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      The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

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          Abstract

          Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.

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          The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

          For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.
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            MicroRNA expression profiles classify human cancers.

            Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.
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              Mitochondrial formation of reactive oxygen species.

              The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2-*). Even though O2-* is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/986726
                URI : https://loop.frontiersin.org/people/788264
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                27 January 2021
                2020
                : 11
                : 561917
                Affiliations
                [1] 1 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                [2] 2 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                [3] 3 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                Author notes

                Edited by: Wilma Barcellini, IRCCS Ca ‘Granda Foundation Maggiore Policlinico Hospital, Italy

                Reviewed by: Claudio Canetti, Federal University of Rio de Janeiro, Brazil; Iqbal Hamza, University of Maryland, College Park, United States; Xiaojing Yuan, University of Maryland, College Park, United States, in collaboration with reviewer IH

                *Correspondence: Gregory J. Kato, gregorykatomd@ 123456gmail.com

                †These authors share first authorship

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.561917
                7873693
                33584641
                b0440119-b648-4efd-8d90-4196de5b2dc4
                Copyright © 2021 Gbotosho, Kapetanaki and Kato

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 May 2020
                : 04 December 2020
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 408, Pages: 22, Words: 7920
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Funded by: National Institutes of Health 10.13039/100000002
                Categories
                Immunology
                Review

                Immunology
                hemolysis,sickle cell disease,free heme,inflammation,oxidative stress,il-6,placental growth factor,pulmonary hypertension

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