Journal articles: 'NADPH oxidase (Nox) family'

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Bedard, Karen, and Karl-Heinz Krause. "The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology." Physiological Reviews 87, no. 1 (January 2007): 245–313. http://dx.doi.org/10.1152/physrev.00044.2005.

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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/gp91phox), 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 actvity 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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Maturana, Andrés, Karl-Heinz Krause, and Nicolas Demaurex. "NOX Family NADPH Oxidases." Journal of General Physiology 120, no. 6 (November 25, 2002): 781–86. http://dx.doi.org/10.1085/jgp.20028713.

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Donkó, Ágnes, Zalán Péterfi, Adrienn Sum, Thomas Leto, and Miklós Geiszt. "Dual oxidases." Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1464 (November 4, 2005): 2301–8. http://dx.doi.org/10.1098/rstb.2005.1767.

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Reactive oxygen species (ROS) have an important role in various physiological processes including host defence, mitogenesis, hormone biosynthesis, apoptosis and fertilization. Currently, the most characterized ROS-producing system operates in phagocytic cells, where ROS generated during phagocytosis act in host defence. Recently, several novel homologues of the phagocytic oxidase have been discovered and this protein family is now designated as the NOX/DUOX family of NADPH oxidases. NOX/DUOX enzymes function in a variety of tissues, including colon, kidney, thyroid gland, testis, salivary glands, airways and lymphoid organs. Importantly, members of the enzyme family are also found in non-mammalian species, including Caenorhabditis elegans and sea urchin. The physiological functions of novel NADPH oxidase enzymes are currently largely unknown. This review focuses on our current knowledge about dual oxidases.

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Vermot, Annelise, Isabelle Petit-Härtlein, Susan M. E. Smith, and Franck Fieschi. "NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology." Antioxidants 10, no. 6 (June 1, 2021): 890. http://dx.doi.org/10.3390/antiox10060890.

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The reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX) was first identified in the membrane of phagocytic cells. For many years, its only known role was in immune defense, where its ROS production leads to the destruction of pathogens by the immune cells. NOX from phagocytes catalyzes, via one-electron trans-membrane transfer to molecular oxygen, the production of the superoxide anion. Over the years, six human homologs of the catalytic subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the NOX2/gp91phox component present in the phagocyte NADPH oxidase assembly itself, the homologs are now referred to as the NOX family of NADPH oxidases. NOX are complex multidomain proteins with varying requirements for assembly with combinations of other proteins for activity. The recent structural insights acquired on both prokaryotic and eukaryotic NOX open new perspectives for the understanding of the molecular mechanisms inherent to NOX regulation and ROS production (superoxide or hydrogen peroxide). This new structural information will certainly inform new investigations of human disease. As specialized ROS producers, NOX enzymes participate in numerous crucial physiological processes, including host defense, the post-translational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. These diversities of physiological context will be discussed in this review. We also discuss NOX misregulation, which can contribute to a wide range of severe pathologies, such as atherosclerosis, hypertension, diabetic nephropathy, lung fibrosis, cancer, or neurodegenerative diseases, giving this family of membrane proteins a strong therapeutic interest.

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Gray, Stephen P., Ajay M. Shah, and Ioannis Smyrnias. "NADPH oxidase 4 and its role in the cardiovascular system." Vascular Biology 1, no. 1 (August 12, 2019): H59—H66. http://dx.doi.org/10.1530/vb-19-0014.

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The heart relies on complex mechanisms that provide adequate myocardial oxygen supply in order to maintain its contractile function. At the cellular level, oxygen undergoes one electron reduction to superoxide through the action of different types of oxidases (e.g. xanthine oxidases, uncoupled nitric oxide synthases, NADPH oxidases or NOX). Locally generated oxygen-derived reactive species (ROS) are involved in various signaling pathways including cardiac adaptation to different types of physiological and pathophysiological stresses (e.g. hypoxia or overload). The specific effects of ROS and their regulation by oxidases are dependent on the amount of ROS generated and their specific subcellular localization. The NOX family of NADPH oxidases is a main source of ROS in the heart. Seven distinct Nox isoforms (NOX1–NOX5 and DUOX1 and 2) have been identified, of which NOX1, 2, 4 and 5 have been characterized in the cardiovascular system. For the purposes of this review, we will focus on the effects of NADPH oxidase 4 (NOX4) in the heart.

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Montezano, Augusto C., Dylan Burger, Graziela S. Ceravolo, Hiba Yusuf, Maria Montero, and Rhian M. Touyz. "Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5." Clinical Science 120, no. 4 (November 2, 2010): 131–41. http://dx.doi.org/10.1042/cs20100384.

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The Noxes (NADPH oxidases) are a family of ROS (reactive oxygen species)-generating enzymes. Of the seven family members, four have been identified as important sources of ROS in the vasculature: Nox1, Nox2, Nox4 and Nox5. Although Nox isoforms can be influenced by the same stimulus and co-localize in cellular compartments, their tissue distribution, subcellular regulation, requirement for cofactors and NADPH oxidase subunits and ability to generate specific ROS differ, which may help to understand the multiplicity of biological functions of these oxidases. Nox4 and Nox5 are the newest isoforms identified in the vasculature. Nox4 is the major isoform expressed in renal cells and appear to produce primarily H2O2. The Nox5 isoform produces ROS in response to increased levels of intracellular Ca2+ and does not require the other NADPH oxidase subunits for its activation. The present review focuses on these unique Noxes, Nox4 and Nox5, and provides novel concepts related to the regulation and interaction in the vasculature, and discusses new potential roles for these isoforms in vascular biology.

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Bánfi, Botond, Brigitte Malgrange, Judit Knisz, Klaus Steger, Michel Dubois-Dauphin, and Karl-Heinz Krause. "NOX3, a Superoxide-generating NADPH Oxidase of the Inner Ear." Journal of Biological Chemistry 279, no. 44 (August 23, 2004): 46065–72. http://dx.doi.org/10.1074/jbc.m403046200.

