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Erythroferrone structure, function, and physiology: Iron homeostasis and beyond.
Srole, DN, Ganz, T
Journal of cellular physiology. 2021;(7):4888-4901
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Abstract
Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.
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Biology of the iron efflux transporter, ferroportin.
Rishi, G, Subramaniam, VN
Advances in protein chemistry and structural biology. 2021;:1-16
Abstract
Iron, the most common metal in the earth, is also an essential component for almost all living organisms. While these organisms require iron for many biological processes, too much or too little iron itself poses many issues; this is most easily recognized in human beings. The control of body iron levels is thus an important metabolic process which is regulated essentially by controlling the expression, activity and levels of the iron transporter ferroportin. Ferroportin is the only known iron exporter. The function and activity of ferroportin is influenced by its interaction with the iron-regulatory peptide hepcidin, which itself is regulated by many factors. Here we review the current state of understanding of the mechanisms that regulate ferroportin and its function.
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Importance of Hepcidin in the Etiopathogenesis of Anemia in Inflammatory Bowel Disease.
Karaskova, E, Pospisilova, D, Velganova-Veghova, M, Geryk, M, Volejnikova, J, Holub, D, Hajduch, M
Digestive diseases and sciences. 2021;(10):3263-3269
Abstract
Anemia is the most common extraintestinal systemic complication of inflammatory bowel disease. Iron deficiency anemia and anemia of chronic disease are among the most frequent types. Intestinal iron absorption is controlled by the activity of ferroportin. Cells with high expression of ferroportin include enterocytes, and also macrophages and hepatocytes. Iron homeostasis is controlled by the hepcidin-ferroportin axis. Hepcidin is a central regulator of iron metabolism and can also serve as a marker of systemic inflammation. During systemic inflammatory response, the synthesis of hepcidin increases, and hepcidin binds to ferroportin and inhibits its activity. Thus, iron is not absorbed from the bowel into the circulation and also remains sequestered in macrophages. Conversely, hepcidin synthesis is suppressed during conditions requiring increased iron intake for enhanced erythropoiesis, such as iron deficiency anemia or hypoxia. Here, ferroportin is not blocked, and iron is actively absorbed into the bloodstream and also released from the stores. Production of hepcidin is influenced by the status of total body iron stores, systemic inflammatory activity and erythropoietic activity. Oral iron therapy is limited in inflammatory bowel diseases due to ongoing gastrointestinal inflammation. It is less effective and may worsen the underlying disease. Therefore, the choice between oral and parenteral iron therapy must be made with caution. Oral iron would be ineffective at high hepcidin levels due to concurrent ferroportin blockage. Contrarily, low levels of hepcidin indicate that oral iron therapy should be successful. An understanding of hepcidin can help in understanding the body's reaction to iron depletion during the inflammatory process.
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The role of iron in viral infections.
Schmidt, SM
Frontiers in bioscience (Landmark edition). 2020;(5):893-911
Abstract
Crucial cellular processes such as DNA synthesis and the generation of ATP require iron. Viruses depend on iron in order to efficiently replicate within living host cells. Some viruses selectively infect iron - acquiring cells or influence the cellular iron metabolism via Human hemochromatosis protein (HFE) or hepcidin. During infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) iron overload is associated with poor prognosis for the patient and enhanced progression of the disease. Recent findings still lack to fully describe the viral interaction with the host iron metabolism during infection. This review summarizes the current knowledge of the viral regulation on the host cell iron metabolism in order to discuss the therapeutic option of iron chelation as a potential and beneficial adjuvant in antiviral therapy.
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How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children.
Abuga, KM, Muriuki, JM, Williams, TN, Atkinson, SH
International journal of molecular sciences. 2020;(18)
Abstract
Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.
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Hepcidin as a Prospective Individualized Biomarker for Individuals at Risk of Low Energy Availability.
Badenhorst, CE, Black, KE, O'Brien, WJ
International journal of sport nutrition and exercise metabolism. 2019;(6):671-681
Abstract
Hepcidin, a peptide hormone with an acknowledged evolutionary function in iron homeostasis, was discovered at the turn of the 21st century. Since then, the implications of increased hepcidin activity have been investigated as a potential advocate for the increased risk of iron deficiency in various health settings. Such implications are particularly relevant in the sporting community where peaks in hepcidin postexercise (∼3-6 hr) are suggested to reduce iron absorption and recycling, and contribute to the development of exercise-induced iron deficiency in athletes. Over the last decade, hepcidin research in sport has focused on acute and chronic hepcidin activity following single and repeated training blocks. This research has led to investigations examining possible methods to attenuate postexercise hepcidin expression through dietary interventions. The majority of macronutrient dietary interventions have focused on manipulating the carbohydrate content of the diet in an attempt to determine the health of athletes adopting the low-carbohydrate or ketogenic diets, a practice that is a growing trend among endurance athletes. During the process of these macronutrient dietary intervention studies, an observable coincidence of increased cumulative hepcidin activity to low energy availability has emerged. Therefore, this review aims to summarize the existing literature on nutritional interventions on hepcidin activity, thus, highlighting the link of hepcidin to energy availability, while also making a case for the use of hepcidin as an individualized biomarker for low energy availability in males and females.
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Disorders of Iron Metabolism: New Diagnostic and Treatment Approaches to Iron Deficiency.
Powers, JM, Buchanan, GR
Hematology/oncology clinics of North America. 2019;(3):393-408
Abstract
Iron deficiency anemia is the leading cause of anemia worldwide and affects many young children and adolescent girls in the United States. Its signs and symptoms are subtle despite significant clinical effects. Iron deficiency anemia is diagnosed clinically by the presence of risk factors and microcytic anemia. Improvement following a trial of oral iron therapy is confirmative. An array of iron laboratory tests is available with variable indications. Clinical trial and iron absorption data support a shift to lower-dose oral iron therapy. Intravenous iron should be considered in children who fail oral iron or who have more complex disorders.
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Therapeutic Opportunities for Hepcidin in Acute Care Medicine.
Chawla, LS, Beers-Mulroy, B, Tidmarsh, GF
Critical care clinics. 2019;(2):357-374
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Abstract
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.
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Improving Erythropoiesis Stimulating Agent Hyporesponsiveness in Hemodialysis Patients: The Role of Hepcidin and Hemodiafiltration Online.
Rosati, A, Ravaglia, F, Panichi, V
Blood purification. 2018;(1-3):139-146
Abstract
Hyporesponsiveness to erythropoietin stimulating agents (ESAs) is a condition associated with increased mortality. Even after identifying the condition, the causes are difficult to treat and only partially reversible in end-stage renal disease patients. Thus, the role of more recent hemodialysis (HD) techniques in improving such conditions is an emerging issue. However, major randomized clinical trials have not confirmed the results of smaller observational studies in which online hemodiafiltration has shown some efficacy in improving patients' response to ESAs. In our interpretation, these findings are not in contrast, but they can be explained by a better understanding of the interactions between HD and ESAs on iron mobilization, first of all through the role of hepcidin. The kinetics of hepcidin removal through HD combined with the action of selected ESAs may help the clinician in prescribing the best association between HD treatment and ESAs to overcome hyporesponsiveness.
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Inflammation, Hemolysis, and Erythropoiesis Lead to Competitive Regulation of Hepcidin and Possibly Systemic Iron Status in Sickle Cell Disease.
Ginzburg, YZ, Glassberg, J
EBioMedicine. 2018;:8-9