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1.
Influence of mitochondrial and systemic iron levels in heart failure pathology.
Lupu, M, Tudor, DV, Filip, GA
Heart failure reviews. 2019;(5):647-659
Abstract
Iron deficiency or overload poses an increasingly complex issue in cardiovascular disease, especially heart failure. The potential benefits and side effects of iron supplementation are still a matter of concern, even though current guidelines suggest therapeutic management of iron deficiency. In this review, we sought to examine the iron metabolism and to identify the rationale behind iron supplementation and iron chelation. Cardiovascular disease is increasingly linked with iron dysmetabolism, with an increased proportion of heart failure patients being affected by decreased plasma iron levels and in turn, by the decreased quality of life. Multiple studies have concluded on a benefit of iron administration, even if just for symptomatic relief. However, new studies field evidence for negative effects of dysregulated non-bound iron and its reactive oxygen species production, with concern to heart diseases. The molecular targets of iron usage, such as the mitochondria, are prone to deleterious effects of the polyvalent metal, added by the scarcely described processes of iron elimination. Iron supplementation and iron chelation show promise of therapeutic benefit in heart failure, with the extent and mechanisms of both prospects not being entirely understood. It may be that a state of decreased systemic and increased mitochondrial iron levels proves to be a useful frame for future advancements in understanding the interconnection of heart failure and iron metabolism.
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2.
Iron considerations for the athlete: a narrative review.
Sim, M, Garvican-Lewis, LA, Cox, GR, Govus, A, McKay, AKA, Stellingwerff, T, Peeling, P
European journal of applied physiology. 2019;(7):1463-1478
Abstract
Iron plays a significant role in the body, and is specifically important to athletes, since it is a dominant feature in processes such as oxygen transport and energy metabolism. Despite its importance, athlete populations, especially females and endurance athletes, are commonly diagnosed with iron deficiency, suggesting an association between sport performance and iron regulation. Although iron deficiency is most common in female athletes (~ 15-35% athlete cohorts deficient), approximately 5-11% of male athlete cohorts also present with this issue. Furthermore, interest has grown in the mechanisms that influence iron absorption in athletes over the last decade, with the link between iron regulation and exercise becoming a research focus. Specifically, exercise-induced increases in the master iron regulatory hormone, hepcidin, has been highlighted as a contributing factor towards altered iron metabolism in athletes. To date, a plethora of research has been conducted, including investigation into the impact that sex hormones, diet (e.g. macronutrient manipulation), training and environmental stress (e.g. hypoxia due to altitude training) have on an athlete's iron status, with numerous recommendations proposed for consideration. This review summarises the current state of research with respect to the aforementioned factors, drawing conclusions and recommendations for future work.
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3.
An overview of the relationship between anaemia, iron, and venous leg ulcers.
Ferris, AE, Harding, KG
International wound journal. 2019;(6):1323-1329
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Abstract
The factors preventing healing in venous leg ulcers are still not fully understood. Iron-mediated tissue damage has been hypothesised, yet anecdotally anaemia is also thought to have a negative effect on wound healing. This article summarises the current evidence for these theories and their likely effects in the context of venous ulceration. A comprehensive search of the literature was conducted. Studies suggest that a number of forms of iron including haemosiderin and ferritin are implicated in progression of venous disease, ulcer formation, and impaired healing, which is thought to be primarily free radical mediated. There is a paucity of evidence for the role of iron deficiency and anaemia on ulcer healing; however, there is likely to be a highly complex interplay between the damaging effects of iron on local tissues and the negative effects of anaemia-mediated tissue hypoxia. Studies looking at options to increase local oxygen delivery such as topical haemoglobin suggest that this may have an impact on some aspects of healing, but findings are generally inconclusive. There is growing evidence that locally elevated iron levels may have a detrimental effect on ulcer healing and formation; however, more robust research is needed.
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4.
Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.
Rayman, MP
The Proceedings of the Nutrition Society. 2019;(1):34-44
Abstract
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.
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5.
Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration.
Masaldan, S, Bush, AI, Devos, D, Rolland, AS, Moreau, C
Free radical biology & medicine. 2019;:221-233
Abstract
Perturbations in iron homeostasis and iron accumulation feature in several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Proteins such as α-synuclein, tau and amyloid precursor protein that are pathologically associated with neurodegeneration are involved in molecular crosstalk with iron homeostatic proteins. Quantitative susceptibility mapping, an MRI based non-invasive technique, offers proximal evaluations of iron load in regions of the brain and powerfully predicts cognitive decline. Further, small molecules that target elevated iron have shown promise against PD and AD in preclinical studies and clinical trials. Despite these strong links between altered iron homeostasis and neurodegeneration the molecular biology to describe the association between enhanced iron levels and neuron death, synaptic impairment and cognitive decline is ill defined. In this review we discuss the current understanding of brain iron homeostasis and how it may be perturbed under pathological conditions. Further, we explore the ramifications of a novel cell death pathway called ferroptosis that has provided a fresh impetus to the "metal hypothesis" of neurodegeneration. While lipid peroxidation plays a central role in the execution of this cell death modality the removal of iron through chelation or genetic modifications appears to extinguish the ferroptotic pathway. Conversely, tissues that harbour elevated iron may be predisposed to ferroptotic damage. These emerging findings are of relevance to neurodegeneration where ferroptotic signalling may offer new targets to mitigate cell death and dysfunction.
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Integration of nanoscale zero-valent iron and functional anaerobic bacteria for groundwater remediation: A review.