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Reactive oxygen species (ROS) play a major role in drug-, noise-, and age-dependent hearing loss, but the source of ROS in the inner ear remains largely unknown. Herein, we demonstrate that NADPH oxidase (NOX) 3, a member of the NOX/dual domain oxidase family of NADPH oxidases, is highly expressed in specific portions of the inner ear. As assessed by real-time PCR, NOX3 mRNA expression in the inner ear is at least 50-fold higher than in any other tissues where its expression has been observed (e.g.fetal kidney, brain, skull). Microdissection andin situhybridization studies demonstrated that NOX3 is localized to the vestibular and cochlear sensory epithelia and to the spiral ganglions. Transfection of human embryonic kidney 293 cells with NOX3 revealed that it generates low levels of ROS on its own but produces high levels of ROS upon co-expression with cytoplasmic NOX subunits. NOX3-dependent superoxide production required a stimulus in the absence of subunits and upon co-expression with phagocyte NADPH oxidase subunits p47phoxand p67phox, but it was stimulus-independent upon co-expression with colon NADPH oxidase subunits NOX organizer 1 and NOX activator 1. Pre-incubation of NOX3-transfected human embryonic kidney 293 cells with the ototoxic drug cisplatin markedly enhanced superoxide production, in both the presence and the absence of subunits. Our data suggest that NOX3 is a relevant source of ROS generation in the cochlear and vestibular systems and that NOX3-dependent ROS generation might contribute to hearing loss and balance problems in response to ototoxic drugs.

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Maraldi, Tullia. "Natural Compounds as Modulators of NADPH Oxidases." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/271602.

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Reactive oxygen species (ROS) are cellular signals generated ubiquitously by all mammalian cells, but their relative unbalance triggers also diseases through intracellular damage to DNA, RNA, proteins, and lipids. NADPH oxidases (NOX) are the only known enzyme family with the sole function to produce ROS. The NOX physiological functions concern host defence, cellular signaling, regulation of gene expression, and cell differentiation. On the other hand, increased NOX activity contributes to a wide range of pathological processes, including cardiovascular diseases, neurodegeneration, organ failure, and cancer. Therefore targeting these enzymatic ROS sources by natural compounds, without affecting the physiological redox state, may be an important tool. This review summarizes the current state of knowledge of the role of NOX enzymes in physiology and pathology and provides an overview of the currently available NADPH oxidase inhibitors derived from natural extracts such as polyphenols.

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Roy, Krishnendu, Yongzhong Wu, Jennifer L. Meitzler, Agnes Juhasz, Han Liu, Guojian Jiang, Jiamo Lu, Smitha Antony, and James H. Doroshow. "NADPH oxidases and cancer." Clinical Science 128, no. 12 (March 27, 2015): 863–75. http://dx.doi.org/10.1042/cs20140542.

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The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1–5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-γ, tumour necrosis factor α, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies.

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Matuz-Mares, Deyamira, Héctor Vázquez-Meza, and María Magdalena Vilchis-Landeros. "NOX as a Therapeutic Target in Liver Disease." Antioxidants 11, no. 10 (October 16, 2022): 2038. http://dx.doi.org/10.3390/antiox11102038.

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The nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NADPH oxidase or NOX) plays a critical role in the inflammatory response and fibrosis in several organs such as the lungs, pancreas, kidney, liver, and heart. In the liver, NOXs contribute, through the generation of reactive oxygen species (ROS), to hepatic fibrosis by acting through multiple pathways, including hepatic stellate cell activation, proliferation, survival, and migration of hepatic stellate cells; hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both Kupffer cells and hepatic stellate cells. ROS are overwhelmingly produced during malignant transformation and hepatic carcinogenesis (HCC), creating an oxidative microenvironment that can cause different and various types of cellular stress, including DNA damage, ER stress, cell death of damaged hepatocytes, and oxidative stress. NOX1, NOX2, and NOX4, members of the NADPH oxidase family, have been linked to the production of ROS in the liver. This review will analyze some diseases related to an increase in oxidative stress and its relationship with the NOX family, as well as discuss some therapies proposed to slow down or control the disease’s progression.

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Case, Christopher L., Jason R. Rodriguez, and Biswarup Mukhopadhyay. "Characterization of an NADH oxidase of the flavin-dependent disulfide reductase family from Methanocaldococcus jannaschii." Microbiology 155, no. 1 (January 1, 2009): 69–79. http://dx.doi.org/10.1099/mic.0.024265-0.

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Methanocaldococcus jannaschii, a deeply rooted hyperthermophilic anaerobic methanarchaeon from a deep-sea hydrothermal vent, carries an NADH oxidase (Nox) homologue (MJ0649). According to the characteristics described here, MJ0649 represents an unusual member within group 3 of the flavin-dependent disulfide reductase (FDR) family. This FDR group comprises Nox, NADH peroxidases (Npx) and coenzyme A disulfide reductases (CoADRs); each carries a Cys residue that forms Cys-sulfenic acid during catalysis. A sequence analysis identified MJ0649 as a CoADR homologue. However, recombinant MJ0649 (rMJNox), expressed in Escherichia coli and purified to homogeneity an 86 kDa homodimer with 0.27 mol FAD (mol subunit)−1, showed Nox but not CoADR activity. Incubation with FAD increased FAD content to 1 mol (mol subunit)−1 and improved NADH oxidase activity 3.4-fold. The FAD-incubated enzyme was characterized further. The optimum pH and temperature were ≥10 and ≥95 °C, respectively. At pH 7 and 83 °C, apparent K m values for NADH and O2 were 3 μM and 1.9 mM, respectively, and the specific activity at 1.4 mM O2 was 60 μmol min−1 mg−1; 62 % of NADH-derived reducing equivalents were recovered as H2O2 and the rest probably generated H2O. rMjNox had poor NADPH oxidase, NADH peroxidase and superoxide formation activities. It reduced ferricyanide, plumbagin and 5,5′-dithiobis(2-nitrobenzoic acid), but not disulfide coenzyme A and disulfide coenzyme M. Due to a high K m, O2 is not a physiologically relevant substrate for MJ0649; its true substrate remains unknown.

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Wang, Yupei, Qing Liu, Weiping Zhao, Xin Zhou, Guoying Miao, Chao Sun, and Hong Zhang. "NADPH Oxidase Activation Contributes to Heavy Ion Irradiation–Induced Cell Death." Dose-Response 15, no. 1 (March 1, 2017): 155932581769969. http://dx.doi.org/10.1177/1559325817699697.

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Increased oxidative stress plays an important role in heavy ion radiation–induced cell death. The mechanism involved in the generation of elevated reactive oxygen species (ROS) is not fully illustrated. Here we show that NADPH oxidase activation is closely related to heavy ion radiation–induced cell death via excessive ROS generation. Cell death and cellular ROS can be greatly reduced in irradiated cancer cells with the preincubation of diphenyleneiodium, an inhibitor of NADPH oxidase. Most of the NADPH oxidase (NOX) family proteins (NOX1, NOX2, NOX3, NOX4, and NOX5) showed increased expression after heavy ion irradiation. Meanwhile, the cytoplasmic subunit p47phox was translocated to the cell membrane and localized with NOX2 to form reactive NADPH oxidase. Our data suggest for the first time that ROS generation, as mediated by NADPH oxidase activation, could be an important contributor to heavy ion irradiation–induced cell death.

