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Review ArticleReview Article
Open Access

On the Clinical Pharmacology of Reactive Oxygen Species

Ana I. Casas, Cristian Nogales, Hermann A. M. Mucke, Alexandra Petraina, Antonio Cuadrado, Ana I. Rojo, Pietro Ghezzi, Vincent Jaquet, Fiona Augsburger, Francois Dufrasne, Jalal Soubhye, Soni Deshwal, Moises Di Sante, Nina Kaludercic, Fabio Di Lisa and Harald H. H. W. Schmidt
Rhian M. Touyz, ASSOCIATE EDITOR
Pharmacological Reviews October 2020, 72 (4) 801-828; DOI: https://doi.org/10.1124/pr.120.019422
Ana I. Casas
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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  • For correspondence: a.casasguijarro@maastrichtuniversity.nl
Cristian Nogales
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Hermann A. M. Mucke
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Alexandra Petraina
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Antonio Cuadrado
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Ana I. Rojo
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Pietro Ghezzi
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Vincent Jaquet
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Fiona Augsburger
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Francois Dufrasne
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Jalal Soubhye
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Soni Deshwal
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Moises Di Sante
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Nina Kaludercic
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Fabio Di Lisa
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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Harald H. H. W. Schmidt
Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy
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  • For correspondence: h.schmidt@maastrichtuniversity.nl
Rhian M. Touyz
Roles: ASSOCIATE EDITOR
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    Fig. 1.

    A mechanotype approach to ROS-related diseases. Red shows validated ROS-related disease targets and their first neighbors (blue). A participation degree score was calculated for each protein by the ratio of total protein-protein interactions in the subnetwork to the total protein-protein interaction in the interactome. A cutoff of 0.25 was chosen for the participation degree score to filter non–cluster-relevant highly promiscuous proteins. These data suggest that ROS pathophysiology is split up into at least 10 distinct mechanotypes, which will become mechanistic disease definitions. Once metabolites are included, possible new module connections may appear, such as NOX4 linking into NOS1 signaling (Casas et al., 2019a).

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    Fig. 2.

    Role of ROS in physiology and disease. ROS plays a crucial role in several physiologic mechanisms, i.e., angiogenesis, cell signaling, immune system, and memory formation. However, ROS have also been suggested to be part of several pathomechanisms because of a dysregulation of specific ROS sources that leads to unphysiological 1) regulation, 2) location, and 3) amount of ROS produced. Our approach is focused on inhibition of ROS formation through NOX, XO, MAO, NOS, and MPO. A parallel strategy focuses on the direct repair of ROS-induced damage through modulation of the cGMP-forming enzyme sGC using both activators [sGC activators (sGCas)] and stimulators (sGCs). ONOO−, peroxynitrite.

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    Fig. 3.

    NADPH oxidase isoforms with clinical potential. NOX1 and 4 need a complete protein complex to be fully activated and generate superoxide (O2−; in the case of NOX1) and H2O2 (in the case of NOX4). NOX5 stands out by being directly calcium-activated and also producing superoxide. Under several pathophysiological conditions, all NADPH oxidase isoforms can be directly induced. Pan-inhibitors, dual NOX1/4 inhibitors, and specific NOX4 and NOX5 inhibitors are shown based on their current status, i.e., under clinical testing or preclinical development.

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    Fig. 4.

    Therapeutic targeting of NO-sGC signaling in physiology and disease. Under physiologic conditions, NO produced by NOS1 and 3 activates the sGC, which results in cGMP formation and cell signaling regulation. However, dysregulation of this mechanism leads to increase NO and superoxide production through NOS1 and NOS3, respectively, resulting in nitrative damage. In oxidative stress conditions, the sGC heme can be either oxidized or removed (apo-sGC) and, therefore, is no longer an active enzyme. NOS inhibitors, sGC stimulators, and activators are shown based on their current status, i.e., already marketed, under clinical testing, or under preclinical development. L-NAME, l-arginine methyl ester; L-NMMA, L-NG-monomethyl arginine; SMTC, S-methyl-L-thiocitrulline; un-NOS3, uncouple endothelial NO synthase.

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    Fig. 5.

    XO as a therapeutic target. In normoxic conditions, ATP levels remain stable, whereas under hypoxia, ATP is catabolized, leading to accumulation of purines, i.e., inosine and hypoxanthine. XDH under oxidative conditions gets oxidized, leading to XO. Later, XO catabolizes purines to uric acid while generating ROS. Uric acid can directly activate inflammatory pathways, resulting in toll-like receptor–independent production of IL-1β and IL-18, activation of NACHT, LRR and PYD domains-containing protein 3 (NALP3) and, therefore, inflammation and oxidative stress coursing with the disease. XO inhibitors are shown based on their current status, i.e., already marketed or under preclinical development.

