Roles of NADPH Oxidase in Modulation of Signal Transduction and Cellular Metabolism

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 53772

Special Issue Editors


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Guest Editor
Department of Molecular Medicine and Medical Biotechnologies, School of Medicine, University of Naples “Federico II”, 80131 Naples, Italy
Interests: redox signaling; NOX; GPCRs; TKRs; cellular metabolism
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Co-Guest Editor
Department of Molecular Medicine and Medical Biotechnologies, School of Medicine, University of Naples “Federico II”, 80131 Naples, Italy
Interests: signal transduction; ROS; formyl peptide receptors; NADPH oxidase; TKR-transactivation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We invite you to submit your latest valuable research outcomes for publication in the Special Issue entitled " Roles of NADPH Oxidase in Modulation of Signal Transduction and Cellular Metabolism" for the Antioxidants journal (MDPI).

This Special Issue will focus on the physiological and pathological functions of the NOX family of NADPH oxidases. The main role of these enzymes is to produce reactive oxygen species (ROS) that can act as second messengers modulating many biological functions and cellular processes. However, ROS derived from deleterious or uncontrolled NADPH oxidase activation can contribute to the etiology of several human diseases. Therefore, a complete understanding of the functions of NADPH oxidase family members provide important information on their role in different cellular systems, as well as in pathological and physiological conditions.

The following topics may be included in this Special Issue: NOX-dependent diseases; aging; signal transduction; cellular metabolism; receptor transactivation; kinase and phosphatase activation; NOX subunits; transcription; angiogenesis; cell proliferation; cell death and apoptosis; stress response; immunoregulation; inflammation; chronic granulomatous disease; NOX activators and inhibitors.
Research or review articles collecting data from both in vitro and in vivo investigations are welcome.

Prof. Dr. Rosario Ammendola
Dr. Fabio Cattaneo
Guest Editors

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Keywords

  • Redox signaling
  • NOX-dependent diseases
  • NOX
  • NADPH oxidase
  • ROS
  • Cell metabolism
  • Redox-state
  • GPCR
  • TKR
  • Cell proliferation

Published Papers (16 papers)

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Research

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15 pages, 2601 KiB  
Article
Healthberry 865® and Its Related, Specific, Single Anthocyanins Exert a Direct Vascular Action, Modulating Both Endothelial Function and Oxidative Stress
by Albino Carrizzo, Rosario Lizio, Paola Di Pietro, Michele Ciccarelli, Antonio Damato, Eleonora Venturini, Patrizia Iannece, Eduardo Sommella, Pietro Campiglia, Philipp Ockermann and Carmine Vecchione
Antioxidants 2021, 10(8), 1191; https://doi.org/10.3390/antiox10081191 - 26 Jul 2021
Cited by 6 | Viewed by 2113
Abstract
In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single [...] Read more.
In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865® exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865® significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865® on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD. Full article
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16 pages, 37563 KiB  
Article
Distinction between 2′- and 3′-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration
by Raoul Manuel, Michelle de Souza Lima, Sébastien Dilly, Sylvain Daunay, Patricia Abbe, Elodie Pramil, Stéphanie Solier, Fabienne Guillaumond, Sarah-Simha Tubiana, Alexandre Escargueil, João Antonio Pêgas Henriques, Nathalie Ferrand, Irène Erdelmeier, Jean-Luc Boucher, Gildas Bertho, Israel Agranat, Stéphane Rocchi, Michèle Sabbah and Anny Slama Schwok
Antioxidants 2021, 10(5), 723; https://doi.org/10.3390/antiox10050723 - 4 May 2021
Cited by 1 | Viewed by 2624
Abstract
Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2′- and 3′-phosphate derivatives, a difference used to improve the specificity [...] Read more.
Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2′- and 3′-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2′- and 3′-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2′-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3′-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2′-phosphate over the 3′-phosphate group, in favor of the 2′-phosphate. Full article
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21 pages, 3513 KiB  
Article
NOX4 Mediates Pseudomonas aeruginosa-Induced Nuclear Reactive Oxygen Species Generation and Chromatin Remodeling in Lung Epithelium
by Panfeng Fu, Ramaswamy Ramchandran, Tara Sudhadevi, Prasanth P. K. Kumar, Yashaswin Krishnan, Yuru Liu, Yutong Zhao, Narasimham L. Parinandi, Anantha Harijith, Junichi Sadoshima and Viswanathan Natarajan
Antioxidants 2021, 10(3), 477; https://doi.org/10.3390/antiox10030477 - 17 Mar 2021
Cited by 13 | Viewed by 3319
Abstract
Pseudomonas aeruginosa (PA) infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in PA-mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC) NOX4 in PA [...] Read more.