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Szanto, Ildiko, Marc Pusztaszeri, and Maria Mavromati. "H2O2 Metabolism in Normal Thyroid Cells and in Thyroid Tumorigenesis: Focus on NADPH Oxidases." Antioxidants 8, no. 5 (May 10, 2019): 126. http://dx.doi.org/10.3390/antiox8050126.

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Thyroid hormone synthesis requires adequate hydrogen peroxide (H2O2) production that is utilized as an oxidative agent during the synthesis of thyroxin (T4) and triiodothyronine (T3). Thyroid H2O2 is generated by a member of the family of NADPH oxidase enzymes (NOX-es), termed dual oxidase 2 (DUOX2). NOX/DUOX enzymes produce reactive oxygen species (ROS) as their unique enzymatic activity in a timely and spatially regulated manner and therefore, are important regulators of diverse physiological processes. By contrast, dysfunctional NOX/DUOX-derived ROS production is associated with pathological conditions. Inappropriate DUOX2-generated H2O2 production results in thyroid hypofunction in rodent models. Recent studies also indicate that ROS improperly released by NOX4, another member of the NOX family, are involved in thyroid carcinogenesis. This review focuses on the current knowledge concerning the redox regulation of thyroid hormonogenesis and cancer development with a specific emphasis on the NOX and DUOX enzymes in these processes.

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Li, Jian, Michael Stouffs, Lena Serrander, Botond Banfi, Esther Bettiol, Yves Charnay, Klaus Steger, Karl-Heinz Krause, and Marisa E. Jaconi. "The NADPH Oxidase NOX4 Drives Cardiac Differentiation: Role in Regulating Cardiac Transcription Factors and MAP Kinase Activation." Molecular Biology of the Cell 17, no. 9 (September 2006): 3978–88. http://dx.doi.org/10.1091/mbc.e05-06-0532.

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Reactive oxygen species (ROS) generated by the NOX family of NADPH oxidases have been described to act as second messengers regulating cell growth and differentiation. However, such a function has hitherto not been convincingly demonstrated. We investigated the role of NOX-derived ROS in cardiac differentiation using mouse embryonic stem cells. ROS scavengers prevented the appearance of spontaneously beating cardiac cells within embryoid bodies. Down-regulation of NOX4, the major NOX isoform present during early stages of differentiation, suppressed cardiogenesis. This was rescued by a pulse of low concentrations of hydrogen peroxide 4 d before spontaneous beating appears. Mechanisms of ROS-dependent signaling included p38 mitogen-activated protein kinase (MAPK) activation and nuclear translocation of the cardiac transcription factor myocyte enhancer factor 2C (MEF2C). Our results provide first molecular evidence that the NOX family of NADPH oxidases regulate vertebrate developmental processes.

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Miyano, Kei, Hirofumi Koga, Reiko Minakami, and Hideki Sumimoto. "The insert region of the Rac GTPases is dispensable for activation of superoxide-producing NADPH oxidases." Biochemical Journal 422, no. 2 (August 13, 2009): 373–82. http://dx.doi.org/10.1042/bj20082182.

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Rac1 and Rac2, which belong to the Rho subfamily of Ras-related GTPases, play an essential role in activation of gp91phox/Nox2 (cytochrome b-245, β polypeptide; also known as Cybb), the catalytic core of the superoxide-producing NADPH oxidase in phagocytes. Rac1 also contributes to activation of the non-phagocytic oxidases Nox1 (NADPH oxidase 1) and Nox3 (NADPH oxidase 3), each related closely to gp91phox/Nox2. It has remained controversial whether the insert region of Rac (amino acids 123–135), unique to the Rho subfamily proteins, is involved in gp91phox/Nox2 activation. In the present study we show that removal of the insert region from Rac1 neither affects activation of gp91phox/Nox2, which is reconstituted under cell-free and whole-cell conditions, nor blocks its localization to phagosomes during ingestion of IgG-coated beads by macrophage-like RAW264.7 cells. The insert region of Rac2 is also dispensable for gp91phox/Nox2 activation at the cellular level. Although Rac2, as well as Rac1, is capable of enhancing superoxide production by Nox1 and Nox3, the enhancements by the two GTPases are both independent of the insert region. We also demonstrate that Rac3, a third member of the Rac family in mammals, has an ability to activate the three oxidases and that the activation does not require the insert region. Thus the insert region of the Rac GTPases does not participate in regulation of the Nox family NADPH oxidases.

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Cave, Alison, David Grieve, Sofian Johar, Min Zhang, and Ajay M. Shah. "NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology." Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1464 (November 4, 2005): 2327–34. http://dx.doi.org/10.1098/rstb.2005.1772.

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Chronic heart failure, secondary to left ventricular hypertrophy or myocardial infarction, is a condition with increasing morbidity and mortality. Although the mechanisms underlying the development and progression of this condition remain a subject of intense interest, there is now growing evidence that redox-sensitive pathways play an important role. This article focuses on the involvement of reactive oxygen species derived from a family of superoxide-generating enzymes, termed NADPH oxidases (NOXs), in the pathophysiology of ventricular hypertrophy, the accompanying interstitial fibrosis and subsequent heart failure. In particular, the apparent ability of the different NADPH oxidase isoforms to define the response of a cell to a range of physiological and pathophysiological stimuli is reviewed. If confirmed, these data would suggest that independently targeting different members of the NOX family may hold the potential for therapeutic intervention in the treatment of cardiac disease.

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Sciarretta, Sebastiano, Derek Yee, Paul Ammann, Narayani Nagarajan, Massimo Volpe, Giacomo Frati, and Junichi Sadoshima. "Role of NADPH oxidase in the regulation of autophagy in cardiomyocytes." Clinical Science 128, no. 7 (December 9, 2014): 387–403. http://dx.doi.org/10.1042/cs20140336.

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In the past several years, it has been demonstrated that the reactive oxygen species (ROS) may act as intracellular signalling molecules to activate or inhibit specific signalling pathways and regulate physiological cellular functions. It is now well-established that ROS regulate autophagy, an intracellular degradation process. However, the signalling mechanisms through which ROS modulate autophagy in a regulated manner have only been minimally clarified. NADPH oxidase (Nox) enzymes are membrane-bound enzymatic complexes responsible for the dedicated generation of ROS. Different isoforms of Nox exist with different functions. Recent studies demonstrated that Nox-derived ROS can promote autophagy, with Nox2 and Nox4 representing the isoforms of Nox implicated thus far. Nox2- and Nox4-dependent autophagy plays an important role in the elimination of pathogens by phagocytes and in the regulation of vascular- and cancer-cell survival. Interestingly, we recently found that Nox is also important for autophagy regulation in cardiomyocytes. We found that Nox4, but not Nox2, promotes the activation of autophagy and survival in cardiomyocytes in response to nutrient deprivation and ischaemia through activation of the PERK (protein kinase RNA-like endoplasmic reticulum kinase) signalling pathway. In the present paper, we discuss the importance of Nox family proteins and ROS in the regulation of autophagy, with a particular focus on the role of Nox4 in the regulation of autophagy in the heart.

