] ng/mL) or the non-bacterial infection group (142 [2.8-409] ng/mL). A significant positive correlation between hepcidin-25 and CRP levels was noted in the bacteremia group (r=0.528, P=0.005) and non-bacterial infection group (r=0.648, P<0.001). Moreover, iron and ferritin levels were significantly lower in the bacteremia group than in the non-bacterial infection group. CONCLUSIONS:Our findings suggest that hepcidin-25 level may reflect the presence of bacteremia as well as the severity of inflammation in patients with SIRS.
10.1272/jnms.JNMS.2019_86-204
Effects of continuous renal replacement therapy on inflammation-related anemia, iron metabolism and prognosis in sepsis patients with acute kidney injury.
World journal of emergency medicine
BACKGROUND:This study aims to evaluate the effect of continuous renal replacement therapy (CRRT) on inflammation-related anemia, iron metabolism, and the prognosis in sepsis patients with acute kidney injury (AKI). METHODS:Sepsis patients with AKI were prospectively enrolled and randomized into the CRRT and control groups. The clinical and laboratory data on days 1, 3 and 7 after intensive care unit (ICU) admission were collected. The serum interleukin (IL)-6, hepcidin, erythropoietin, ferritin, and soluble transferrin receptor (sTfR) were determined by enzyme-linked immunosorbent assay. The Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were recorded. Data were analyzed using Pearson's Chi-square test or Fisher's exact test (categorical variables), and Mann-Whitney -test or t-test (continuous variables). RESULTS:The hemoglobin and serum erythropoietin levels did not significantly differ between the CRRT and control groups though gradually decreased within the first week of ICU admission. On days 3 and 7, the serum IL-6, hepcidin, ferritin, and red blood cell distribution width significantly decreased in the CRRT group compared to the control group (all <0.05). On day 7, the serum iron was significantly elevated in the CRRT group compared to the control group (<0.05). However, the serum sTfR did not significantly differ between the groups over time. In addition, the SOFA scores were significantly lower in the CRRT group compared to the control group on day 7. The 28-day mortality did not significantly differ between the control and CRRT groups (38.0% vs. 28.2%, =0.332) . CONCLUSION:CRRT might have beneficial effects on the improvement in inflammation-related iron metabolism and disease severity during the first week of ICU admission but not anemia and 28-day mortality in sepsis patients with AKI.
10.5847/wjem.j.1920-8642.2023.052
Caspse-11-GSDMD pathway is required for serum ferritin secretion in sepsis.
Wang Dan,Yu Songlin,Zhang Yening,Huang Lingmin,Luo Ruiheng,Tang Yiting,Zhao Kai,Lu Ben
Clinical immunology (Orlando, Fla.)
Ferritin is the major iron storage molecule of vertebrates, which can be detected in serum under numerous conditions, including inflammatory, neurodegenerative, and malignant diseases. Given this character, serum ferritin is frequently used as a biomarker in clinical settings. How the ferritin secreted to the serum has attracted much attention. Although some studies have found ferritin was mediated via the endoplasmic reticulum (ER)-Golgi secretion pathway or secretory lysosomes trafficking pathway under normal conditions, the secretion pathway of ferritin under pathological conditions, especially in sepsis is not very clear. In this report, we adopt a murine sepsis model to study the secretion pathway of ferritin in sepsis. We demonstrated caspase-11-GSDMD pathway and associated pyroptosis are required for secretion of ferritin in vitro and in vivo in sepsis. Moreover, our work connects pyroptosis to serum ferritin secretion and suggests a passive release process of ferritin, enhancing our understanding of the mechanism of ferritin secretion.
10.1016/j.clim.2018.11.005
Linkage of alterations in systemic iron homeostasis to patients' outcome in sepsis: a prospective study.
