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      Iron Homeostasis in the Lungs—A Balance between Health and Disease

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          Abstract

          A strong mechanistic link between the regulation of iron homeostasis and oxygen sensing is evident in the lung, where both systems must be properly controlled to maintain lung function. Imbalances in pulmonary iron homeostasis are frequently associated with respiratory diseases, such as chronic obstructive pulmonary disease and with lung cancer. However, the underlying mechanisms causing alterations in iron levels and the involvement of iron in the development of lung disorders are incompletely understood. Here, we review current knowledge about the regulation of pulmonary iron homeostasis, its functional importance, and the link between dysregulated iron levels and lung diseases. Gaining greater knowledge on how iron contributes to the pathogenesis of these diseases holds promise for future iron-related therapeutic strategies.

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          Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

          Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration 1,2 . Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo including organelles, proteins, or intracellular pathogens are targeted for selective autophagy is limited 3 . We employed quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors. Like known cargo receptors, NCOA4 was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species 4 but is degraded via autophagy to release iron 5,6 through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.
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            Iron and cancer: more ore to be mined.

            Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.
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              Asthma

              Asthma-one of the most common chronic, non-communicable diseases in children and adults-is characterised by variable respiratory symptoms and variable airflow limitation. Asthma is a consequence of complex gene-environment interactions, with heterogeneity in clinical presentation and the type and intensity of airway inflammation and remodelling. The goal of asthma treatment is to achieve good asthma control-ie, to minimise symptom burden and risk of exacerbations. Anti-inflammatory and bronchodilator treatments are the mainstay of asthma therapy and are used in a stepwise approach. Pharmacological treatment is based on a cycle of assessment and re-evaluation of symptom control, risk factors, comorbidities, side-effects, and patient satisfaction by means of shared decisions. Asthma is classed as severe when requiring high-intensity treatment to keep it under control, or if it remains uncontrolled despite treatment. New biological therapies for treatment of severe asthma, together with developments in biomarkers, present opportunities for phenotype-specific interventions and realisation of more personalised treatment. In this Seminar, we provide a clinically focused overview of asthma, including epidemiology, pathophysiology, clinical diagnosis, asthma phenotypes, severe asthma, acute exacerbations, and clinical management of disease in adults and children older than 5 years. Emerging therapies, controversies, and uncertainties in asthma management are also discussed.
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                01 January 2019
                March 2019
                : 12
                : 1
                : 5
                Affiliations
                [1 ]Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany; joanamatosneves@ 123456gmail.com
                [2 ]Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120 Heidelberg, Germany
                [3 ]Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland; thomas.j.haider@ 123456gmail.com
                [4 ]Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, 8091 Zurich, Switzerland
                [5 ]Molecular Medicine Partnership Unit, University of Heidelberg, 69120 Heidelberg, Germany
                Author notes
                [†]

                These authors contributed equally and share first-authorship.

                [‡]

                These authors contributed equally and share the senior authorship.

                Article
                pharmaceuticals-12-00005
                10.3390/ph12010005
                6469191
                30609678
                414f877b-527a-45e6-85fb-48b86063459a
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 November 2018
                : 25 December 2018
                Categories
                Review

                iron homeostasis,lung diseases,oxygen sensing,hypoxia
                iron homeostasis, lung diseases, oxygen sensing, hypoxia

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