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1.
The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
Habib, HM, Ibrahim, S, Zaim, A, Ibrahim, WH
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111228
Abstract
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.
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2.
A Systematic Review and Meta-Analysis of Stature Growth Complications in β-thalassemia Major Patients.
Arab-Zozani, M, Kheyrandish, S, Rastgar, A, Miri-Moghaddam, E
Annals of global health. 2021;(1):48
Abstract
BACKGROUND Blood transfusion is a traditional treatment for β-thalassemia (β-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in parenchymal tissue organs and endocrine glands that cause their dysfunctions as the iron regulatory system can't excrete excess iron from the bloodstream. OBJECTIVE To evaluate the prevalence of iron-related complications (short stature, growth retardation, and growth hormone deficiency) in β-thalassemia major (βTM) patients. METHODS We performed an electronic search in PubMed, Scopus, and Web of Sciences to evaluate the prevalence of growth hormone impairment in β-thalassemia major (βTM) patients worldwide. Qualities of eligible studies were assessed by the Joanna Briggs Institute checklist for the prevalence study. We used Comprehensive Meta-Analysis (Version 2) to calculate the event rate with 95% CIs, using a random-effects model for all analyses. FINDINGS Seventy-four studies were included from five continents between 1978 and 2019; 70.27% (Asia), 16.21% (Europe), 6.75% (Africa), 2.70% (America), 1.35% (Oceania), and 2.70% (Multicenter). The overall mean age of the participants was about 14 years. The pooled prevalence of short stature (ST) was 48.9% (95% CI 35.3-62.6) and in male was higher than female (61.9%, 95% CI 53.4-69.7 vs. 50.9%, CI 41.8-59.9). The pooled prevalence of growth retardation (GR) was 41.1% and in male was higher than in female (51.6%, 95% CI 17.8-84 vs. 33.1%, CI 9.4-70.2). The pooled prevalence of growth hormone deficiency (GHD) was 26.6% (95% CI 16-40.8). CONCLUSION Our study revealed that near half of thalassemia patients suffer from growth impairments. However, regular evaluation of serum ferritin levels, close monitoring in a proper institute, suitable and acceptable treatment methods besides regular chelation therapy could significantly reduce the patients' complications.
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3.
Dysmetabolic Hyperferritinemia and Dysmetabolic Iron Overload Syndrome (DIOS): Two Related Conditions or Different Entities?
Rametta, R, Fracanzani, AL, Fargion, S, Dongiovanni, P
Current pharmaceutical design. 2020;(10):1025-1035
Abstract
Hyperferritinemia is observed in one-third of patients with non-alcoholic fatty liver disease (NAFLD) and Metabolic Syndrome (MetS). The condition characterized by increased body iron stores associated with components of MetS has been defined as Dysmetabolic Iron Overload Syndrome (DIOS). DIOS represents the most frequent iron overload condition, since it is observed in 15% of patients with MetS and in half of those with NAFLD and its clinical presentation overlaps almost completely with that of dysmetabolic hyperferritinemia (DH). The pathogenetic mechanisms linking insulin resistance (IR), NAFLD and DIOS to iron overload are still debated. Hepcidin seems to play a role in iron accumulation in DIOS and NAFLD patients who show elevated serum hepcidin levels. The iron challenge does not restrain iron absorption despite adequate hepcidin production, suggesting that an impaired hepcidin activity rather than a deficit of hormone production underlies DIOS pathogenesis. Acquired and genetic factors are recognized to contribute to iron accumulation in NAFLD whereas additional studies are required to clearly demonstrate whether the same or different genetic factors lead to iron overload in DIOS. Finally, iron depletion by phlebotomy, together with the modification of diet and life-style habits, represents the therapeutic approach to decrease metabolic alterations and liver enzymes in NAFLD and DIOS patients. In this review, we summarized the current knowledge on the dysregulation of iron homeostasis in NAFLD and DIOS in the attempt to clarify whether they are different or more likely strictly related conditions, sharing the same pathogenic cause i.e. the MetS.
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4.
The Effect of Abnormal Iron Metabolism on Osteoporosis.