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Kim, Taeshin, and Mark A. Lawson. "GnRH Regulates Gonadotropin Gene Expression Through NADPH/Dual Oxidase-Derived Reactive Oxygen Species." Endocrinology 156, no. 6 (June 1, 2015): 2185–99. http://dx.doi.org/10.1210/en.2014-1709.

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Abstract The appropriate control of synthesis and secretion of the gonadotropin hormones LH and FSH by pituitary gonadotropes is essential for the regulation of reproduction. The hypothalamic neuropeptide GnRH is the central regulator of both processes, coordinating secretion with transcription and translation of the gonadotropin hormone subunit genes. The MAPK family of second messengers is strongly induced in gonadotropes upon GnRH stimulation, and multiple pathways activate these kinases. Intracellular reactive oxygen species participate in signaling cascades that target MAPKs, but also participate in signaling events indicative of cell stress. The NADPH oxidase (NOX)/dual oxidase (DUOX) family is a major enzymatic source of intracellular reactive oxygen, and we show that GnRH stimulation of mouse primary pituitary cells and the LβT2 gonadotrope cell line elevates intracellular reactive oxygen via NOX/DUOX activity. Mouse pituitary and LβT2 cells abundantly express NOX/DUOX and cofactor mRNAs. Pharmacological inhibition of NOX/DUOX activity diminishes GnRH-stimulated activation of MAPKs, immediate-early gene expression, and gonadotropin subunit gene expression. Inhibitor studies implicate the calcium-activated DUOX family as a major, but not exclusive, participant in GnRH signaling. Knockdown of DUOX2 in LβT2 cells reduces GnRH-induced Fshb, but not Lhb mRNA levels, suggesting differential sensitivity to DUOX activity. Finally, GnRH pulse-stimulated FSH and LH secretion are suppressed by inhibition of NOX/DUOX activity. These results indicate that reactive oxygen is a potent signaling intermediate produced in response to GnRH stimulation and further suggest that reactive oxygen derived from other sources may influence the gonadotrope response to GnRH stimulation.

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BEDARD, K., B. LARDY, and K. KRAUSE. "NOX family NADPH oxidases: Not just in mammals." Biochimie 89, no. 9 (September 2007): 1107–12. http://dx.doi.org/10.1016/j.biochi.2007.01.012.

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Brandes, Ralf P., and Katrin Schröder. "Differential vascular functions of Nox family NADPH oxidases." Current Opinion in Lipidology 19, no. 5 (October 2008): 513–18. http://dx.doi.org/10.1097/mol.0b013e32830c91e3.

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Nauseef, William M. "Biological Roles for the NOX Family NADPH Oxidases." Journal of Biological Chemistry 283, no. 25 (April 17, 2008): 16961–65. http://dx.doi.org/10.1074/jbc.r700045200.

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Brandes, Ralf P., Norbert Weissmann, and Katrin Schröder. "Nox family NADPH oxidases: Molecular mechanisms of activation." Free Radical Biology and Medicine 76 (November 2014): 208–26. http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.046.

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Ago, Tetsuro, Junya Kuroda, Masahiro Kamouchi, Junichi Sadoshima, and Takanari Kitazono. "Pathophysiological Roles of NADPH Oxidase/Nox Family Proteins in the Vascular System." Circulation Journal 75, no. 8 (2011): 1791–800. http://dx.doi.org/10.1253/circj.cj-11-0388.

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Wu, Qin, Ayse Gurpinar, Maxwell Roberts, Patrizia Camelliti, Michael R. Ruggieri, and Changhao Wu. "Identification of the NADPH Oxidase (Nox) Subtype and the Source of Superoxide Production in the Micturition Centre." Biology 11, no. 2 (January 24, 2022): 183. http://dx.doi.org/10.3390/biology11020183.

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Oxidative inflammatory damage to specialised brain centres may lead to dysfunction of their associated peripheral organs, such as the bladder. However, the source of reactive oxygen species (ROS) in specific brain regions that regulate bladder function is poorly understood. Of all ROS-generating enzymes, the NADPH oxidase (Nox) family produces ROS as its sole function and offers an advantage over other enzymes as a drug-targetable molecule to selectively control excessive ROS. We investigated whether the Nox 2 subtype is expressed in the micturition regulatory periaqueductal gray (PAG) and Barrington’s nucleus (pontine micturition centre, PMC) and examined Nox-derived ROS production in these structures. C57BL/6J mice were used; PAG, PMC, cardiac tissue, and aorta were isolated. Western blot determined Nox 2 expression. Lucigenin-enhanced chemiluminescence quantified real-time superoxide production. Western blot experiments demonstrated the presence of Nox 2 in PAG and PMC. There was significant NADPH-dependent superoxide production in both brain tissues, higher than that in cardiac tissue. Superoxide generation in these brain tissues was significantly suppressed by the Nox inhibitor diphenyleneiodonium (DPI) and also reduced by the Nox-2 specific inhibitor GSK2795039, comparable to aorta. These data provide the first evidence for the presence of Nox 2 and Nox-derived ROS production in micturition centres.

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Serrander, Lena, Laetitia Cartier, Karen Bedard, Botond Banfi, Bernard Lardy, Olivier Plastre, Andrzej Sienkiewicz, Lászlo Fórró, Werner Schlegel, and Karl-Heinz Krause. "NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation." Biochemical Journal 406, no. 1 (July 26, 2007): 105–14. http://dx.doi.org/10.1042/bj20061903.

