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1
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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Piszczatowska, Katarzyna, Dorota Przybylska, Ewa Sikora, and Grażyna Mosieniak. "Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells." Antioxidants 9, no. 12 (December 8, 2020): 1248. http://dx.doi.org/10.3390/antiox9121248.
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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.
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Youssef, Natalie, Mohamed Noureldein, Rachel Njeim, Hilda Ghadieh, Frederic Harb, Sami Azar, Nassim Fares, and Assaad Eid. "Reno-Protective Effect of GLP-1 Receptor Agonists in Type1 Diabetes: Dual Action on TRPC6 and NADPH Oxidases." Biomedicines 9, no. 10 (September 30, 2021): 1360. http://dx.doi.org/10.3390/biomedicines9101360.
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Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague–Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases.
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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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Nauseef, William M. "Nox enzymes in immune cells." Seminars in Immunopathology 30, no. 3 (May 1, 2008): 195–208. http://dx.doi.org/10.1007/s00281-008-0117-4.
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Stanton, Thad B., Everett L. Rosey, Michael J. Kennedy, Neil S. Jensen, and Brad T. Bosworth. "Isolation, Oxygen Sensitivity, and Virulence of NADH Oxidase Mutants of the Anaerobic Spirochete Brachyspira(Serpulina) hyodysenteriae, Etiologic Agent of Swine Dysentery." Applied and Environmental Microbiology 65, no. 11 (November 1, 1999): 5028–34. http://dx.doi.org/10.1128/aem.65.11.5028-5034.1999.
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ABSTRACT Brachyspira (Serpulina)hyodysenteriae, the etiologic agent of swine dysentery, uses the enzyme NADH oxidase to consume oxygen. To investigate possible roles for NADH oxidase in the growth and virulence of this anaerobic spirochete, mutant strains deficient in oxidase activity were isolated and characterized. The cloned NADH oxidase gene (nox; GenBank accession no. U19610 ) on plasmid pER218 was inactivated by replacing 321 bp of coding sequence with either a gene for chloramphenicol resistance (cat) or a gene for kanamycin resistance (kan). The resulting plasmids, respectively, pCmΔNOX and pKmΔNOX, were used to transform wild-type B. hyodysenteriae B204 cells and generate the antibiotic-resistant strains Nox-Cm and Nox-Km. PCR and Southern hybridization analyses indicated that the chromosomal wild-type nox genes in these strains had been replaced, through allelic exchange, by the inactivatednox gene containing cat or kan. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western immunoblot analysis revealed that both nox mutant cell lysates were missing the 48-kDa Nox protein. Soluble NADH oxidase activity levels in cell lysates of Nox-Cm and Nox-Km were reduced 92 to 96% compared to the activity level in parent strain B204. In an aerotolerance test, cells of both nox mutants were at least 100-fold more sensitive to oxygen exposure than were cells of the wild-type parent strain B204. In swine experimental infections, bothnox mutants were less virulent than strain B204 in that fewer animals were colonized by the mutant cells and infected animals displayed mild, transient signs of disease, with no deaths. These results provide evidence that NADH oxidase serves to protect B. hyodysenteriae cells against oxygen toxicity and that the enzyme, in that role, contributes to the pathogenic ability of the spirochete.
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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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Williams, Jeffrey G., Caroline Ojaimi, Khaled Qanud, Suhua Zhang, Xiaobin Xu, Fabio A. Recchia, and Thomas H. Hintze. "Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 6 (June 2008): H2516—H2523. http://dx.doi.org/10.1152/ajpheart.01196.2007.