Pseudomonas aeruginosa (PA) infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in PA-mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC) NOX4 in PA-mediated chromatin remodeling and lung inflammation. Intratracheal administration of PA to Nox4flox/flox mice for 24 h caused lung inflammatory injury; however, epithelial cell-deleted Nox4 mice exhibited reduced lung inflammatory injury, oxidative stress, secretion of pro-inflammatory cytokines, and decreased histone acetylation. In LEpCs, NOX4 was localized both in the cytoplasmic and nuclear fractions, and PA stimulation increased the nuclear NOX4 expression and ROS production. Downregulation or inhibition of NOX4 and PKC δ attenuated the PA-induced nuclear ROS. PA-induced histone acetylation was attenuated by Nox4-specific siRNA, unlike Nox2. PA stimulation increased HDAC1/2 oxidation and reduced HDAC1/2 activity. The PA-induced oxidation of HDAC2 was attenuated by N-acetyl-L-cysteine and siRNA specific for Pkc δ, Sphk2, and Nox4. PA stimulated RAC1 activation in the nucleus and enhanced the association between HDAC2 and RAC1, p-PKC δ, and NOX4 in LEpCs. Our results revealed a critical role for the alveolar epithelial NOX4 in mediating PA-induced lung inflammatory injury via nuclear ROS generation, HDAC1/2 oxidation, and chromatin remodeling. Full article
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25 pages, 7870 KiB  
Article
Actin Cytoskeleton Regulation by the Yeast NADPH Oxidase Yno1p Impacts Processes Controlled by MAPK Pathways
by Manuela Weber, Sukanya Basu, Beatriz González, Gregor P. Greslehner, Stefanie Singer, Danusa Haskova, Jiri Hasek, Michael Breitenbach, Campbell W.Gourlay, Paul J. Cullen and Mark Rinnerthaler
Antioxidants 2021, 10(2), 322; https://doi.org/10.3390/antiox10020322 - 22 Feb 2021
Cited by 9 | Viewed by 3369
Abstract
Reactive oxygen species (ROS) that exceed the antioxidative capacity of the cell can be harmful and are termed oxidative stress. Increasing evidence suggests that ROS are not exclusively detrimental, but can fulfill important signaling functions. Recently, we have been able to demonstrate that [...] Read more.
Reactive oxygen species (ROS) that exceed the antioxidative capacity of the cell can be harmful and are termed oxidative stress. Increasing evidence suggests that ROS are not exclusively detrimental, but can fulfill important signaling functions. Recently, we have been able to demonstrate that a NADPH oxidase-like enzyme (termed Yno1p) exists in the single-celled organism Saccharomyces cerevisiae. This enzyme resides in the peripheral and perinuclear endoplasmic reticulum and functions in close proximity to the plasma membrane. Its product, hydrogen peroxide, which is also produced by the action of the superoxide dismutase, Sod1p, influences signaling of key regulatory proteins Ras2p and Yck1p/2p. In the present work, we demonstrate that Yno1p-derived H2O2 regulates outputs controlled by three MAP kinase pathways that can share components: the filamentous growth (filamentous growth MAPK (fMAPK)), pheromone response, and osmotic stress response (hyperosmolarity glycerol response, HOG) pathways. A key structural component and regulator in this process is the actin cytoskeleton. The nucleation and stabilization of actin are regulated by Yno1p. Cells lacking YNO1 showed reduced invasive growth, which could be reversed by stimulation of actin nucleation. Additionally, under osmotic stress, the vacuoles of a ∆yno1 strain show an enhanced fragmentation. During pheromone response induced by the addition of alpha-factor, Yno1p is responsible for a burst of ROS. Collectively, these results broaden the roles of ROS to encompass microbial differentiation responses and stress responses controlled by MAPK pathways. Full article
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16 pages, 13031 KiB  
Article
Human Placental NADPH Oxidase Mediates sFlt-1 and PlGF Secretion in Early Pregnancy: Exploration of the TGF-β1/p38 MAPK Pathways
by Isabelle Hernandez, Audrey Chissey, Jean Guibourdenche, Roger Atasoy, Xavier Coumoul, Thierry Fournier, Jean-Louis Beaudeux and Amal Zerrad-Saadi
Antioxidants 2021, 10(2), 281; https://doi.org/10.3390/antiox10020281 - 12 Feb 2021
Cited by 9 | Viewed by 2433
Abstract
Preeclampsia, a hypertensive disorder occurring during pregnancy, is characterized by excessive oxidative stress and trophoblast dysfunction with dysregulation of soluble Fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) production. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase (Nox) is the major source of [...] Read more.