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NOX4 is an enigmatic member of the NOX (NADPH oxidase) family of ROS (reactive oxygen species)-generating NADPH oxidases. NOX4 has a wide tissue distribution, but the physiological function and activation mechanisms are largely unknown, and its pharmacology is poorly understood. We have generated cell lines expressing NOX4 upon tetracycline induction. Tetracycline induced a rapid increase in NOX4 mRNA (1 h) followed closely (2 h) by a release of ROS. Upon tetracycline withdrawal, NOX4 mRNA levels and ROS release decreased rapidly (<24 h). In membrane preparations, NOX4 activity was selective for NADPH over NADH and did not require the addition of cytosol. The pharmacological profile of NOX4 was distinct from other NOX isoforms: DPI (diphenyleneiodonium chloride) and thioridazine inhibited the enzyme efficiently, whereas apocynin and gliotoxin did not (IC50>100 μM). The pattern of NOX4-dependent ROS generation was unique: (i) ROS release upon NOX4 induction was spontaneous without need for a stimulus, and (ii) the type of ROS released from NOX4-expressing cells was H2O2, whereas superoxide (O2−) was almost undetectable. Probes that allow detection of intracellular O2− generation yielded differential results: DHE (dihydroethidium) fluorescence and ACP (1-acetoxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine) ESR measurements did not detect any NOX4 signal, whereas a robust signal was observed with NBT. Thus NOX4 probably generates O2− within an intracellular compartment that is accessible to NBT (Nitro Blue Tetrazolium), but not to DHE or ACP. In conclusion, NOX4 has a distinct pharmacology and pattern of ROS generation. The close correlation between NOX4 mRNA and ROS generation might hint towards a function as an inducible NOX isoform.

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Judkins, Courtney P., Henry Diep, Brad R. S. Broughton, Anja E. Mast, Elizabeth U. Hooker, Alyson A. Miller, Stavros Selemidis, Gregory J. Dusting, Christopher G. Sobey, and Grant R. Drummond. "Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/−mice." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 1 (January 2010): H24—H32. http://dx.doi.org/10.1152/ajpheart.00799.2009.

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The Nox family NADPH oxidases are reactive oxygen species (ROS)-generating enzymes that are strongly implicated in atherogenesis. However, no studies have examined which Nox isoform(s) are involved. Here we investigated the role of the Nox2-containing NADPH oxidase in atherogenesis in apolipoprotein E-null (ApoE−/−) mice. Wild-type (C57Bl6/J), ApoE−/−, and Nox2−/y/ApoE−/−mice were maintained on a high-fat (21%) diet from 5 wk of age until they were 12 or 19 wk old. Mice were euthanized and their aortas removed for measurement of Nox2 expression (Western blot analysis and immunohistochemistry), ROS production (L012-enhanced chemiluminescence), nitric oxide (NO) bioavailability (contractions to Nω-nitro-l-arginine), and atherosclerotic plaque development along the aorta and in the aortic sinus. Nox2 expression was upregulated in the aortic endothelium of ApoE−/−mice before the appearance of lesions, and this was associated with elevated ROS levels. Within developing plaques, macrophages were also a prominent source of Nox2. The absence of Nox2 in Nox2−/y/ApoE−/−double-knockout mice had minimal effects on plasma lipids or lesion development in the aortic sinus in animals up to 19 wk of age. However, an en face examination of the aorta from the arch to the iliac bifurcation revealed a 50% reduction in lesion area in Nox2−/y/ApoE−/−versus ApoE−/−mice, and this was associated with a marked decrease in aortic ROS production and an increased NO bioavailability. In conclusion, this is the first demonstration of a role for Nox2-NADPH oxidase in vascular ROS production, reduced NO bioavailability, and early lesion development in ApoE−/−mice, highlighting this Nox isoform as a potential target for future therapies for atherosclerosis.

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Sofiullah, Siti Sarah M., Dharmani Devi Murugan, Suhaila Abd Muid, Wu Yuan Seng, Sharifah Zamiah Syed Abdul Kadir, Razif Abas, Nurul Raudzah Adib Ridzuan, Nor Hisam Zamakshshari, and Choy Ker Woon. "Natural Bioactive Compounds Targeting NADPH Oxidase Pathway in Cardiovascular Diseases." Molecules 28, no. 3 (January 20, 2023): 1047. http://dx.doi.org/10.3390/molecules28031047.

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Cardiovascular disease (CVD) is the leading cause of death worldwide, in both developed and developing countries. According to the WHO report, the morbidity and mortality caused by CVD will continue to rise with the estimation of death going up to 22.2 million in 2030. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) production induces endothelial nitric oxide synthase (eNOS) uncoupling and mitochondrial dysfunction, resulting in sustained oxidative stress and the development of cardiovascular diseases. Seven distinct members of the family have been identified of which four (namely, NOX1, 2, 4 and 5) may have cardiovascular functions. Currently, the treatment and management plan for patients with CVDs mainly depends on the drugs. However, prolonged use of prescribed drugs may cause adverse drug reactions. Therefore, it is crucial to find alternative treatment options with lesser adverse effects. Natural products have been gaining interest as complementary therapy for CVDs over the past decade due to their wide range of medicinal properties, including antioxidants. These might be due to their potent active ingredients, such as flavonoid and phenolic compounds. Numerous natural compounds have been demonstrated to have advantageous effects on cardiovascular disease via NADPH cascade. This review highlights the potential of natural products targeting NOX-derived ROS generation in treating CVDs. Emphasis is put on the activation of the oxidases, including upstream or downstream signalling events.

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Leto, Thomas L., and Miklos Geiszt. "Role of Nox Family NADPH Oxidases in Host Defense." Antioxidants & Redox Signaling 8, no. 9-10 (September 2006): 1549–61. http://dx.doi.org/10.1089/ars.2006.8.1549.

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Szanto, Ildiko. "NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation." International Journal of Molecular Sciences 23, no. 5 (February 28, 2022): 2702. http://dx.doi.org/10.3390/ijms23052702.

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Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.

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Maraldi, Tullia, Cristina Angeloni, Cecilia Prata, and Silvana Hrelia. "NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function." Antioxidants 10, no. 6 (June 17, 2021): 973. http://dx.doi.org/10.3390/antiox10060973.

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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.

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Minakami, Reiko, and Hideki Sumimotoa. "Phagocytosis-Coupled Activation of the Superoxide-Producing Phagocyte Oxidase, a Member of the NADPH Oxidase (Nox) Family." International Journal of Hematology 84, no. 3 (October 1, 2006): 193–98. http://dx.doi.org/10.1532/ijh97.06133.

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Heidari, Yasin, Ajay M. Shah, and Chris Gove. "NOX-2S is a new member of the NOX family of NADPH oxidases." Gene 335 (June 2004): 133–40. http://dx.doi.org/10.1016/j.gene.2004.03.019.

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Lassègue, Bernard, and Roza E. Clempus. "Vascular NAD(P)H oxidases: specific features, expression, and regulation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 2 (August 2003): R277—R297. http://dx.doi.org/10.1152/ajpregu.00758.2002.