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The aim of this study was to examine the role of nitric oxide (NO) in the control of cardiac metabolism at 60 days of pregnancy (P60) in the dog. There was a basal increase in diastolic coronary blood flow during pregnancy and a statistically significant increase in cardiac output (55 ± 4%) and in cardiac NOx production (44 ± 4 to 59 ± 3 nmol/min, P < 0.05). Immunohistochemistry of the left ventricle showed an increase in endothelial nitric oxide synthase staining in the endothelial cells at P60. NO-dependent coronary vasodilation (Bezold-Jarisch reflex) was increased by 20% and blocked by NG-nitro-l-arginine methyl ester (l-NAME). Isotopically labeled substrates were infused to measure oleate, glucose uptake, and oxidation. Glucose oxidation was not significantly different in P60 hearts (5.4 ± 0.5 vs. 6.2 ± 0.4 μmol/min) but greatly increased in response to l-NAME injection (to 19.9 ± 0.9 μmol/min, P < 0.05). Free fatty acid (FFA) oxidation was increased in P60 (from 5.3 ± 0.6 to 10.4 ± 0.5 μmol/min, P < 0.05) and decreased in response to l-NAME (to 4.5 ± 0.5 μmol/min, P < 0.05). There was an increased oxidation of FFA for ATP production but no change in the respiratory quotient during pregnancy. Genes associated with glucose and glycogen metabolism were downregulated, whereas genes involved in FFA oxidation were elevated. The acute inhibition of NO shifts the heart away from FFA and toward glucose metabolism despite the downregulation of the carbohydrate oxidative pathway. The increase in endothelium-derived NO during pregnancy results in a tonic inhibition of glucose oxidation and reliance on FFA uptake and oxidation to support ATP synthesis in conjunction with upregulation of FFA metabolic enzymes.
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Ritsick, Darren R., William A. Edens, James W. McCoy, and J. David Lambeth. "The use of model systems to study biological functions of Nox/Duox enzymes." Biochemical Society Symposia 71 (March 1, 2004): 85–96. http://dx.doi.org/10.1042/bss0710085.
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ROS (reactive oxygen species; including superoxide and H2O2) are conventionally thought of as being broadly reactive and cytotoxic. Phagocytes utilize an NADPH oxidase to generate large amounts of ROS, and exploit their toxic properties as a host-defence mechanism to kill invading microbes. However, the recent discovery of the Nox and Duox enzymes that are expressed in many non-phagocytic cells implies that the 'deliberate' generation of ROS has additional cellular roles, which are currently incompletely understood. Functions of ROS in mammals have been inferred primarily from cell-culture experiments, and include signalling for mitogenic growth, apoptosis and angiogenesis. Nox/Duox enzymes may also provide H2O2 as a substrate for peroxidase enzymes (or, in the case of Duox, for its own peroxidase domain), thereby supporting peroxidative reactions. A broad comparison of biological functions of ROS and Nox enzymes across species and kingdoms provides insights into possible functions in mammals. To further understand novel biological roles for Nox/Duox enzymes, we are manipulating the expression of Nox/Duox enzymes in model organisms including Caenorhabditis elegans, Drosophila melanogaster and mouse. This chapter focuses on new insights into the roles of Nox enzymes gained from these approaches.
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van Bree, L., I. MCM Rietjens, G. M. Alink, J. AMA Dormans, M. Marra, and P. JA Rombout. "Biochemical and morphological changes in lung tissue and isolated lung cells of rats induced by short-term nitrogen dioxide exposure." Human & Experimental Toxicology 19, no. 7 (July 2000): 392–401. http://dx.doi.org/10.1191/096032700678816151.
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To investigate the effects of repeated exposure to nitrogen dioxide (NO2) on antioxidant enzymes in lung tissue and isolated lung cells, rats were continuously exposed to 20 mg/m3 NO2 (10.6 ppm) for 4 days. The activities of glucose-6-phosphate dehydrogenase (G6PDH), glutathione reductase (GR), and glutathione peroxidase (GSHPx) were measured in the cytosolic fraction of lung tissue of both control and NO2-exposed rats as well as in isolated alveolar macrophages (AMs) and type II cells. Qualitative and quantitative changes in AM and type II cells were studied by electron microscopy and by morphometric analyses using enzyme and immunohistochemistry. NO2 exposure resulted in significantly increased pulmonary activities of G6PDH, GR, and GSHPx, both expressed per lung and per gram of lung weight. Morphometric data show that NO2 exposure significantly increased the number of type II cells, predominantly in the centriacinar region, indicating proliferation of epithelium following cellular injury. Type II cells in lungs of NO2-exposed rats had a squamous, less cuboidal appearance with more lamellar bodies compared to type II cells in lungs of control rats. Compared to control lungs, a higher number of macrophages could be isolated from NO2-exposed lungs, while numbers of type II cells isolated from lungs of control and NO2-exposed rats were the same. Isolated type II cells from control and NO2-exposed rats were polymorphic, with a small number of lamellar bodies and without polarity. Isolated macro-phages were rounded and contained many filopodia. NO2 exposure caused increases in the activities of G6PDH and GSHPx in isolated type II cells and of GSHPx in isolated macrophages, when expressed per number of cells. Macrophages and type II cells isolated from control and NO2-exposed rats and re-exposed in vitro to NO2, showed no differences in phagocytosis and viability features. Our results indicate that NO2-induced increases in pulmonary antioxidant enzymes are also reflected in isolated AM and type II cells. Since these lung cells do not display a decreased sensitivities toward an in vitro NO2 exposure, overall increase in antioxidant enzyme activities do not seem to play the most pivotal role in controlling cellular NO2 sensitivity and oxidant defence. Combined data from biochemical, morphological, and morphometric analyses of lungs and lung cells suggest that lung cell and tissue oxidant sensitivity and defence largely depends on the cell and tissue organisation, i.e., cell numbers and morphology as well as the ratio of surface area to cytoplasmic volume.