Preeclampsia, a hypertensive disorder occurring during pregnancy, is characterized by excessive oxidative stress and trophoblast dysfunction with dysregulation of soluble Fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) production. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase (Nox) is the major source of placental superoxide in early pregnancy and its activation with the subsequent formation of superoxide has been demonstrated for various agents including Transforming Growth Factor beta-1 (TGF-β1), a well-known p38 MAPK pathway activator. However, the bridge between Nox and sFlt-1 remains unknown. The purpose of this study was to explore the possible signaling pathway of TGF-β1/Nox/p38 induced sFlt-1 production in human chorionic villi (CV). Methods: Human chorionic villi from first trimester placenta (7–9 Gestational Weeks (GW)) were treated with TGF-β1 or preincubated with p38 inhibitor, SB203580. For NADPH oxidase inhibition, CV were treated with diphenyleneiodonium (DPI). The protein levels of phospho-p38, p38, phospho-Mothers Against Decapentaplegic homolog 2 (SMAD2), and SMAD2 were detected by Western blot. The secretion of sFlt-1 and PlGF by chorionic villi were measured with Electrochemiluminescence Immunologic Assays, and NADPH oxidase activity was monitored by lucigenin method. Results: We demonstrate for the first time that NADPH oxidase is involved in sFlt-1 and PlGF secretion in first trimester chorionic villi. Indeed, the inhibition of Nox by DPI decreases sFlt-1, and increases PlGF secretions. We also demonstrate the involvement of p38 MAPK in sFlt-1 secretion and Nox activation as blocking the p38 MAPK phosphorylation decreases both sFlt-1 secretion and superoxide production. Nevertheless, TGF-β1-mediated p38 activation do not seem to be involved in regulation of the first trimester placental angiogenic balance and no crosstalk was found between SMAD2 and p38 MAPK pathways. Conclusions: Thus, the placental NADPH oxidase play a major role in mediating the signal transduction cascade of sFlt-1 production. Furthermore, we highlight for the first time the involvement of p38 activation in first trimester placental Nox activity. Full article
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17 pages, 4535 KiB  
Article
Pan-Cancer Analysis Shows TP53 Mutations Modulate the Association of NOX4 with Genetic Programs of Cancer Progression and Clinical Outcome
by Wei Feng Ma, Howard E. Boudreau and Thomas L. Leto
Antioxidants 2021, 10(2), 235; https://doi.org/10.3390/antiox10020235 - 4 Feb 2021
Cited by 9 | Viewed by 3140
Abstract
Previously, we have shown TGF-β-induced NOX4 expression is involved in the epithelial-to-mesenchymal transition (EMT), a process critical for cancer metastasis, and that wild-type (WT) and mutant (Mut) p53 have divergent effects on TGF-β induction of NOX4: WT-p53 suppresses whereas Mut-p53 augments NOX4 mRNA [...] Read more.