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The importance of reactive oxygen species (ROS) in vascular physiology and pathology is becoming increasingly evident. All cell types in the vascular wall produce ROS derived from superoxide-generating protein complexes similar to the leukocyte NADPH oxidase. Specific features of the vascular enzymes include constitutive and inducible activities, substrate specificity, and intracellular superoxide production. Most phagocyte enzyme subunits are found in vascular cells, including the catalytic gp91phox (aka, nox2), which was the earliest member of the newly discovered nox family. However, smooth muscle frequently expresses nox1 rather than gp91phox, and nox4 is additionally present in all cell types. In cell culture, agonists increase ROS production by activating multiple signals, including protein kinase C and Rac, and by upregulating oxidase subunits. The oxidases are also upregulated in vascular disease and are involved in the development of atherosclerosis and a significant part of angiotensin II-induced hypertension, possibly via nox1 and nox4. Likewise, enhanced vascular oxidase activity is associated with diabetes. Therefore, members of this enzyme family appear to be important in vascular biology and disease and constitute promising targets for future therapeutic interventions.

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Kallenborn-Gerhardt, Wiebke, Katrin Schröder, and Achim Schmidtko. "NADPH Oxidases in Pain Processing." Antioxidants 11, no. 6 (June 14, 2022): 1162. http://dx.doi.org/10.3390/antiox11061162.

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Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.

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Landry, William D., and Thomas G. Cotter. "ROS signalling, NADPH oxidases and cancer." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 934–38. http://dx.doi.org/10.1042/bst20140060.

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ROS (reactive oxygen species) have long been regarded as a series of destructive molecules that have a detrimental effect on cell homoeostasis. In support of this are the myriad antioxidant defence systems nearly all eukaryotic cells have that are designed to keep the levels of ROS in check. However, research data emerging over the last decade have demonstrated that ROS can influence a range of cellular events in a manner similar to that seen for traditional second messenger molecules such as cAMP. Hydrogen peroxide (H2O2) appears to be the main ROS with such signalling properties, and this molecule has been shown to affect a wide range of cellular functions. Its localized synthesis by the Nox (NADPH oxidase) family of enzymes and how these enzymes are regulated is of particular interest to those who work in the field of tumour biology.

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Gabler, Christoph, Mohamed Elnageeb, Christoph Holder, and Ralf Einspanier. "Different mRNA Expression Pattern of NADPH Oxidase (NOX) Family Members in the Bovine Oviduct." Biology of Reproduction 81, Suppl_1 (July 1, 2009): 309. http://dx.doi.org/10.1093/biolreprod/81.s1.309.

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Kawahara, By, Mark T. Quinn, and J. David Lambeth. "Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes." BMC Evolutionary Biology 7, no. 1 (2007): 109. http://dx.doi.org/10.1186/1471-2148-7-109.

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Sedeek, Mona, Richard L. Hébert, Chris R. Kennedy, Kevin D. Burns, and Rhian M. Touyz. "Molecular mechanisms of hypertension: role of Nox family NADPH oxidases." Current Opinion in Nephrology and Hypertension 18, no. 2 (March 2009): 122–27. http://dx.doi.org/10.1097/mnh.0b013e32832923c3.

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Brandes, Ralf P., Norbert Weissmann, and Katrin Schröder. "Nox Family NADPH Oxidases in Mechano-Transduction: Mechanisms and Consequences." Antioxidants & Redox Signaling 20, no. 6 (February 20, 2014): 887–98. http://dx.doi.org/10.1089/ars.2013.5414.

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Bryk, Dorota, Wioletta Olejarz, and Danuta Zapolska-Downar. "The role of oxidative stress and NADPH oxidase in the pathogenesis of atherosclerosis." Postępy Higieny i Medycyny Doświadczalnej 71, no. 1 (January 28, 2017): 57–68. http://dx.doi.org/10.5604/01.3001.0010.3790.

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Reactive oxygen species (ROS) play a key role in the pathogenesis of atherosclerosis. The main mechanisms which are involved are low-density lipoprotein oxidative modification, inactivation of nitric oxide and modulation of redox-sensitive signaling pathways. ROS contribute to several aspects of atherosclerosis including endothelial cell dysfunction, monocyte/macrophage recruitment and activation, stimulation of inflammation, and inducing smooth muscle cell migration and proliferation. NADPH oxidase is the main source of ROS in the vasculature. This enzyme consists of a membrane-bound heterodimer of gp91phox and p22phox, cytosolic regulatory subunits p47phox, p67phox and p40phox, and small GTP-binding proteins rac1 and rac 2. Seven distinct isoforms of this enzyme have been identified, of which four (NOX1, 2, 4 and 5) may have cardiovascular function. In this paper, we review the current state of knowledge concerning the role of oxidative stress and NOX enzymes in pathogenesis of atherosclerosis. Moreover, we analyze the experimental studies that explore the relationship between the NOX family and atherosclerosis.

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Pecchillo Cimmino, Tiziana Pecchillo, Rosario Ammendola, Fabio Cattaneo, and Gabriella Esposito. "NOX Dependent ROS Generation and Cell Metabolism." International Journal of Molecular Sciences 24, no. 3 (January 20, 2023): 2086. http://dx.doi.org/10.3390/ijms24032086.

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Reactive oxygen species (ROS) represent a group of high reactive molecules with dualistic natures since they can induce cytotoxicity or regulate cellular physiology. Among the ROS, the superoxide anion radical (O2·−) is a key redox signaling molecule prominently generated by the NADPH oxidase (NOX) enzyme family and by the mitochondrial electron transport chain. Notably, altered redox balance and deregulated redox signaling are recognized hallmarks of cancer and are involved in malignant progression and resistance to drugs treatment. Since oxidative stress and metabolism of cancer cells are strictly intertwined, in this review, we focus on the emerging roles of NOX enzymes as important modulators of metabolic reprogramming in cancer. The NOX family includes seven isoforms with different activation mechanisms, widely expressed in several tissues. In particular, we dissect the contribute of NOX1, NOX2, and NOX4 enzymes in the modulation of cellular metabolism and highlight their potential role as a new therapeutic target for tumor metabolism rewiring.

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Sirokmány, Gábor, Ágnes Donkó, and Miklós Geiszt. "Nox/Duox Family of NADPH Oxidases: Lessons from Knockout Mouse Models." Trends in Pharmacological Sciences 37, no. 4 (April 2016): 318–27. http://dx.doi.org/10.1016/j.tips.2016.01.006.

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Li, Ganglei, Changsheng Ye, Yu Zhu, Tiesong Zhang, Jun Gu, Jianwei Pan, Feng Wang, et al. "Oxidative Injury in Ischemic Stroke: A Focus on NADPH Oxidase 4." Oxidative Medicine and Cellular Longevity 2022 (February 3, 2022): 1–12. http://dx.doi.org/10.1155/2022/1148874.

