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1.
A review on bacterial redox dependent iron transporters and their evolutionary relationship.
Banerjee, S, Chanakira, MN, Hall, J, Kerkan, A, Dasgupta, S, Martin, DW
Journal of inorganic biochemistry. 2022;:111721
Abstract
Iron is an essential yet toxic micronutrient and its transport across biological membranes is tightly regulated in all living organisms. One such iron transporter, the Ftr-type permeases, is found in both eukaryotic and prokaryotic cells. These Ftr-type transporters are required for iron transport, predicted to form α-helical transmembrane structures, and conserve two ArgGluxxGlu (x = any amino acid) motifs. In the yeast Ftr transporter (Ftr1p), a ferroxidase (Fet3p) is required for iron transport in an oxidation coupled transport step. None of the bacterial Ftr-type transporters (EfeU and FetM from E. coli; cFtr from Campylobacter jejuni; FtrC from Brucella, Bordetella, and Burkholderia spp.) contain a ferroxidase protein. Bioinformatics report predicted periplasmic EfeO and FtrB (from the EfeUOB and FtrABCD systems) as novel cupredoxins. The Cu2+ binding and the ferrous oxidation properties of these proteins are uncharacterized and the other two bacterial Ftr-systems are expressed without any ferroxidase/cupredoxin, leading to controversy about the mode of function of these transporters. Here, we review published data on Ftr-type transporters to gain insight into their functional diversity. Based on original bioinformatics data presented here evolutionary relations between these systems are presented.
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2.
Impaired bone marrow microenvironment and stem cells in transfusion-dependent beta-thalassemia.
Zhou, X, Huang, L, Wu, J, Qu, Y, Jiang, H, Zhang, J, Qiu, S, Liao, C, Xu, X, Xia, J, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112548
Abstract
Beta-thalassemia (BT) is a hereditary disease caused by abnormal hemoglobin synthesis with consequent ineffective erythropoiesis. Patients with thalassemia major are dependent on long-term blood transfusions with associated long-term complications such as iron overload (IO). This excess iron can result in tissue damage, impaired organ function, and increased morbidity. Growing evidence has demonstrated that IO contributes to impairment of the bone marrow (BM) microenvironment that largely impacts the function of BM mesenchymal stem cells, hematopoietic stem cells, and endothelial cells. In this article, we review recent progress in the understanding of iron metabolism and the perniciousness induced by IO. We highlight the importance of understanding the cross-talk between BM stem cells and the BM microenvironment, particularly the pathological effect of IO on BM stem cells and BT-associated complications. We also provide an update on recent novel therapies to cure transfusion-dependent beta-thalassemia and iron overload-induced complications for their future clinical application.
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3.
Ferroptosis: mechanisms and links with diseases.
Yan, HF, Zou, T, Tuo, QZ, Xu, S, Li, H, Belaidi, AA, Lei, P
Signal transduction and targeted therapy. 2021;(1):49
Abstract
Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.
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4.
GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism.
Rochette, L, Zeller, M, Cottin, Y, Vergely, C
Trends in endocrinology and metabolism: TEM. 2021;(11):875-889
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-β (TGF-β) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.
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5.
Broadening horizons: the role of ferroptosis in cancer.
Chen, X, Kang, R, Kroemer, G, Tang, D
Nature reviews. Clinical oncology. 2021;(5):280-296
Abstract
The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.
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6.
The role of iron in doxorubicin-induced cardiotoxicity: recent advances and implication for drug delivery.
Qin, Y, Guo, T, Wang, Z, Zhao, Y
Journal of materials chemistry. B. 2021;(24):4793-4803
Abstract
As an anthracycline antibiotic, doxorubicin (DOX) is one of the most potent and widely used chemotherapeutic agents for treating various types of tumors. Unfortunately, the clinical application of this drug results in severe side effects, particularly dose-dependent cardiotoxicity. There are multiple mechanisms involved with the cardiotoxicity caused by DOX, among which intracellular iron homeostasis plays an essential role based on a recent discovery. In this mini-review, we summarize the clinical features and symptoms of DOX-dependent cardiotoxicity, discuss the correlation between iron and cardiotoxicity, and highlight the involvement of iron-dependent ferroptotic cell death therein. Recent advances in this topic will aid the development of novel DOX delivery systems with reduced adverse effects, and expand the clinical application of anthracycline.
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7.
