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      The role of dual oxidases in physiology and cancer

      review-article
      1 , 1
      Genetics and Molecular Biology
      Sociedade Brasileira de Genética
      Dual oxidases, NADPH oxidases, reactive oxygen species, oxidative stress, cancer

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          Abstract

          NOX/DUOX enzymes are transmembrane proteins that carry electrons through biological membranes generating reactive oxygen species. The NOX family is composed of seven members, which are NOX1 to NOX5 and DUOX1 and 2. DUOX enzymes were initially called thyroid oxidases, based on their high expression level in the thyroid tissue. However, DUOX expression has been documented in several extrathyroid tissues, mostly at the apical membrane of the salivary glands, the airways, and the intestinal tract, revealing additional cellular functions associated with DUOX-related H 2O 2 generation. In this review, we will briefly summarize the current knowledge regarding DUOX structure and physiological functions, as well as their possible role in cancer biology.

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          Most cited references72

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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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            Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement.

            Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition.
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              NADPH oxidases: functions and pathologies in the vasculature.

              Reactive oxygen species are ubiquitous signaling molecules in biological systems. Four members of the NADPH oxidase (Nox) enzyme family are important sources of reactive oxygen species in the vasculature: Nox1, Nox2, Nox4, and Nox5. Signaling cascades triggered by stresses, hormones, vasoactive agents, and cytokines control the expression and activity of these enzymes and of their regulatory subunits, among which p22phox, p47phox, Noxa1, and p67phox are present in blood vessels. Vascular Nox enzymes are also regulated by Rac, ClC-3, Poldip2, and protein disulfide isomerase. Multiple Nox subtypes, simultaneously present in different subcellular compartments, produce specific amounts of superoxide, some of which is rapidly converted to hydrogen peroxide. The identity and location of these reactive oxygen species, and of the enzymes that degrade them, determine their downstream signaling pathways. Nox enzymes participate in a broad array of cellular functions, including differentiation, fibrosis, growth, proliferation, apoptosis, cytoskeletal regulation, migration, and contraction. They are involved in vascular pathologies such as hypertension, restenosis, inflammation, atherosclerosis, and diabetes. As our understanding of the regulation of these oxidases progresses, so will our ability to alter their functions and associated pathologies.
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                Author and article information

                Journal
                Genet Mol Biol
                Genet. Mol. Biol
                gmb
                Genetics and Molecular Biology
                Sociedade Brasileira de Genética
                1415-4757
                1678-4685
                20 May 2020
                2020
                : 43
                : 1 Suppl 1
                : e20190096
                Affiliations
                [ 1 ]Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil.
                Author notes
                Send orrespondence to Rodrigo Soares Fortunato. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho 373, CCS - Bloco G, Sala G0-031, Cidade Universitária - Ilha do Fundão, 21941-902 Rio de Janeiro, RJ, Brazil. E-mail: rodrigof@ 123456biof.ufrj.br .

                Author Contributions

                CCF and RSF contributed to all sections of the manuscript; RSF conceived the study. All authors read and approved the final version.

                The authors declare that they have no conflict of interest.

                Associate Editor: Nadja Souza Pinto

                Author information
                http://orcid.org/0000-0003-3497-8173
                Article
                00313
                10.1590/1678-4685/GMB-2019-0096
                7265977
                32453337
                cc92e253-d632-41e4-8958-d7704cffd7e5

                License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (type CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original article is properly cited.

                History
                : 20 March 2019
                : 24 January 2020
                Categories
                Review Article

                Molecular biology
                dual oxidases,nadph oxidases,reactive oxygen species,oxidative stress,cancer
                Molecular biology
                dual oxidases, nadph oxidases, reactive oxygen species, oxidative stress, cancer

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