Che, J, Yang, J, Zhao, B, Zhang, G, Wang, L, Peng, S, Shang, P
Biological trace element research. 2020;(2):353-365
Abstract
Iron is one of the important trace elements in life activities. Abnormal iron metabolism increases the incidence of many skeletal diseases, especially for osteoporosis. Iron metabolism plays a key role in the bone homeostasis. Disturbance of iron metabolism not only promotes osteoclast differentiation and apoptosis of osteoblasts but also inhibits proliferation and differentiation of osteoblasts, which eventually destroys the balance of bone remodeling. The strength and density of bone can be weakened by the disordered iron metabolism, which increases the incidence of osteoporosis. Clinically, compounds or drugs that regulate iron metabolism are used for the treatment of osteoporosis. The goal of this review summarizes the new progress on the effect of iron overload or deficiency on osteoporosis and the mechanism of disordered iron metabolism on osteoporosis. Explaining the relationship of iron metabolism with osteoporosis may provide ideas for clinical treatment and development of new drugs.
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5.
Too much iron: A masked foe for leukemias.
Brissot, E, Bernard, DG, Loréal, O, Brissot, P, Troadec, MB
Blood reviews. 2020;:100617
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Abstract
The role of iron in non-erythroid hematopoietic lineages and its implication in hemato-oncogenesis are still debated. Iron exerts an important role on hematopoietic stem cell transformation and on mature white blood cell differentiation. Iron acts experimentally as an oncogenic cofactor but its exact role in the transformation of the myelodysplastic syndrome into leukemia continues to be discussed. Body iron overload frequently develops mainly as the result of multiple erythrocyte transfusions in patients with leukemia or myelodysplastic syndrome, and, in the latter, as a result of increased ineffective erythropoiesis. Iron overload, especially through the deleterious effects of reactive oxygen species, leads to organ damage that likely impacts the global outcome of patients, especially after hematopoietic stem cell transplantation (HSCT). In these pathological settings (before and after HSCT), oral iron chelation should be considered whenever body iron overload has been firmly established, ideally by magnetic resonance imaging.
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6.
Dysmetabolic Iron Overload in Metabolic Syndrome.
Sachinidis, A, Doumas, M, Imprialos, K, Stavropoulos, K, Katsimardou, A, Athyros, VG
Current pharmaceutical design. 2020;(10):1019-1024
Abstract
BACKGROUND We sought to determine the association of dysmetabolic iron overload syndrome (DIOS) with metabolic syndrome (MetS). METHODS Several studies have shown that DIOS is associated with Mets, mainly through the pathogenesis of its components: type 2 diabetes mellitus (T2DM), essential hypertension, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (POS). RESULTS Serum ferritin levels increase proportionally according to the degree of insulin resistance (IR) and the number of components of Mets. Moreover, DIOS predicts the onset of T2DM and NAFLD. Dysregulation of iron metabolism in DIOS is due to a multifactorial and dynamic process triggered by an unhealthy diet, facilitated by environmental and genetic cofactors, and resulting in a bidirectional relation between the liver and visceral adipose tissue (VAT). Iron removal combined with a healthy diet improved both insulin sensitivity and beta-cell function, but had no significant effect on blood glucose; however, phlebotomy therapy might be considered with conflicting results. CONCLUSION Iron overload is closely associated with metabolic syndrome and its components; however, it remains under-appreciated in everyday clinical practice. Diet and lifestyle modification offer some clinical benefit; however, it is not adequate for successful management of the disease. The results of phlebotomy remain controversial, underlying the necessity of further efforts in this field.
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Cardiomyopathy in Thalassemia: Quick Review from Cellular Aspects to Diagnosis and Current Treatments.
