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The Role of GSH in Intracellular Iron Trafficking.
Hider, R, Aviles, MV, Chen, YL, Latunde-Dada, GO
International journal of molecular sciences. 2021;(3)
Abstract
Evidence is reviewed for the role of glutathione in providing a ligand for the cytosolic iron pool. The possibility of histidine and carnosine forming ternary complexes with iron(II)glutathione is discussed and the physiological significance of these interactions considered. The role of carnosine in muscle, brain, and kidney physiology is far from established and evidence is presented that the iron(II)-binding capability of carnosine relates to this role.
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2.
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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3.
Iron and Ferroptosis as Therapeutic Targets in Alzheimer's Disease.
Gleason, A, Bush, AI
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2021;(1):252-264
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Abstract
Alzheimer's disease (AD), one of the most common neurodegenerative diseases worldwide, has a devastating personal, familial, and societal impact. In spite of profound investment and effort, numerous clinical trials targeting amyloid-β, which is thought to have a causative role in the disease, have not yielded any clinically meaningful success to date. Iron is an essential cofactor in many physiological processes in the brain. An extensive body of work links iron dyshomeostasis with multiple aspects of the pathophysiology of AD. In particular, regional iron load appears to be a risk factor for more rapid cognitive decline. Existing iron-chelating agents have been in use for decades for other indications, and there are preliminary data that some of these could be effective in AD. Many novel iron-chelating compounds are under development, some with in vivo data showing potential Alzheimer's disease-modifying properties. This heretofore underexplored therapeutic class has considerable promise and could yield much-needed agents that slow neurodegeneration in AD.
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Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature.
Miyake, Z, Nakamagoe, K, Yoshida, K, Kondo, T, Tamaoka, A
Internal medicine (Tokyo, Japan). 2020;(14):1755-1761
Abstract
The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.
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5.
COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy.
Perricone, C, Bartoloni, E, Bursi, R, Cafaro, G, Guidelli, GM, Shoenfeld, Y, Gerli, R
Immunologic research. 2020;(4):213-224
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Abstract
SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.
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6.
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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Management of the aging beta-thalassemia transfusion-dependent population - The Italian experience.
Pinto, VM, Poggi, M, Russo, R, Giusti, A, Forni, GL
Blood reviews. 2019;:100594
Abstract
Thalassemia is among the most common monogenic diseases worldwide. Stem cell transplantation can be curative but is reserved for young patients, as probably gene therapy will be in the future. Adult thalassemia patients are treated with transfusion therapy and iron chelation, and improvements in the safety of transfusion protocols, use of iron chelation, monitoring of iron overload, and management of comorbidities have substantially prolonged survival, increasing the proportion of adult patients in the thalassemic population. However, older patients are more likely to develop multiple disease-related morbidities, including osteoporosis, endocrine disorders, liver disease, renal dysfunction, and cancer. Thus, the main objective of this article is to describe new challenges posed by the increasing life expectancy of patients with thalassemia, focusing on data from Italy where there is a well-documented history of thalassemia management. It is hoped that the mortality and morbidity benefits already seen in patients with thalassemia will continue to improve with ongoing advances in the quality of treatment.
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Hematologic improvement with iron chelation therapy in myelodysplastic syndromes: Clinical data, potential mechanisms, and outstanding questions.
Leitch, HA, Gattermann, N
Critical reviews in oncology/hematology. 2019;:54-72
Abstract
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.
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9.
Iron and liver fibrosis: Mechanistic and clinical aspects.
Mehta, KJ, Farnaud, SJ, Sharp, PA
World journal of gastroenterology. 2019;(5):521-538
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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10.
Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity.
Moussa, RS, Park, KC, Kovacevic, Z, Richardson, DR
Free radical biology & medicine. 2019;:276-294
Abstract
Iron (Fe) has become an important target for the development of anti-cancer therapeutics with a number of Fe chelators entering human clinical trials for advanced and resistant cancer. An important aspect of the activity of these compounds is their multiple molecular targets, including those that play roles in arresting the cell cycle, such as the cyclin-dependent kinase inhibitor, p21. At present, the exact mechanism by which Fe chelators regulate p21 expression remains unclear. However, recent studies indicate the ability of chelators to up-regulate p21 at the mRNA level was dependent on the chelator and cell-type investigated. Analysis of the p21 promoter identified that the Sp1-3-binding site played a significant role in the activation of p21 transcription by Fe chelators. Furthermore, there was increased Sp1/ER-α and Sp1/c-Jun complex formation in melanoma cells, suggesting these complexes were involved in p21 promoter activation. Elucidating the mechanisms involved in the regulation of p21 expression in response to Fe chelator treatment in neoplastic cells will further clarify how these agents achieve their anti-tumor activity. It will also enhance our understanding of the complex roles p21 may play in neoplastic cells and lead to the development of more effective and specific anti-cancer therapies.