Journal of intensive care
BACKGROUND:Sepsis, a dysregulated host response following infection, is associated with massive immune activation and high mortality rates. There is still a need to define further risk factors and laboratory parameters predicting the clinical course. Iron metabolism is regulated by both, the body's iron status and the immune response. Iron itself is required for erythropoiesis but also for many cellular and metabolic functions. Moreover, iron availability is a critical determinant in infections because it is an essential nutrient for most microbes but also impacts on immune function and intravascular oxidative stress. Herein, we used a prospective study design to investigate the putative impact of serum iron parameters on the outcome of sepsis. METHODS:Serum markers of iron metabolism were measured in a prospective cohort of 61 patients (37 males, 24 females) with sepsis defined by Sepsis-3 criteria in a medical intensive care unit (ICU) and compared between survivors and non-survivors. Regulation of iron parameters in patients stratified by focus of infection and co-medication as well as association of the markers with sepsis severity scores and survival were investigated with linear and logistic regression corrected for sex and age effects. RESULTS:Positive correlations of increased serum iron and ferritin concentrations upon ICU admission with the severity of organ failure (SOFA score) and with mortality were observed. Moreover, high TF-Sat, elevated ferritin and serum iron levels and low transferrin concentrations were associated with reduced survival. A logistic regression model consisting of SOFA and transferrin saturation (SOFA-TF-Sat) had the best predictive power for survival in septic ICU patients. Of note, administration of blood transfusions prior to ICU admission resulted in increased TF-Sat and reduced survival of septic patients. CONCLUSIONS:Our study could show an important impact of serum iron parameters on the outcome of sepsis. Furthermore, we identified transferrin saturation as a stand-alone predictor of sepsis survival and as a parameter of iron metabolism which may in a combined model improve the prediction power of the SOFA score. TRIAL REGISTRATION:The study was carried out in accordance with the recommendations of the Declaration of Helsinki on biomedical research. The study was approved by the institutional ethics review board of the Medical University Innsbruck (study AN2013-0006).
10.1186/s40560-020-00495-8
Persistent inflammation and anemia among critically ill septic patients.
Loftus Tyler J,Mira Juan C,Stortz Julie A,Ozrazgat-Baslanti Tezcan,Ghita Gabriella L,Wang Zhongkai,Brumback Babette A,Ungaro Ricardo F,Bihorac Azra,Leeuwenburgh Christiaan,Moore Frederick A,Moldawer Lyle L,Brakenridge Scott C,Efron Philip A,Mohr Alicia M
The journal of trauma and acute care surgery
BACKGROUND:Associations among inflammatory cytokines, erythropoietin (EPO), and anemia in critically ill septic patients remain unclear. This study tested the hypothesis that elevated inflammatory cytokines and decreased EPO would be associated with iron-restricted anemia while accounting for operative blood loss, phlebotomy blood loss, and red blood cell (RBC) transfusion volume. METHODS:Prospective observational cohort study of 42 critically ill septic patients was conducted. Hemoglobin (Hb) at sepsis onset and hospital discharge were used to calculate ΔHb. Operative blood loss, phlebotomy blood loss, and RBC transfusion volume were used to calculate adjusted ΔHb (AdjΔHb) assuming that 300 mL RBC is equal to 1 g/dL Hb. Patients with AdjΔHb of greater than 0 (positive AdjΔHb, n = 18) were compared with patients with AdjΔHb of less than or equal to 0 (negative AdjΔHb, n = 24). RESULTS:Plasma tumor necrosis factor α, granulocyte colony-stimulating factor, interleukin (IL)-6, IL-8, EPO, erythrocyte mean corpuscular volume, and serum transferrin receptor were measured on days 0, 1, 4, 7, and 14. Patients with negative AdjΔHb had significantly higher day 14 levels of IL-6 (37.4 vs. 15.2 pg/mL, p < 0.05), IL-8 (39.1 vs. 18.2 pg/mL, p = 0.01), and granulocyte colony-stimulating factor (101.3 vs. 60.5 pg/mL, p = 0.01), but not EPO. On linear regression analysis, lower AdjΔHb was associated with higher day 14 levels of IL-6 (r = 0.22, p < 0.01), IL-8 (r = 0.10, p = 0.04), stromal cell-derived factor 1 (r = 0.14, p = 0.02), and tumor necrosis factor α (r = 0.13, p = 0.02), but not EPO. Patients with negative AdjΔHb had significantly lower mean corpuscular volume on days 4 (89.6 vs. 93.2 fL/cell, p = 0.04), 7 (92.3 vs. 94.9 fL/cell, p = 0.04), and 14 (92.1 vs. 96.0 fL/cell, p = 0.03) but similar serum transferrin receptor levels. CONCLUSION:Persistent elevation of inflammatory cytokines was associated with iron-restricted anemia among critically ill septic patients, occurring in the absence of systemic iron deficiency, independent of endogenous EPO. LEVEL OF EVIDENCE:Prognostic study, level II.