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Wen, Yi, Ruohong Liu, Ning Lin, Hao Luo, Jiajia Tang, Qilin Huang, Hongyu Sun, and Lijun Tang. "NADPH Oxidase Hyperactivity Contributes to Cardiac Dysfunction and Apoptosis in Rats with Severe Experimental Pancreatitis through ROS-Mediated MAPK Signaling Pathway." Oxidative Medicine and Cellular Longevity 2019 (May 9, 2019): 1–18. http://dx.doi.org/10.1155/2019/4578175.
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NADPH oxidase (Nox) is considered a major source of reactive oxygen species (ROS) in the heart in normal and pathological conditions. However, the role of Nox in severe acute pancreatitis- (SAP-) associated cardiac injury remains unclear. Therefore, we aim to investigate the contribution of Nox to SAP-associated cardiac injury and to explore the underlying molecular mechanisms. Apocynin, a Nox inhibitor, was given at 20 mg/kg for 30 min before SAP induction by a retrograde pancreatic duct injection of 5% sodium taurocholate. Histopathological staining, Nox activity and protein expression, oxidative stress markers, apoptosis and associated proteins, cardiac-related enzyme indexes, and cardiac function were assessed in the myocardium in SAP rats. The redox-sensitive MAPK signaling molecules were also examined by western blotting. SAP rats exhibited significant cardiac impairment along with increased Nox activity and protein expression, ROS production, cell apoptosis, and proapoptotic Bax and cleaved caspase-3 protein levels. Notably, Nox inhibition with apocynin prevented SAP-associated cardiac injury evidenced by a decreased histopathologic score, cardiac-related enzymes, and cardiac function through the reduction of ROS production and cell apoptosis. This protective role was further confirmed by a simulation experiment in vitro. Moreover, we found that SAP-induced activation in MAPK signaling molecules in cardiomyocytes was significantly attenuated by Nox inhibition. Our data provide the first evidence that Nox hyperactivation acts as the main source of ROS production in the myocardium, increases oxidative stress, and promotes cell apoptosis via activating the MAPK pathway, which ultimately results in cardiac injury in SAP.
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Michaeloudes, Charalambos, Maria B. Sukkar, Nadia M. Khorasani, Pankaj K. Bhavsar, and Kian Fan Chung. "TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 2 (February 2011): L295—L304. http://dx.doi.org/10.1152/ajplung.00134.2010.
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Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidyl-inositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β.
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Jiang, S., P. Park, and H. Ishii. "Ultrastructural Study on Acibenzolar-S-Methyl-Induced Scab Resistance in Epidermal Pectin Layers of Japanese Pear Leaves." Phytopathology® 98, no. 5 (May 2008): 585–91. http://dx.doi.org/10.1094/phyto-98-5-0585.
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The infection behavior of Japanese pear scab pathogen Venturia nashicola race 1 was studied ultrastructurally in acibenzolar-S-methyl (ASM)-pretreated susceptible Japanese pear (cv. Kousui) leaves to determine the mechanism of ASM-induced scab resistance. On ASM-pretreated leaf surfaces, the infection behavior (conidial germination and appressorial formation) was similar to that on distilled water (DW)-pretreated leaves prior to cuticle penetration by the pathogen. However, after penetration, differentiated behavior was found in epidermal pectin layers and middle lamellae of the ASM-pretreated leaves. Subcuticular hyphae in epidermal pectin layers and middle lamellae of ASM-pretreated pear leaves were observed at lower frequency than in DW-treated leaves. The results indicated that fungal growth was suppressed in ASM-pretreated pear leaves. In the pectin layers of ASM- and DW-pretreated leaves, some hyphae showed morphological modifications, which were used as criteria to judge collapse of hyphal cells, including plasmolysis, necrotic cytoplasm, and cell wall destruction. More hyphae had collapsed in ASM-pretreated leaves than in DW-treated ones. In addition, the cell walls of collapsed hyphae broke into numerous fibrous and amorphous pieces, suggesting that ASM-induced scab resistance might be associated with cell-wall-degrading enzymes from pear plants. In addition, results from morphometrical analysis suggested that the activity or production of pectin-degrading enzyme from hyphae were inhibited by ASM application when compared with DW treatment.