Iron at the Interface of Hepatocellular Carcinoma.
Paganoni, R, Lechel, A, Vujic Spasic, M
International journal of molecular sciences. 2021;(8)
Abstract
Cancer incidence and mortality are rapidly growing, with liver cancer being the sixth most diagnosed cancer worldwide and the third leading cause of cancer death in 2020. A number of risk factors have been identified that trigger the progression to hepatocellular carcinoma. In this review, we focus on iron as a potential risk factor for liver carcinogenesis. Molecules involved in the regulation of iron metabolism are often upregulated in cancer cells, in order to provide a supply of this essential trace element for all stages of tumor development, survival, proliferation, and metastasis. Thus, cellular and systemic iron levels must be tightly regulated to prevent or delay liver cancer progression. Disorders associated with dysregulated iron metabolism are characterized with increased susceptibility to hepatocellular carcinoma. This review discusses the association of iron with metabolic disorders such as hereditary hemochromatosis, non-alcoholic fatty liver disease, obesity, and type 2 diabetes, in the background of hepatocellular carcinoma.
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8.
Iron metabolism: an emerging therapeutic target underlying the anti-cancer effect of quercetin.
Yin, M, Liu, Y, Chen, Y
Free radical research. 2021;(3):296-303
Abstract
Iron, an essential micronutrient for all kinds of cells, is essential for the balance of body internal environment. Notably, cancer cells exhibit a strong dependence on iron and require a large amount of iron for proliferation. A growing number of studies suggested that iron metabolism imbalance and subsequent excess iron accumulation are closely related to the occurrence and progression of cancer. Precisely, excess iron promotes the development of cancer due to the pro-oxidative nature of iron and its damaging effects on DNA. Simultaneously, tumor cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide a new way for the treatment of cancer. Quercetin, a natural flavonoid, has long been regarded as potential drug for cancer treatments owing to its anti-inflammatory, antioxidant and anti-tumor effects. It is proven that quercetin possesses a high iron-chelating capacity, depriving cancer cells of iron or altering iron metabolism. Herein, we conduct a review on the mechanisms of iron imbalance in tumors and the role of quercetin in iron chelation, which will provide insight into the potential for quercetin as an anti-cancer drug.
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9.
Iron in immune cell function and host defense.
Haschka, D, Hoffmann, A, Weiss, G
Seminars in cell & developmental biology. 2021;:27-36
Abstract
The control over iron availability is crucial under homeostatic conditions and even more in the case of an infection. This results from diverse properties of iron: first, iron is an important trace element for the host as well as for the pathogen for various cellular and metabolic processes, second, free iron catalyzes Fenton reaction and is therefore producing reactive oxygen species as a part of the host defense machinery, third, iron exhibits important effects on immune cell function and differentiation and fourth almost every immune activation in turn impacts on iron metabolism and spatio-temporal iron distribution. The central importance of iron in the host and microbe interplay and thus for the course of infections led to diverse strategies to restrict iron for invading pathogens. In this review, we focus on how iron restriction to the pathogen is a powerful innate immune defense mechanism of the host called "nutritional immunity". Important proteins in the iron-host-pathogen interplay will be discussed as well as the influence of iron on the efficacy of innate and adaptive immunity. Recently described processes like ferritinophagy and ferroptosis are further covered in respect to their impact on inflammation and infection control and how they impact on our understanding of the interaction of host and pathogen.
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10.
Iron status in athletic females, a shift in perspective on an old paradigm.
Badenhorst, CE, Goto, K, O'Brien, WJ, Sims, S
Journal of sports sciences. 2021;(14):1565-1575
Abstract
Iron deficiency is a common nutrient deficiency within athletes, with sport scientists and medical professionals recognizing that athletes require regular monitoring of their iron status during intense training periods. Revised considerations for athlete iron screening and monitoring have suggested that males get screened biannually during heavy training periods and females require screening biannually or quarterly, depending on their previous history of iron deficiency. The prevalence of iron deficiency in female athletes is higher than their male counterparts and is often cited as being a result of the presence of a menstrual cycle in the premenopausal years. This review has sought to revise our current understanding of female physiology and the interaction between primary reproductive hormones (oestrogen and progesterone) and iron homoeostasis in females. The review highlights an apparent symbiotic relationship between iron metabolism and the menstrual cycle that requires additional research as well as identifying areas of the menstrual cycle that may be primed for nutritional iron supplementation.