Previously, we have shown TGF-β-induced NOX4 expression is involved in the epithelial-to-mesenchymal transition (EMT), a process critical for cancer metastasis, and that wild-type (WT) and mutant (Mut) p53 have divergent effects on TGF-β induction of NOX4: WT-p53 suppresses whereas Mut-p53 augments NOX4 mRNA and protein production in several tumor cell models. We sought to validate and extend our model by analyzing whole-exome data of primary tumor samples in The Cancer Genome Atlas (TCGA). We constructed a Pan-Cancer dataset from 23 tumor types and explored NOX4 expression patterns in relation to EMT and patient survival. NOX4 mRNA levels increase as a function of cancer progression in several cancers and correlate with Mut-p53 mRNA and genes involved in programs of EMT, cellular adhesion, migration, and angiogenesis. Tumor macrophages appear to be a source of NOX2, whose association with genetic programs of cancer progression emulate that of NOX4. Notably, increased NOX4 expression is linked to poorer survival in patients with Mut-TP53, but better survival in patients with WT-TP53. NOX4 is negatively associated with markers of apoptosis and positively with markers of proliferation in patients with Mut-TP53, consistent with their poorer survival. These findings suggest that TP53 mutations could “switch” NOX4 from being protective and an indicator of good prognosis to deleterious by promoting programs favoring cancer progression. Full article
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22 pages, 2388 KiB  
Article
Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases
by Rosario Ammendola, Melania Parisi, Gabriella Esposito and Fabio Cattaneo
Antioxidants 2021, 10(1), 134; https://doi.org/10.3390/antiox10010134 - 19 Jan 2021
Cited by 16 | Viewed by 3696
Abstract
Background: Formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of chronic inflammatory diseases, being activated either by pro-resolving or proinflammatory ligands. FPR2-associated signal transduction pathways result in phosphorylation of several proteins and in NADPH oxidase activation. We, herein, investigated molecular mechanisms [...] Read more.
Background: Formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of chronic inflammatory diseases, being activated either by pro-resolving or proinflammatory ligands. FPR2-associated signal transduction pathways result in phosphorylation of several proteins and in NADPH oxidase activation. We, herein, investigated molecular mechanisms underlying phosphorylation of heat shock protein 27 (HSP27), oxidative stress responsive kinase 1 (OSR1), and myristolated alanine-rich C-kinase substrate (MARCKS) elicited by the pro-resolving FPR2 agonists WKYMVm and annexin A1 (ANXA1). Methods: CaLu-6 cells or p22phoxCrispr/Cas9 double nickase CaLu-6 cells were incubated for 5 min with WKYMVm or ANXA1, in the presence or absence of NADPH oxidase inhibitors. Phosphorylation at specific serine residues of HSP27, OSR1, and MARCKS, as well as the respective upstream kinases activated by FPR2 stimulation was analysed. Results: Blockade of NADPH oxidase functions prevents WKYMVm- and ANXA1-induced HSP-27(Ser82), OSR1(Ser339) and MARCKS(Ser170) phosphorylation. Moreover, NADPH oxidase inhibitors prevent WKYMVm- and ANXA1-dependent activation of p38MAPK, PI3K and PKCδ, the kinases upstream to HSP-27, OSR1 and MARCKS, respectively. The same results were obtained in p22phoxCrispr/Cas9 cells. Conclusions: FPR2 shows an immunomodulatory role by regulating proinflammatory and anti-inflammatory activities and NADPH oxidase is a key regulator of inflammatory pathways. The activation of NADPH oxidase-dependent pro-resolving downstream signals suggests that FPR2 signalling and NADPH oxidase could represent novel targets for inflammation therapeutic intervention. Full article
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15 pages, 3234 KiB  
Communication
Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells
by Katarzyna Piszczatowska, Dorota Przybylska, Ewa Sikora and Grażyna Mosieniak
Antioxidants 2020, 9(12), 1248; https://doi.org/10.3390/antiox9121248 - 8 Dec 2020
Cited by 17 | Viewed by 3186
Abstract
NADPH oxidases (NOX) are commonly expressed ROS-producing enzymes that participate in the regulation of many signaling pathways, which influence cell metabolism, survival, and proliferation. Due to their high expression in several different types of cancer it was postulated that NOX promote tumor progression, [...] Read more.