Dong, H, Li, L, Lu, Y, Cheng, Y, Wang, Y, Ning, Q, Wang, B, Zhang, L, Zeng, G
Environment international. 2019;:265-277
Abstract
The technology of integrating nanoscale zero-valent iron (nZVI) and functional anaerobic bacteria has broad prospects for groundwater remediation. This review focuses on the interactions between nZVI and three kinds of functional anaerobic bacteria: organohalide-respiring bacteria (OHRB), sulfate reducing bacteria (SRB) and iron reducing bacteria (IRB), which are commonly used in the anaerobic bioremediation. The coupling effects of nZVI and the functional bacteria on the contaminant removal in the integrated system are summarized. Generally, nZVI could create a suitable living condition for the growth and activity of anaerobic bacteria. OHRB and SRB could synergistically degrade organic halides and remove heavy metals with nZVI, and IRB could reactive the passivated nZVI by reducing the iron (hydr)oxides on the surface of nZVI. Moreover, the roles of these anaerobic bacteria in contaminant removal coupling with nZVI and the degradation mechanisms are illustrated. In addition, this review also discusses the main factors influencing the removal efficiency of contaminants in the integrated treatment system, including nZVI species and dosage, inorganic ions, organic matters, pH, type of pollutants, temperature, and carbon/energy sources, etc. Among these factors, the nZVI species and dosage play a fundamental role due to the potential cytotoxicity of nZVI, which might exert a negative impact on the performance of this integrated system. Lastly, the future research needs are proposed to better understand this integrated technology and effectively apply it in groundwater remediation.
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Iron deficiency among blood donors: experience from the Danish Blood Donor Study and from the Copenhagen ferritin monitoring scheme.
Rigas, AS, Pedersen, OB, Magnussen, K, Erikstrup, C, Ullum, H
Transfusion medicine (Oxford, England). 2019;:23-27
Abstract
Blood components collected from blood donors are an invaluable part of modern-day medicine. A healthy blood donor population is therefore of paramount importance. The results from the Danish Blood Donor Study (DBDS) indicate that gender, number of previous donations, time since last donation and menopausal status are the strongest predictors of iron deficiency. Only little information on the health effects of iron deficiency in blood donors exits. Possibly, after a standard full blood donation, a temporarily reduced physical performance for women is observed. However, iron deficiency among blood donors is not reflected in a reduced self-perceived mental and physical health. In general, the high proportion of iron-deficient donors can be alleviated either by extending the inter-donation intervals or by guided iron supplementation. The experience from Copenhagen, the Capital Region of Denmark, is that routine ferritin measurements and iron supplementation are feasible and effective ways of reducing the proportion of donors with low haemoglobin levels.
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8.
Dysregulation of iron metabolism in cancer stem cells.
Recalcati, S, Gammella, E, Cairo, G
Free radical biology & medicine. 2019;:216-220
Abstract
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.
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Strategies for managing transfusional iron overload: conventional treatments and novel strategies.
Sheth, S
Current opinion in hematology. 2019;(3):139-144
Abstract
PURPOSE OF REVIEW For individuals who have transfusion-dependent anemia, iron overload is the long-term complication, which results in significant morbidity. Ameliorating this is now the biggest unmet need. This review specifically addresses this issue. RECENT FINDINGS Over the last decade or so, major advances in the treatment of these individuals, has resulted from novel strategies aimed at reducing transfusion requirement as well as optimizing chelation therapy. This review will summarize these advances and provide insights into some of the therapies in the pipeline. Strategies aimed at reducing transfusion requirement include modulation of erythropoietic regulation by reducing ineffective red cell production through activin trapping, as well as stem cell gene modification approaches, which aim for a cure, and transfusion independence. Refined means of assessing tissue iron and the introduction of oral chelators have facilitated tailoring chelation regimens with closer monitoring and improved compliance. Newer approaches to ameliorate iron toxicity have focused on the hepcidin pathway, all of which would result in increased hepcidin levels and reduction of iron absorption from the intestine, sequestration of iron in normal storage sites and reduced exposure of more susceptible organs, such as the heart and endocrine organs, to the toxic effects of increased iron. SUMMARY These advances offer the promise of improved management of transfusion-dependent individuals.
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10.
Connecting iron regulation and mitochondrial function in Cryptococcus neoformans.
Horianopoulos, LC, Kronstad, JW
Current opinion in microbiology. 2019;:7-13
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Abstract
Iron acquisition is essential for the proliferation of microorganisms, and human pathogens such as the fungus Cryptococcus neoformans must use sophisticated uptake mechanisms to overcome host iron sequestration. Iron is of particular interest for C. neoformans because its availability is an important cue for the elaboration of virulence factors. In fungi, extracellular iron is taken up through high affinity, low affinity, siderophore-mediated, and heme uptake pathways, and the details of these mechanisms are under active investigation in C. neoformans. Following uptake, iron is transported to intracellular organelles including mitochondria where it is used in heme biosynthesis and the synthesis of iron-sulfur (Fe-S) cluster precursors. One Fe-S cluster binding protein of note is the monothiol glutaredoxin Grx4 which has emerged as a master regulator of iron sensing in C. neoformans and other fungi through its influence on the expression of proteins for iron uptake or use. The activity of Grx4 likely occurs through interactions with Fe-S clusters and transcription factors known to control expression of the iron-related functions. Although the extent to which Grx4 controls the iron regulatory network is still being investigated in C. neoformans, it is remarkable that it also influences the expression of many genes encoding mitochondrial functions. Coupled with recent studies linking mitochondrial morphology and electron transport to virulence factor elaboration, there is an emerging appreciation of mitochondria as central players in cryptococcal disease.