10.1097/TA.0000000000002147
Effect of Sepsis on Iron Parameters in a Population with High Prevalence of Malnutrition and Iron Deficiency: A Cross-Sectional Case-Control Pilot Study.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion
There is lack of data on iron metabolism in critically ill sepsis children from population with high prevalence of iron deficiency (ID). The study was designed to study impact of sepsis on iron parameters in children with ID. Sepsis patients (age 6-59 months) and their apparently healthy sibling/cousin as controls were enrolled in this case-control pilot study. Serum iron, TIBC, transferrin saturation, ferritin and sTfR were measured in the two groups. sTfR-Ferritin index was calculated. Patients ( = 134) were significantly underweight compared to controls ( = 54) (WAZ score < - 2; 58% vs. 28%; < 0.001). Serum iron and sTfR (mg/L) were lower [71.5 (51.0, 115.0) vs. 87.0 (64.5, 130.5), = 0.068; 3.1 (2.1, 4.5) vs. 3.5 (2.8, 4.8), = 0.026 respectively] while serum ferritin was higher [229 (94, 484.5) vs. 22 (9.2, 51); < 0.001] in patients compared to controls. sTfR-Ferritin index was lower in patients [1.3 (0.8, 2.3) vs. 2.5 (1.8, 4.5); < 0.001]. ROC AUC (patients vs. controls) were 0.89 (95% CI 0.83-0.95) and 0.76 (95% CI 0.68-0.85) for ferritin and sTfR-ferritin index respectively. Survivors and non-survivors were similar in terms of iron parameters. Sepsis-induced alterations in iron parameters among ID children are complex. Qualitatively it is similar (with quantitative differences) to non-ID adult population. Lack of correlation of iron parameters with mortality may be due to ID-associated immune dysfunction.
10.1007/s12288-020-01393-7
Serum iron concentration in cattle with endotoxaemia.
Tsukano Kenji,Shimamori Toshio,Suzuki Kazuyuki
Acta veterinaria Hungarica
The objective of this study was to examine whether serum iron (Fe) concentration is useful as a prognostic biomarker for cows with acute coliform mastitis (ACM). Our study was composed of determining the reproducibility of serum Fe concentration as a prognostic criterion in cows with ACM (Study 1) and clarifying the sequential changes in serum Fe concentration in cattle that received endotoxin (Study 2). Seventy-seven cows with (n = 47) or without (n = 30) ACM were enrolled in Study 1. The proposed diagnostic cut-off value of serum Fe concentration indicating a poor prognosis of ACM based on the analysis of the receiver operating characteristic curves was < 31.5 µg/dL. Ten young cattle aged 176.8 ± 23.7 days were enrolled in Study 2. Five young cattle received endotoxin (LPS group) and the remaining five received physiological saline (control group). Blood collections were carried out before endotoxin challenge (pre), and 0.5, 1, 2, 4, 8, 12, 24, and 48 h after the challenge. As a result, a significant decrease in serum Fe concentration was not observed until 24 h after endotoxin challenge. Because in cows with clinical ACM it is difficult to know the time course after infection, the alteration in serum Fe concentrations alone may be an insufficient prognostic criterion.
