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Nature Reviews. Cancer Jul 2022Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years,... (Review)
Review
Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.
Topics: Apoptosis; Cell Death; Ferroptosis; Humans; Iron; Neoplasms
PubMed: 35338310
DOI: 10.1038/s41568-022-00459-0 -
Acta Haematologica 2019As the adverse effects of iron deficiency are better recognized, the use of oral and intravenous iron has increased dramatically. Oral iron is often poorly tolerated,... (Review)
Review
As the adverse effects of iron deficiency are better recognized, the use of oral and intravenous iron has increased dramatically. Oral iron is often poorly tolerated, with up to 70% or more of patients noting gastrointestinal issues; this may affect adherence to therapy. In addition, many patients will not respond to oral iron due to their underlying illness. Intravenous iron is being used more frequently to replete iron stores. True anaphylaxis is very rare, but complement-mediated infusion reactions may be seen in up to 1 in every 200 patients. Previous concerns about intravenous iron increasing the risk of infection or cardiovascular disease are unfounded.
Topics: Administration, Intravenous; Administration, Oral; Anemia, Iron-Deficiency; Cardiovascular Diseases; Humans; Hypophosphatemia; Iron; Risk Factors
PubMed: 30970354
DOI: 10.1159/000496966 -
Theranostics 2021Iron is a critical component of many cellular functions including DNA replication and repair, and it is essential for cell vitality. As an essential element, iron is... (Review)
Review
Iron is a critical component of many cellular functions including DNA replication and repair, and it is essential for cell vitality. As an essential element, iron is critical for maintaining human health. However, excess iron can be highly toxic, resulting in oxidative DNA damage. Many studies have observed significant associations between iron and cancer, and the association appears to be more than just coincidental. The chief characteristic of cancers, hyper-proliferation, makes them even more dependent on iron than normal cells. Cancer therapeutics are becoming as diverse as the disease itself. Targeting iron metabolism in cancer cells is an emerging, formidable field of therapeutics. It is a strategy that is highly diverse with regard to specific targets and the various ways to reach them. This review will discuss the importance of iron metabolism in cancer and highlight the ways in which it is being explored as the medicine of tomorrow.
Topics: Humans; Iron; Neoplasms
PubMed: 34373750
DOI: 10.7150/thno.59092 -
Hematology. American Society of... Dec 2019Iron deficiency (ID) affects billions of people worldwide and remains the leading cause of anemia with significant negative impacts on health. Our approach to ID and...
Iron deficiency (ID) affects billions of people worldwide and remains the leading cause of anemia with significant negative impacts on health. Our approach to ID and iron deficiency anemia (IDA) involves three steps (I3): (1) identification of ID/IDA, (2) investigation of and management of the underlying etiology of ID, and (3) iron repletion. Iron repletion options include oral and intravenous (IV) iron formulations. Oral iron remains a therapeutic option for the treatment of ID in stable patients, but there are many populations for whom IV iron is more effective. Therefore, IV iron should be considered when there are no contraindications, when poor response to oral iron is anticipated, when rapid hematologic responses are desired, and/or when there is availability of and accessibility to the product. Judicious use of red cell blood transfusion is recommended and should be considered only for severe, symptomatic IDA with hemodynamic instability. Identification and management of ID and IDA is a central pillar in patient blood management.
Topics: Administration, Intravenous; Administration, Oral; Anemia, Iron-Deficiency; Homeostasis; Humans; Iron; Iron Deficiencies
PubMed: 31808874
DOI: 10.1182/hematology.2019000034 -
Annual Review of Nutrition Aug 2019Iron deficiency is the most common micronutrient deficiency in the world and disproportionately affects pregnant women and young children. Iron deficiency has negative...
Iron deficiency is the most common micronutrient deficiency in the world and disproportionately affects pregnant women and young children. Iron deficiency has negative effects on pregnancy outcomes in women and on immune function and neurodevelopment in children. Iron supplementation programs have been successful in reducing this health burden. However, iron supplementation of iron-sufficient individuals is likely not necessary and may carry health risks for iron-sufficient and potentially some iron-deficient populations. This review considers the physiology of iron as a nutrient and how this physiology informs decision-making about weighing the benefits and risks of iron supplementation in iron-deficient, iron-sufficient, and iron-overloaded pregnant women and children.
Topics: Child; Child Nutritional Physiological Phenomena; Dietary Supplements; Dose-Response Relationship, Drug; Female; Humans; Iron; Iron Deficiencies; Pregnancy; Prenatal Nutritional Physiological Phenomena
PubMed: 31091416
DOI: 10.1146/annurev-nutr-082018-124213 -
Haematologica May 2020In iron-depleted women without anemia, oral iron supplements induce an increase in serum hepcidin (SHep) that persists for 24 hours, decreasing iron absorption from...