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Ischemic stroke is a leading cause of disability and mortality worldwide. Thus, it is urgent to explore its pathophysiological mechanisms and find new therapeutic strategies for its successful treatment. The relationship between oxidative stress and ischemic stroke is increasingly appreciated and attracting considerable attention. ROS serves as a source of oxidative stress. It is a byproduct of mitochondrial metabolism but primarily a functional product of NADPH oxidases (NOX) family members. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is most closely related to the formation of ROS during ischemic stroke. Its expression is significantly upregulated after cerebral ischemia, making it a promising target for treating ischemic stroke. Several drugs targeting NOX4, such as SCM-198, Iso, G-Rb1, betulinic acid, and electroacupuncture, have shown efficacy as treatments of ischemic stroke. MTfp-NOX4 POC provides a novel insight for the treatment of stroke. Combinations of these therapies also provide new approaches for the therapy of ischemic stroke. In this review, we summarize the subcellular location, expression, and pathophysiological mechanisms of NOX4 in the occurrence and development of ischemic stroke. We also discuss the therapeutic strategies and related regulatory mechanisms for treating ischemic stroke. We further comment on the shortcomings of current NOX4-targeted therapy studies and the direction for improvement.

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Wilkinson-Berka, Jennifer L., Indrajeetsinh Rana, Roksana Armani, and Alex Agrotis. "Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy." Clinical Science 124, no. 10 (February 4, 2013): 597–615. http://dx.doi.org/10.1042/cs20120212.

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Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, although the mechanisms by which this occurs are not fully understood. ROS is produced by a number of pathways, including the mitochondrial electron transport chain, cytochrome P450, xanthine oxidase and uncoupled nitric oxide synthase. The family of NADPH oxidase (Nox) enzymes are likely to be important given that their primary function is to produce ROS. Seven isoforms of Nox have been identified named Nox1–5, Duox (dual oxidase) 1 and Duox2. Nox1, Nox2 and Nox4 have been most extensively studied and are implicated in the development of conditions such as hypertension, cardiovascular disease and diabetic nephropathy. In recent years, evidence has accumulated to suggest that Nox1, Nox2 and Nox4 participate in pathological angiogenesis; however, there is no clear consensus about which Nox isoform is primarily responsible. In terms of retinopathy, there is growing evidence that Nox contribute to vascular injury. The RAAS (renin–angiotensin–aldosterone system), and particularly AngII (angiotensin II), is a key stimulator of Nox. It is known that a local RAAS exists in the retina and that blockade of AngII and aldosterone attenuate pathological angiogenesis in the retina. Whether the RAAS influences the production of ROS derived from Nox in retinopathy is yet to be fully determined. These topics will be reviewed with a particular emphasis on ROP and DR.

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Gorin, Yves, and Karen Block. "Nox as a target for diabetic complications." Clinical Science 125, no. 8 (June 14, 2013): 361–82. http://dx.doi.org/10.1042/cs20130065.

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Oxidative stress has been linked to the pathogenesis of the major complications of diabetes in the kidney, the heart, the eye or the vasculature. NADPH oxidases of the Nox family are a major source of ROS (reactive oxygen species) and are critical mediators of redox signalling in cells from different organs afflicted by the diabetic milieu. In the present review, we provide an overview of the current knowledge related to the understanding of the role of Nox in the processes that control cell injury induced by hyperglycaemia and other predominant factors enhanced in diabetes, including the renin–angiotensin system, TGF-β (transforming growth factor-β) and AGEs (advanced glycation end-products). These observations support a critical role for Nox homologues in diabetic complications and indicate that NADPH oxidases are an important therapeutic target. Therefore the design and development of small-molecule inhibitors that selectively block Nox oxidases appears to be a reasonable approach to prevent or retard the complications of diabetes in target organs. The bioefficacy of these agents in experimental animal models is also discussed in the present review.

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Pantoja, Lucas Villar Pedrosa da Silva, Surianne Samantha Amorim Trindade, Agnaldo da Silva Carneiro, João Paulo Bastos Silva, Thiago Portal da Paixão, Camila Fernanda Rodrigues Romeiro, Cleiane Santana Pinheiro de Moraes, Ana Carla Godinho Pinto, Nádia Rezende Barbosa Raposo, and Marcieni Ataíde de Andrade. "Computational study of the main flavonoids from Chrysobalanus icaco L. against NADPH-oxidase and in vitro Antioxidant Activity." Research, Society and Development 11, no. 6 (April 19, 2022): e5011628542. http://dx.doi.org/10.33448/rsd-v11i6.28542.

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The generation of free radicals is a physiological event resulting mainly from the cellular respiration process and the overactivation of the NOX leads to an excess production of ROS that is associated with oxidative stress. Chrysobalanus icaco, a medicinal plant that belongs to the Chrysobalanaceae family, possesses a high number of polyphenols, including phenolic acids and flavonoids. Due to its phytochemical composition, this study aimed to evaluate the antioxidant potential of the hydroalcoholic extract from the leaves of Chrysobalanus icaco (HECi) and the inhibitory potential of its main flavonoids against NOX. The in silico predictions of absorption, distribution, metabolism, excretion, and toxicity (ADMET), drug-likeness properties, and molecular docking with the enzyme NOX (PDB code 2CDU) were also performed to support the experimental results. The phytochemical screening of the HECi showed the presence of phenols and flavonoids. HECi performed an excellent antioxidant activity (IC50 = 8.1 μg/mL), probably due to its rich phenolic (220.11 ± 0.4 mg GAE/g) and flavonoid (110.98 ± 0.37 mg QE/g) constitution. The ADMET prediction indicated that myricetin and quercetin had the best pharmacokinetic parameters. The molecular docking results showed that myricetin and especially quercetin had strong docking score on NOX (ΔG = –8.1 kcal/mol and ΔG = –8.3 kcal/mol, respectively). Frontier Orbital’s analyzes (HOMO and LUMO) suggested that quercetin has better antioxidant properties than myricetin. Our results demonstrate for the first time the in silico action of quercetin against NOX, as well as reiterate the antioxidant potential of C. icaco.

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Dennis, Kathleen E., J. L. Aschner, D. Milatovic, J. W. Schmidt, M. Aschner, M. R. Kaplowitz, Y. Zhang, and Candice D. Fike. "NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 4 (October 2009): L596—L607. http://dx.doi.org/10.1152/ajplung.90568.2008.

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Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia ( Am J Physiol Lung Cell Mol Physiol 295: L881–L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F2-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.