10.1556/004.2020.00016
Evaluation of perturbed iron-homeostasis in a prospective cohort of patients with COVID-19.
Wellcome open research
Marked reductions in serum iron concentrations are commonly induced during the acute phase of infection. This phenomenon, termed hypoferremia of inflammation, leads to inflammatory anemia, but could also have broader pathophysiological implications. In patients with coronavirus disease 2019 (COVID-19), hypoferremia is associated with disease severity and poorer outcomes, although there are few reported cohorts. In this study, we leverage a well characterised prospective cohort of hospitalised COVID-19 patients and perform a set of analyses focussing on iron and related biomarkers and both acute severity of COVID-19 and longer-term symptomatology. We observed no associations between acute serum iron and long-term outcomes (including fatigue, breathlessness or quality of life); however, lower haemoglobin was associated with poorer quality of life. We also quantified iron homeostasis associated parameters, demonstrating that among 50 circulating mediators of inflammation IL-6 concentrations were strongly associated with serum iron, consistent with its central role in inflammatory control of iron homeostasis. Surprisingly, we observed no association between serum hepcidin and serum iron concentrations. We also observed elevated erythroferrone concentrations in COVID-19 patients with anaemia of inflammation. These results enhance our understanding of the regulation and pathophysiological consequences of disturbed iron homeostasis during SARS-CoV-2 infection.
10.12688/wellcomeopenres.17904.1
Lactoferrin in Aseptic and Septic Inflammation.
Lepanto Maria Stefania,Rosa Luigi,Paesano Rosalba,Valenti Piera,Cutone Antimo
Molecules (Basel, Switzerland)
Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer's disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in infection, cystic fibrosis and inflammatory bowel disease, Lf, besides the anti-inflammatory activity, exerts a significant activity against bacterial adhesion, invasion and colonization. Lastly, a critical analysis of literature in vitro data reporting contradictory results on the Lf role in inflammatory processes, ranging from pro- to anti-inflammatory activity, highlighted that they depend on cell models, cell metabolic status, stimulatory or infecting agents as well as on Lf iron saturation degree, integrity and purity.
10.3390/molecules24071323
Serum trace element and heavy metal levels in patients with sepsis.
Akkaş İdris,Ince Nevin,Sungur Mehmet Ali
The aging male : the official journal of the International Society for the Study of the Aging Male
Sepsis is defined as a life-threatening organ dysfunction syndrome, which occurs when the body's immune response to infection is impaired. The aim of the present study was to investigate serum Iron, Copper, Zinco, Cobalt, Chromium, Selenium, Vanadium, Nickel, Cadmium, and Aliminium levels in patients with sepsis. This prospective and observational study was conducted at a tertiary care university hospital of Turkey from 2015 to 2016, and comprised patients with sepsis. Serum concentrations of 10 elements were analyzed using inductively coupled plasma mass spectrometry. Analyses were performed at the laboratory of Düzce University Scientific and Technological Research Application and Research Center. A total of 87 participants (52 men, 35 women; average age, 74.11 ± 14.26) were enrolled. When evaluated in terms of trace elements, a significant difference was noted between the sepsis and control groups in terms of the levels of the five elements. Chromium, Iron, Nickel, Copper, and Cadmium levels were significantly higher in the sepsis group. Our study indicated in particular, Iron, Copper, Chromium, Nickel, and Cadmium levels were elevated in patients with sepsis.
10.1080/13685538.2020.1740200
Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.
Science advances
Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.
10.1126/sciadv.abf0466
Increasing serum iron levels and their role in the risk of infectious diseases: a Mendelian randomization approach.
International journal of epidemiology
OBJECTIVES:Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. METHODS:As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). RESULTS:Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05). CONCLUSION:Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.
10.1093/ije/dyad010