NADPH oxidases (NOX) are commonly expressed ROS-producing enzymes that participate in the regulation of many signaling pathways, which influence cell metabolism, survival, and proliferation. Due to their high expression in several different types of cancer it was postulated that NOX promote tumor progression, growth, and survival. Thus, the inhibition of NOX activity was considered to have therapeutic potential. One of the possible outcomes of anticancer therapy, which has recently gained much interest, is cancer cell senescence. The induction of senescence leads to prolonged inhibition of proliferation and contributes to tumor growth restriction. The aim of our studies was to investigate the influence of low, non-toxic doses of diphenyleneiodonium chloride (DPI), a potent inhibitor of flavoenzymes including NADPH oxidases, on p53-proficient and p53-deficient HCT116 human colon cancer cells and MCF-7 breast cancer cells. We demonstrated that the temporal treatment of HCT116 and MCF-7 cancer cells (both p53 wild-type) with DPI caused induction of senescence, that was correlated with decreased level of ROS and upregulation of p53/p21 proteins. On the contrary, in the case of p53−/− HCT116 cells, apoptosis was shown to be the prevailing effect of DPI treatment. Thus, our studies provided a proof that inhibiting ROS production, and by this means influencing ROS sensitive pathways, remains an alternative strategy to facilitate so called therapy-induced senescence in cancers. Full article
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14 pages, 1992 KiB  
Article
Nox4 Facilitates TGFβ1-Induced Fibrotic Response in Human Tenon’s Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery
by Manisha H. Shah, Elsa C. Chan, Nicole J. Van Bergen, Surinder S. Pandav, Sze Ng, Jonathan G. Crowston and Hitesh M. Peshavariya
Antioxidants 2020, 9(11), 1126; https://doi.org/10.3390/antiox9111126 - 13 Nov 2020
Cited by 11 | Viewed by 2479
Abstract
Collagen accumulation in sub-conjunctival tissue at the surgical wound is one of the major complications associated with glaucoma filtration surgery (GFS). This process often leads to unwanted fibrotic scar formation at the lesion site and dysfunction of tissues. Previously, we demonstrated that NADPH [...] Read more.
Collagen accumulation in sub-conjunctival tissue at the surgical wound is one of the major complications associated with glaucoma filtration surgery (GFS). This process often leads to unwanted fibrotic scar formation at the lesion site and dysfunction of tissues. Previously, we demonstrated that NADPH oxidase 4 (Nox4) is implicated in transforming growth factor-beta (TGFβ)-induced collagen production in ocular fibroblasts and scarring responses in a mouse model of corneal injury. Here, we propose that Nox4 is an important facilitator of TGFβ-induced responses. We tested this hypothesis in human Tenon’s fibroblasts (HTF) and also assessed a role of Nox4 in an experimental mouse model of GFS. TGFβ1 induced Nox4 mRNA expression but downregulated Nox5 in HTF. Targeting Nox4 gene expression with an adenovirus carrying a Nox4 small interfering RNA (siRNA) (Ad-Nox4i) or removal of hydrogen peroxide (H2O2) with EUK-134 (25 μM) in HTFs significantly reduced TGFβ1-induced Nox4 expression, H2O2 production, and collagen synthesis (p < 0.05, n = 3–6). SIS3 (5 μM) that prevents Smad3 phosphorylation is found to suppress TGFβ1-induced collagen production in HTFs. Furthermore, Ad-Nox4i and EUK-134 both abolished TGFβ1-stimulated proliferation of HTFs. We also compared collagen deposition at the wound arising from GFS between wildtype (WT) and Nox4 knockout (KO) mice. Both collagen deposition and fibrovascularization at the wound were significantly decreased in Nox4 KO mice at 14 days after GFS. Our results provide comprehensive evidence that Nox4 is an important mediator for TGFβ1-induced responses in HTFs and collagen deposition in surgical wound following GFS in mice. As such, pharmacological inhibition of Nox4 would be a viable therapeutic strategy for the control of scarring after glaucoma surgery. Full article
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19 pages, 3994 KiB  
Article
NOX2ko Mice Show Largely Increased Expression of a Mutated NOX2 mRNA Encoding an Inactive NOX2 Protein
by Monika Göllner, Irmgard Ihrig-Biedert, Victoria Petermann, Sabrina Saurin, Matthias Oelze, Swenja Kröller-Schön, Ksenija Vujacic-Mirski, Marin Kuntic, Andrea Pautz, Andreas Daiber and Hartmut Kleinert
Antioxidants 2020, 9(11), 1043; https://doi.org/10.3390/antiox9111043 - 26 Oct 2020
Cited by 4 | Viewed by 3093
Abstract
Background: The superoxide-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2 or gp91phox, the phagocytic isoform) was reported as a major source of oxidative stress in various human diseases. Genetic deletion is widely used to study the impact of NOX2-derived reactive oxygen species [...] Read more.