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    Fig. 6.

    Clinical perspective of monoamine oxidase inhibitors. MAO-A and MAO-B catalyze the oxidative deamination of endogenous and exogenous amines including several neurotransmitters, i.e., serotonin, norepinephrine, and dopamine, leading to H2O2 and aldehyde production. Dysregulation of MAOs under certain pathologic conditions results in MAO activity and, therefore, elevated availability of MAO subproducts, i.e., H2O2. MAO inhibitors are shown based on their current status, i.e., already marketed or under clinical development.

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    Fig. 7.

    Role of myeloperoxidase in physiology and disease. MPO generates through H2O2 several reactive chlorinating (Cl−), bromating (Br−), and radical (SCN− NO2) species, which are later transformed into more reactive hypohalous acids [hypobromous acid (HOBr), hypothiocyanous acid (HOSCN), hypochlorous acid (HOCl)] and reactive nitric species (NO•/ONNO−). Thus, MPO actively contributes to nucleoside and lipid oxidation, together with protein (Tyr) nitration (NO2Tyr) and chlorination (ClTyr). Dysregulation of MPO results in a broad oxidative environment that contributes to several pathologic conditions. MPO inhibitors are shown based on their current status, i.e., already marketed, under clinical testing, or under preclinical development. 8-oxoG, 8-oxo-guanosine.

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    Fig. 8.

    Clinical pharmacology of NRF2. The KEAP1 E3 ligase adapter is a homodimer that presents NRF2 to the cullin3 (CUL3)/RING-box protein (RBX) complex for ubiquitination and further proteasome degradation. This process restrains NRF2 protein levels. ROS (H2O2) and electrophiles alter KEAP1 and lead to a stalled KEAP1/NRF2/CUL3/RBX complex. Then, newly synthetized NRF2 accumulates in the nucleus, makes heterodimers with small transcription factor MAF (MAF) proteins, and activates target genes that contain the antioxidant response element (ARE). Clinically relevant electrophiles, such as sulforaphane, dimethyl fumarate, bardoxolone, or omaveloxone, disrupt the capacity of KEAP1 to target NRF2 for degradation and therefore increase NRF2 levels.

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    TABLE 1

    NOX isoforms: function and potential pathologic role

    Functional NOXLoss of FunctionPotential Role of Excessive Activity in Disease
    NOX1Increased susceptibility for inflammatory bowel disease (NOX1)Ischemic retinal diseases; atherosclerosis
    NOX2Chronic granulomatous disease (NOX2, CYBA, NCF1, NCF2, and NCF4), increased incidence of lupus (NOX2, NCF1)Metastasis, acute lung inflammation, chronic obstructive pulmonary disease, pulmonary hypertension, and neurodegenerative diseases (Alzheimer and Parkinson disease); pancreatitis
    NOX3Not described in humans., balance defects due to lack of otoconia in rodents (CYBA, NOXO1, and NOX3)Hearing loss
    NOX4Not described in humans, no phenotype in mouse knockoutsStroke, diabetic nephropathy
    NOX5Not described in humans, no animal knockouts, not expressed in rodentsCardiovascular disease
    DUOX1Not described in humans, no phenotype in mouse knockoutsThyroid cancer
    DUOX2, DUOXA2Hypothyroidism (DUOX2, DUOXA2), increased susceptibility for inflammatory bowel disease (DUOX2).Cancer
    • CYBA, cytochrome b-245 light chain; NCF, neutrophil cytosol factor.