Ghanavat, M, Haybar, H, Pezeshki, SMS, Shahjahani, M, Jodat, H, Elyasi, M, Saki, N
Laboratory medicine. 2020;(2):143-150
Abstract
BACKGROUND Cardiomyopathic manifestations induced by continuous blood transfusion are the leading cause of death among patients with thalassemia major (TM). Despite introduction of chelation therapy, heart failure after cardiomyopathic manifestations is still a major threat to patients. METHODS We performed a search of relevant English-language literature, retrieving publications from the PubMed database and the Google Scholar search engine (2005-2018). We used "thalassemia major", "cardiomyopathy", "iron overload", "cardiac magnetic resonance T2" "chelation therapy", and "iron burden" as keywords. RESULTS The results of the studies we found suggest that cardiac hepcidin is a major regulator of iron homeostasis in cardiac tissue. Unlike previous assumptions, the heart appears to have a limited regeneration capability, originating from a small population of hypoxic cardiomyocytes. CONCLUSIONS Oxygen levels determine cardiomyocyte gene-expression patterns. Upregulation of cardiac hepcidin in hypoxia preserves cardiomyocytes from forming out of reactive oxygen species catalyzed by free cellular iron in cardiomyocytes. Using the limited regeneration capacity of cardiac cells and gaining further understanding of the cellular aspects of cardiomyopathic manifestations may help health care professionals to develop new therapeutic strategies.
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Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis?
Edeas, M, Saleh, J, Peyssonnaux, C
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2020;:303-305
Abstract
The coronavirus 2 (SARS-CoV-2) pandemic is viciously spreading through the continents with rapidly increasing mortality rates. Current management of COVID-19 is based on the premise that respiratory failure is the leading cause of mortality. However, mounting evidence links accelerated pathogenesis in gravely ill COVID-19 patients to a hyper-inflammatory state involving a cytokine storm. Several components of the heightened inflammatory state were addressed as therapeutic targets. Another key component of the heightened inflammatory state is hyper-ferritinemia which reportedly identifies patients with increased mortality risk. In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic marker of disease progression, or a key modulator in disease pathogenesis. Here we address implications of a possible role for hyper-ferritinemia, and altered iron homeostasis in COVID-19 pathogenesis, and potential therapeutic targets in this regard.
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The Case for an Estrogen-iron Axis in Health and Disease.
Hamad, M, Bajbouj, K, Taneera, J
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2020;(4):270-277
Abstract
Clinical and experimental evidence suggest that estrogen manipulates intracellular iron metabolism and that elevated levels of estrogen associate with increased systemic iron availability. This has been attributed to the ability of estrogen to suppress hepcidin synthesis, maintain ferroportin integrity and enhance iron release from iron-absorbing duodenal enterocytes and iron-storing macrophages and hepatocytes. These observations speak of a potential "estrogen-iron" axis that manipulates iron metabolism in response to hematologic (erythropoiesis) and non-hematologic (uterine growth, pregnancy, lactation) needs for iron. Such an axis could contribute to minimizing iron deficiency in premenopausal women and iron overload in postmenopausal women. It could also exacerbate iron overload and related clinical consequences including cancer, osteoporosis, cardiovascular complications and neurodegenerative symptoms, especially in postmenopausal women on hormonal replacement therapy. Understanding the role of estrogen in iron metabolism may shed some light on the pleotropic, but often paradoxical, roles of estrogen in human health and disease.
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10.
Impact of iron overload on bone remodeling in thalassemia.
Piriyakhuntorn, P, Tantiworawit, A, Phimphilai, M, Shinlapawittayatorn, K, Chattipakorn, SC, Chattipakorn, N
Archives of osteoporosis. 2020;(1):143
Abstract
INTRODUCTION Iron overload, a state with excessive iron storage in the body, is a common complication in thalassemia patients which leads to multiple organ dysfunctions including the bone. Iron overload-induced bone disease is one of the most common and severe complications of thalassemia including osteoporosis. Currently, osteoporosis is still frequently found in thalassemia even with widely available iron chelation therapy. STUDY SELECTION Relevant publications published before December 2019 in PubMed database were reviewed. Both pre-clinical studies and clinical trials were obtained using iron overload, thalassemia, osteoporosis, osteoblast, and osteoclast as keywords. RESULTS Increased ROS production is a hallmark of iron overload-induced impaired bone remodeling. At the cellular level, oxidative stress affects bone remodeling by both osteoblast inhibition and osteoclast activation via many signaling pathways. In thalassemia patients, it has been shown that bone resorption was increased while bone formation was concurrently reduced. CONCLUSION In this review, reports on the cellular mechanisms of iron overload-associated bone remodeling are comprehensively summarized and presented to provide current understanding this pathological condition. Moreover, current treatments and potential interventions for attenuating bone remodeling in iron overload are also summarized to pave ways for the future discoveries of novel agents that alleviate this condition.