Background: The superoxide-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2 or gp91phox, the phagocytic isoform) was reported as a major source of oxidative stress in various human diseases. Genetic deletion is widely used to study the impact of NOX2-derived reactive oxygen species (ROS) on disease development and progression in various animal models. Here, we investigate why NOX2 knockout mice show no NOX2 activity but express NOX2 mRNA and protein. Methods and Results: Oxidative burst (NOX2-dependent formation of ROS) was measured by L-012-based chemiluminescence and was largely absent in whole blood of NOX2 knockout mice. Protein expression was still detectable in different tissues of the NOX2 knockout mice, at the expected and a slightly lower molecular weight (determined by Western blot). The NOX2 gene was even largely enhanced at its expressional level in NOX2 knockout mice. RNA sequencing revealed a modified NOX2 mRNA in the knockout mice that is obviously translated to a truncated inactive mutant enzyme. Conclusion: Although the commercial NOX2 knockout mice display no considerable enzymatic NOX2 activity, expression of the NOX2 gene (when using standard primers) and protein (when using antibodies binding to the carboxy-terminal end) can still be detected, which may lead to confusion among investigators. Full article
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Review

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28 pages, 1792 KiB  
Review
NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function
by Tullia Maraldi, Cristina Angeloni, Cecilia Prata and Silvana Hrelia
Antioxidants 2021, 10(6), 973; https://doi.org/10.3390/antiox10060973 - 17 Jun 2021
Cited by 32 | Viewed by 4189
Abstract
One of the major sources of reactive oxygen species (ROS) generated within stem cells is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOXs), which are critical determinants of the redox state beside antioxidant defense mechanisms. This balance is involved in [...] Read more.
One of the major sources of reactive oxygen species (ROS) generated within stem cells is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOXs), which are critical determinants of the redox state beside antioxidant defense mechanisms. This balance is involved in another one that regulates stem cell fate: indeed, self-renewal, proliferation, and differentiation are decisive steps for stem cells during embryo development, adult tissue renovation, and cell therapy application. Ex vivo culture-expanded stem cells are being investigated for tissue repair and immune modulation, but events such as aging, senescence, and oxidative stress reduce their ex vivo proliferation, which is crucial for their clinical applications. Here, we review the role of NOX-derived ROS in stem cell biology and functions, focusing on positive and negative effects triggered by the activity of different NOX isoforms. We report recent findings on downstream molecular targets of NOX-ROS signaling that can modulate stem cell homeostasis and lineage commitment and discuss the implications in ex vivo expansion and in vivo engraftment, function, and longevity. This review highlights the role of NOX as a pivotal regulator of several stem cell populations, and we conclude that these aspects have important implications in the clinical utility of stem cells, but further studies on the effects of pharmacological modulation of NOX in human stem cells are imperative. Full article
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13 pages, 841 KiB  
Review
Diabetic Retinopathy and NADPH Oxidase-2: A Sweet Slippery Road
by Renu A. Kowluru
Antioxidants 2021, 10(5), 783; https://doi.org/10.3390/antiox10050783 - 15 May 2021
Cited by 22 | Viewed by 2971
Abstract
Diabetic retinopathy remains the leading cause of vision loss in working-age adults. The multi-factorial nature of the disease, along with the complex structure of the retina, have hindered in elucidating the exact molecular mechanism(s) of this blinding disease. Oxidative stress appears to play [...] Read more.
Diabetic retinopathy remains the leading cause of vision loss in working-age adults. The multi-factorial nature of the disease, along with the complex structure of the retina, have hindered in elucidating the exact molecular mechanism(s) of this blinding disease. Oxidative stress appears to play a significant role in its development and experimental models have shown that an increase in cytosolic Reacttive Oxygen Speies (ROS) due to the activation of NADPH oxidase 2 (Nox2), is an early event, which damages the mitochondria, accelerating loss of capillary cells. One of the integral proteins in the assembly of Nox2 holoenzyme, Rac1, is also activated in diabetes, and due to epigenetic modifications its gene transcripts are upregulated. Moreover, addition of hyperlipidemia in a hyperglycemic milieu (type 2 diabetes) further exacerbates Rac1-Nox2-ROS activation, and with time, this accelerates and worsens the mitochondrial damage, ultimately leading to the accelerated capillary cell loss and the development of diabetic retinopathy. Nox2, a multicomponent enzyme, is a good candidate to target for therapeutic interventions, and the inhibitors of Nox2 and Rac1 (and its regulators) are in experimental or clinical trials for other diseases; their possible use to prevent/halt retinopathy will be a welcoming sign for diabetic patients. Full article
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14 pages, 4521 KiB  
Review
The Role of NADPH Oxidase in Neuronal Death and Neurogenesis after Acute Neurological Disorders
by Song Hee Lee, Minwoo Lee, Dong Gyun Ko, Bo Young Choi and Sang Won Suh
Antioxidants 2021, 10(5), 739; https://doi.org/10.3390/antiox10050739 - 7 May 2021
Cited by 15 | Viewed by 3523
Abstract
Oxidative stress is a well-known common pathological process involved in mediating acute neurological injuries, such as stroke, traumatic brain injury, epilepsy, and hypoglycemia-related neuronal injury. However, effective therapeutic measures aimed at scavenging free reactive oxygen species have shown little success in clinical trials. [...] Read more.