    • View popup
    TABLE 2

    Inhibition of ROS formation and toxification: translation to the clinics

    TargetDrug ClassCompound NamePathologyClinical Trial IdentifierCurrent Status
    NOX1/4NOX inhibitorsGKT137831Idiopathic pulmonary fibrosisNCT03865927Phase II
    Type 2 diabetes and albuminuriaNCT02010242Completed (phase III in preparation)
    Primary biliary cholangitis receiving ursodeoxycholic acidNCT03226067Phase II
    NOSNOS inhibitorL-NMMAGLP-2–mediated intestinal lipoprotein releaseNCT03534661Phase I
    Non–small-cell lung cancer, malignant melanoma, head and neck squamous cell carcinoma (three more)NCT03236935Phase I
    Metastatic triple negative breast cancer patientsNCT02834403Phase II
    2-IminobiotinPerinatal asphyxiaNCT01626924Phase II, recently terminated
    Out-of-hospital cardiac arrestNCT02836340Phase II
    VAS203Traumatic brain injuryNCT02794168Phase III
    XOXO inhibitorAllopurinol (approved)Chronic gout——
    Ischemic stroke and transient ischemic attackNCT02122718Phase IV
    Hypoxic-ischemic brain injury on neurocognitive outcomeNCT03162653Phase III
    Complications of renal transplantNCT01332799Phase IV
    Congestive heart failureNCT00181155Phase II
    Chronic heart failureNCT00997542Phase IV
    Febuxostat (approved)Gout——
    Endothelial function, cardiovascular system, hypertensionNCT03395977N/A
    Hematologic malignancies of pediatric patients and adultsNCT03605212Phase II
    Chronic renal diseaseNCT03425708Phase IV
    TopiroxostatDiabetic nephropathyNCT02327754Phase II
    HyperuricemiaNCT02837198Phase II
    MAOMAO inhibitorSafinamide, selegilineParkinson disease——
    Rasagiline (approved)Macula-off retinal detachmentNCT02068625Phase IV
    Toloxatone (approved)Depression——
    Pirlindole (approved)Depression, anxiety——
    Phenelzine, isocarboxazid, tranylcypromine (approved)Major depressive disorder——
    Moclobemide (approved)Addiction and major depression——
    MPOMPO inhibitorAZD3241Parkinson diseaseNCT01527695, NCT01603069Phase II
    Multiple system atrophyNCT02388295Phase II (negative)
    AZD4831Heart failureNCT03756285, NCT03611153Phase II
    • GLP-2, glucagon-like peptide-2; L-NMMA, L-NG-monomethyl arginine.

    • View popup
    TABLE 3

    Targeting ROS beyond oxidases: translation to the clinics

    TargetDrug ClassCompound NamePathologyClinical Trial IdentifierCurrent Status
    Nrf2-Keap1Nrf2 activatorSulforaphane (approved)Anthracycline-related cardiotoxicity in breast cancerNCT03934905Phase II
    AgingNCT03730649, NCT03126539Phase II
    SchizophreniaNCT02810964Phase II
    Lung cancerNCT03232138Phase II
    AutismNCT02677051Phase II
    Bladder cancerNCT03517995Phase II
    Clinical high-risk syndrome of psychosisNCT03932136Phase III
    Subarachnoid hemorrhageNCT02614742Phase II
    Bardoxolone (RTA402, CDDO-me)Chronic kidney diseasesNCT03749447Phase III
    Pulmonary hypertensionNCT03068130Phase III
    Autosomal dominant polycystic kidneyNCT03918447Phase III
    Omaveloxolone (RTA 408)Friedreich ataxiaNCT02255435Phase II
    DMF (approved)Multiple sclerosis——
    sGCsGC activatorCinaciguatHeart failureTerminatedTerminated
    HMR1766Aortic valve stenosisNCT02481258Phase II
    PainNCT00799656Phase II
    sGC stimulatorAdempas, riociguat (approved)Pulmonary hypertension——
    VericiguatChronic heart failure with preserved ejection fractionNCT02861534Phase III
    IW-1701Sickle cell diseaseNCT03285178Phase II
    AchalasiaNCT02931565Phase II
    Nelociguat (BAY60-4552)Male erectile dysfunctionNCT01168817Phase II
    • CDDO, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate.

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Pharmacological Reviews: 72 (4)
Pharmacological Reviews
Vol. 72, Issue 4
1 Oct 2020
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Review ArticleReview Article

On the Clinical Pharmacology of Reactive Oxygen Species

Ana I. Casas, Cristian Nogales, Hermann A. M. Mucke, Alexandra Petraina, Antonio Cuadrado, Ana I. Rojo, Pietro Ghezzi, Vincent Jaquet, Fiona Augsburger, Francois Dufrasne, Jalal Soubhye, Soni Deshwal, Moises Di Sante, Nina Kaludercic, Fabio Di Lisa and Harald H. H. W. Schmidt
Pharmacological Reviews October 1, 2020, 72 (4) 801-828; DOI: https://doi.org/10.1124/pr.120.019422

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Review ArticleReview Article

On the Clinical Pharmacology of Reactive Oxygen Species

Ana I. Casas, Cristian Nogales, Hermann A. M. Mucke, Alexandra Petraina, Antonio Cuadrado, Ana I. Rojo, Pietro Ghezzi, Vincent Jaquet, Fiona Augsburger, Francois Dufrasne, Jalal Soubhye, Soni Deshwal, Moises Di Sante, Nina Kaludercic, Fabio Di Lisa and Harald H. H. W. Schmidt
Pharmacological Reviews October 1, 2020, 72 (4) 801-828; DOI: https://doi.org/10.1124/pr.120.019422
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    • Abstract
    • I. Introduction
    • II. ROS Revisited: From Oxidative Stress and Redox Biology to Redox Medicine
    • III. ROS Generators and Toxifiers in Disease
    • IV. Pharmacological Modulation of ROS
    • V. Targeting ROS Beyond Oxidases
    • VI. Biomarkers of ROS
    • VII. Summary
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