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Leclerc, Joan, Debeissat Christelle, Socco-Lucca Marion, Ducrocq Elfi, Gouilleux Fabrice, Stasia Marie José, and Olivier Herault. "Influence of NADPH Oxidase Activity On the Reactive Oxygen Species Level in Human Leukemic Cells." Blood 120, no. 21 (November 16, 2012): 4801. http://dx.doi.org/10.1182/blood.v120.21.4801.4801.

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Abstract Abstract 4801 Redox metabolism plays an important role in self-renewal and differentiation of hematopoietic and leukemic cells. Reactive oxygen species (ROS) level is highly regulated. This regulation involves antioxydative enzymes and it has been recently described that leukemic stem cells (LSC) overexpress glutathione peroxydase 3 (Herault O et al, J. Exp. Med, 2012). This overexpression is associated with a decrease in ROS level and p38MAPK inactivation. ROS level in leukemic cells could be also regulated by the activity of ROS producers, such as NADPH oxidase, known to catalyze an electron transfer from NADPH to oxygen producing superoxides which could generate other downstream ROS. The expression of this enzymatic complex (NOX family, 6 isoforms) has been established in the plasma cell membrane of normal CD34+ hematopoietic progenitors (Piccoli C et al, Biochem. Biophys. Res. Commun., 2007). The aim of this study was to decipher the expression of NADPH oxydase components in various human acute myeloid leukemia (AML) Different leukemic cell lines were used according FAB classification: KG1a (MO/M1), KG1 (M1), HL60 (M2), Kasumi 1 (M2), NB4 (M3), ML2 (M4), THP1 (M5), U937 (M5), MV4–11 (M5), K562 (M6). The cells were cultured (2.105 cells/mL, 37°C in 95% humidified air and 5% CO2) in RPMI 1640 with 20mmoL/L L-glutamine supplemented with 10% FCS, 100 units/mL penicillin G, and 100mg/mL streptomycin. The expression of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, DUOX2, P22phox and P40phox, P47phox, P67phox, NOXO1, NOXA1 was quantified by RT-qPCR (Universal Probe Library, Roche). NOX2 and its regulatory subunits expression was quantified by SDS-PAGE and western-blot experiments. The effects of diphenylene iodonium (DPI), a specific NOX inhibitor, were evaluated by ROS quantification using dichlorodihydrofluorescein diacetate (DCF-DA) staining followed by fluorimetry and flow cytometry analyses. The cells were washed twice in the physiological saline buffer (PBS) without calcium and magnesium, then incubated in PBS complemented with 0.5M MgCl2, 0.9M CaCl2, 20mM glucose (Picciocchi A et al, J. Biol. Chem., 2011) with or without 20μM DPI for 1 hour. The cells were distributed at 106cells per 200μL well in 96 wells plates. DCF-DA (10μM) was added to quantify the ROS level (flow cytometry) and to monitor ROS production kinetic (fluorimetry). NOX family genes expression showed that phagocyte oxidase NOX2 is expressed in all leukemic cell lines. Conversely the NOX2 isoforms were not expressed, or very weakly expressed in leukemic cell lines (NOX3 in KG1a; NOX4 in K562; DUOX1 in KG1a, KG1; DUOX2 in KG1a, KG1, HL60). P22phox, the second cytochrome b558 component was also expressed in all cell lines, this expression being higher than NOX2. The cytochrome b558 components were more expressed in differentiated leukemic cells (granulocytic and monocytic) than in undifferentiated cells (KG1a, KG1). NOX2 regulatory subunits were expressed in all leukemic cell lines, the lower level (especially P40phox, P47phox) being observed in KG1a. Proteins quantification confirmed RNA results. Cytochrome b558 components and regulatory subunits were expressed in all cell lines with a higher level in differentiated leukemias. Interestingly, the regulatory subunits were not observed in KG1a cells. Functional flow cytometry and fluorimetry studies revealed a decrease in ROS production in DPI exposed leukemic cell lines. This effect was higher in monocytic cell lines than in granulocytic and undifferentiated leukemias. In conclusion, NADPH oxidases are present in the AML cell membrane, and NOX contribution to the ROS level is higher in differentiated cells than in immature leukemias. Altogether these results suggest that NADPH oxidase is constitutively active in leukemic cells and influences the ROS level, suggesting a role in the pathophysiology of AML. Disclosures: No relevant conflicts of interest to declare.

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Tarafdar, Anuradha, and Giordano Pula. "The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders." International Journal of Molecular Sciences 19, no. 12 (November 30, 2018): 3824. http://dx.doi.org/10.3390/ijms19123824.

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For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91phox and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation—primarily superoxide anion (O2●−), although hydrogen peroxide (H2O2) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.

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Ueyama, Takehiko, Miklós Geiszt, and Thomas L. Leto. "Involvement of Rac1 in Activation of Multicomponent Nox1- and Nox3-Based NADPH Oxidases." Molecular and Cellular Biology 26, no. 6 (March 15, 2006): 2160–74. http://dx.doi.org/10.1128/mcb.26.6.2160-2174.2006.

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ABSTRACT Several Nox family NADPH oxidases function as multicomponent enzyme systems. We explored determinants of assembly of the multicomponent oxidases Nox1 and Nox3 and examined the involvement of Rac1 in their regulation. Both enzymes are supported by p47 phox and p67 phox or homologous regulators called Noxo1 and Noxa1, although Nox3 is less dependent on these cofactors for activity. Plasma membrane targeting of Noxa1 depends on Noxo1, through tail-to-tail interactions between these proteins. Noxa1 can support Nox1 without Noxo1, when targeted to the plasma membrane by fusing membrane-binding sequences from Rac1 (amino acids 183 to 192) to the C terminus of Noxa1. However, membrane targeting of Noxa1 is not sufficient for activation of Nox1. Both the Noxo1-independent and -dependent Nox1 systems involve Rac1, since they are affected by Rac1 mutants or Noxa1 mutants defective in Rac binding or short interfering RNA-mediated Rac1 silencing. Nox1 or Nox3 expression promotes p22 phox transport to the plasma membrane, and both oxidases are inhibited by mutations in the p22 phox binding sites (SH3 domains) of the Nox organizers (p47 phox or Noxo1). Regulation of Nox3 by Rac1 was also evident from the effects of mutant Rac1 or mutant Nox3 activators (p67 phox or Noxa1) or Rac1 silencing. In the absence of Nox organizers, the Nox activators (p67 phox or Noxa1) colocalize with Rac1 within ruffling membranes, independently of their ability to bind Rac1. Thus, Rac1 regulates both oxidases through the Nox activators, although it does not appear to direct the subcellular localization of these activators.

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Journal articles on the topic 'NADPH oxidase (Nox) family'

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