Oxidative stress is a well-known common pathological process involved in mediating acute neurological injuries, such as stroke, traumatic brain injury, epilepsy, and hypoglycemia-related neuronal injury. However, effective therapeutic measures aimed at scavenging free reactive oxygen species have shown little success in clinical trials. Recent studies have revealed that NADPH oxidase, a membrane-bound enzyme complex that catalyzes the production of a superoxide free radical, is one of the major sources of cellular reactive oxygen species in acute neurological disorders. Furthermore, several studies, including our previous ones, have shown that the inhibition of NADPH oxidase can reduce subsequent neuronal injury in neurological disease. Moreover, maintaining appropriate levels of NADPH oxidase has also been shown to be associated with proper neurogenesis after neuronal injury. This review aims to present a comprehensive overview of the role of NADPH oxidase in neuronal death and neurogenesis in multiple acute neurological disorders and to explore potential pharmacological strategies targeting the NADPH-related oxidative stress pathways. Full article
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17 pages, 1054 KiB  
Review
Oxidative Stress and the Role of NADPH Oxidase in Glaucoma
by Jennifer C. Fan Gaskin, Manisha H. Shah and Elsa C. Chan
Antioxidants 2021, 10(2), 238; https://doi.org/10.3390/antiox10020238 - 4 Feb 2021
Cited by 26 | Viewed by 3568
Abstract
Glaucoma is characterised by loss of retinal ganglion cells, and their axons and many pathophysiological processes are postulated to be involved. It is increasingly understood that not one pathway underlies glaucoma aetiology, but rather they occur as a continuum that ultimately results in [...] Read more.
Glaucoma is characterised by loss of retinal ganglion cells, and their axons and many pathophysiological processes are postulated to be involved. It is increasingly understood that not one pathway underlies glaucoma aetiology, but rather they occur as a continuum that ultimately results in the apoptosis of retinal ganglion cells. Oxidative stress is recognised as an important mechanism of cell death in many neurodegenerative diseases, including glaucoma. NADPH oxidase (NOX) are enzymes that are widely expressed in vascular and non-vascular cells, and they are unique in that they primarily produce reactive oxygen species (ROS). There is mounting evidence that NOX are an important source of ROS and oxidative stress in glaucoma and other retinal diseases. This review aims to provide a perspective on the complex role of oxidative stress in glaucoma, in particular how NOX expression may influence glaucoma pathogenesis as illustrated by different experimental models of glaucoma and highlights potential therapeutic targets that may offer a novel treatment option to glaucoma patients. Full article
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22 pages, 2137 KiB  
Review
Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer’s Disease Murine Models
by Leticia Guadalupe Fragoso-Morales, José Correa-Basurto and Martha Cecilia Rosales-Hernández
Antioxidants 2021, 10(2), 218; https://doi.org/10.3390/antiox10020218 - 2 Feb 2021
Cited by 18 | Viewed by 4285
Abstract
Alzheimer’s disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory [...] Read more.
Alzheimer’s disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD. Full article
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16 pages, 1954 KiB  
Review
Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages
by Steen Vang Petersen, Nanna Bach Poulsen, Cecilie Linneberg Matthiesen and Frederik Vilhardt
Antioxidants 2021, 10(2), 172; https://doi.org/10.3390/antiox10020172 - 25 Jan 2021
Cited by 12 | Viewed by 3823
Abstract
Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, [...] Read more.
Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells. Full article
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