In iron-depleted women without anemia, oral iron supplements induce an increase in serum hepcidin (SHep) that persists for 24 hours, decreasing iron absorption from supplements given later on the same or next day. Consequently, iron absorption from supplements is highest if iron is given on alternate days. Whether this dosing schedule is also beneficial in women with iron-deficiency anemia (IDA) given high-dose iron supplements is uncertain. The primary objective of this study was to assess whether, in women with IDA, alternate-day administration of 100 and 200 mg iron increases iron absorption compared to consecutive-day iron administration. Secondary objectives were to correlate iron absorption with SHep and iron status parameters. We performed a cross-over iron absorption study in women with IDA (n=19; median hemoglobin 11.5 mg/dL; mean serum ferritin 10 mg/L) who received either 100 or 200 mg iron as ferrous sulfate given at 8 AM on days 2, 3 and 5 labeled with stable iron isotopes 57Fe, 58Fe and 54Fe; after a 16-day incorporation period, the other labeled dose was given at 8 AM on days 23, 24 and 26 (days 2, 3 and 5 of the second period). Iron absorption on days 2 and 3 (consecutive) and day 5 (alternate) was assessed by measuring erythrocyte isotope incorporation. For both doses, SHep was higher on day 3 than on day 2 (<0.001) or day 5 (<0.01) with no significant difference between days 2 and 5. Similarly, for both doses, fractional iron absorption (FIA) on days 2 and 5 was 40-50% higher than on day 3 (<0.001), while absorption on day 2 did not differ significantly from day 5. There was no significant difference in the incidence of gastrointestinal side effects comparing the two iron doses (=0.105). Alternate day dosing of oral iron supplements in anemic women may be preferable because it sharply increases FIA. If needed, to provide the same total amount of iron with alternate day dosing, twice the daily target dose should be given on alternate days, as total iron absorption from a single dose of 200 mg given on alternate days was approximately twice that from 100 mg given on consecutive days (<0.001). In IDA, even if hepatic hepcidin expression is strongly suppressed by iron deficiency and erythropoietic drive, the intake of oral iron supplements leads to an acute hepcidin increase for 24 hours. The study was funded by ETH Zürich, Switzerland. This study has been registered at .
Topics: Anemia, Iron-Deficiency; Cross-Over Studies; Dietary Supplements; Female; Hepcidins; Humans; Iron; Switzerland
PubMed: 31413088
DOI: 10.3324/haematol.2019.220830 -
British Journal of Pharmacology Nov 2015Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV-iron is considered a safe... (Review)
Review
Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV-iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empirical measures which neglect the fact that the majority of IV-iron reactions are not IgE-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV-iron reactions represent complement activation-related pseudo-allergy (CARPA), at least in part. The review compares the features of IV-iron reactions to those of immune and non-immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV-iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV-iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high-risk IV-iron patients.
Topics: Anemia, Iron-Deficiency; Drug Hypersensitivity; Humans; Infusions, Intravenous; Iron
PubMed: 26265306
DOI: 10.1111/bph.13268 -
Trends in Biochemical Sciences Mar 2016Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis.... (Review)
Review
Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed 'ferroptosis', the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy.
Topics: Cell Death; Homeostasis; Humans; Iron
PubMed: 26725301
DOI: 10.1016/j.tibs.2015.11.012 -
Cell Stress & Chaperones Mar 2021In patients with ischemic heart disease, myocardial ischemia-reperfusion injury (IRI) can aggravate their condition even worse, and diabetes increases their risk of...
In patients with ischemic heart disease, myocardial ischemia-reperfusion injury (IRI) can aggravate their condition even worse, and diabetes increases their risk of myocardial IRI. Pathological pathways of common diseases and surgical operations like diabetes, obesity, coronary artery angioplasty, and heart transplantation entail disorders of iron metabolism. Ferroportin1 (FPN1) is the only mammalian protein associated with iron release and thus plays a vital role in iron homeostasis, while nuclear factor E2-related factor 2 (NRF2) controls the transcription of FPN1. Since the NRF2/FPN1 pathway may play a favorable role in the therapy of diabetic myocardial IRI, this work investigated the possible mechanism. In this study, we investigated the effects of ferroptosis in STZ-induced diabetic rats following myocardial IRI in vivo, and its alteration in glucose and hypoxia/reoxygenation-induced cardiomyocytes injury in vitro. Rats and H9c2 cardiomyocytes were randomly divided into 6 groups and treated with sulforaphane and erastin besides the establishment of diabetic myocardial IRI and hyperglycemic hypoxia-reoxygenation models. Cardiac functional and structural damage were detected by Evans blue/TTC double staining, echocardiography, HE staining, and serological indices. CCK-8 assay and ROS production were used to measure cardiomyocyte viability and oxidative stress level. Additionally, the changes in cell supernatant levels of Fe, SOD, MDA, and mRNA and protein expression of ferroptosis marker proteins confirmed the beneficial effects of the NRF2/FPN1 pathway on diabetic myocardial IRI related to iron metabolism and ferroptosis. Overall, these findings suggest that iron homeostasis-related ferroptosis plays an important role in aggravating myocardial IRI in diabetic rats, and NRF2/FPN1 pathway-mediated iron homeostasis and ferroptosis might be a promising therapeutic target against myocardial IRI in diabetes.
Topics: Animals; Diabetes Mellitus, Experimental; Ferroptosis; Homeostasis; Humans; Iron; Mammals; Myocardial Reperfusion Injury; Myocytes, Cardiac; NF-E2-Related Factor 2; Rats
PubMed: 35124772
DOI: 10.1007/s12192-022-01257-1 -
Neurotoxicology Jan 2022Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress.... (Review)
Review
Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.
Topics: Animals; Humans; Iron; Mitochondria; Neurodegenerative Diseases
PubMed: 34748789
DOI: 10.1016/j.neuro.2021.11.003