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Skonieczna, Magdalena, Tomasz Hejmo, Aleksandra Poterala-Hejmo, Artur Cieslar-Pobuda, and Rafal J. Buldak. "NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/9420539.
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NADPH oxidases (NOX) are reactive oxygen species- (ROS-) generating enzymes regulating numerous redox-dependent signaling pathways. NOX are important regulators of cell differentiation, growth, and proliferation and of mechanisms, important for a wide range of processes from embryonic development, through tissue regeneration to the development and spread of cancer. In this review, we discuss the roles of NOX and NOX-derived ROS in the functioning of stem cells and cancer stem cells and in selected aspects of cancer cell physiology. Understanding the functions and complex activities of NOX is important for the application of stem cells in tissue engineering, regenerative medicine, and development of new therapies toward invasive forms of cancers.
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Bhushan, Bharat, Louise Paquet, Jim C. Spain, and Jalal Hawari. "Biotransformation of 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-Hexaazaisowurtzitane (CL-20) by Denitrifying Pseudomonas sp. Strain FA1." Applied and Environmental Microbiology 69, no. 9 (September 2003): 5216–21. http://dx.doi.org/10.1128/aem.69.9.5216-5221.2003.
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ABSTRACT The microbial and enzymatic degradation of a new energetic compound, 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20), is not well understood. Fundamental knowledge about the mechanism of microbial degradation of CL-20 is essential to allow the prediction of its fate in the environment. In the present study, a CL-20-degrading denitrifying strain capable of utilizing CL-20 as the sole nitrogen source, Pseudomonas sp. strain FA1, was isolated from a garden soil. Studies with intact cells showed that aerobic conditions were required for bacterial growth and that anaerobic conditions enhanced CL-20 biotransformation. An enzyme(s) involved in the initial biotransformation of CL-20 was shown to be membrane associated and NADH dependent, and its expression was up-regulated about 2.2-fold in CL-20-induced cells. The rates of CL-20 biotransformation by the resting cells and the membrane-enzyme preparation were 3.2 ± 0.1 nmol h−1 mg of cell biomass−1 and 11.5 ± 0.4 nmol h−1 mg of protein−1, respectively, under anaerobic conditions. In the membrane-enzyme-catalyzed reactions, 2.3 nitrite ions (NO2 −), 1.5 molecules of nitrous oxide (N2O), and 1.7 molecules of formic acid (HCOOH) were produced per reacted CL-20 molecule. The membrane-enzyme preparation reduced nitrite to nitrous oxide under anaerobic conditions. A comparative study of native enzymes, deflavoenzymes, and a reconstituted enzyme(s) and their subsequent inhibition by diphenyliodonium revealed that biotransformation of CL-20 is catalyzed by a membrane-associated flavoenzyme. The latter catalyzed an oxygen-sensitive one-electron transfer reaction that caused initial N denitration of CL-20.
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Manuel, Raoul, Michelle de Souza Lima, Sébastien Dilly, Sylvain Daunay, Patricia Abbe, Elodie Pramil, Stéphanie Solier, et al. "Distinction between 2′- and 3′-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration." Antioxidants 10, no. 5 (May 4, 2021): 723. http://dx.doi.org/10.3390/antiox10050723.
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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.
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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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He, Aimin, and John P. N. Rosazza. "GTP Cyclohydrolase I: Purification, Characterization, and Effects of Inhibition on Nitric Oxide Synthase in Nocardia Species." Applied and Environmental Microbiology 69, no. 12 (December 2003): 7507–13. http://dx.doi.org/10.1128/aem.69.12.7507-7513.2003.
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ABSTRACT GTP cyclohydrolase I (GTPCH) catalyzes the first step in pteridine biosynthesis in Nocardia sp. strain NRRL 5646. This enzyme is important in the biosynthesis of tetrahydrobiopterin (BH4), a reducing cofactor required for nitric oxide synthase (NOS) and other enzyme systems in this organism. GTPCH was purified more than 5,000-fold to apparent homogeneity by a combination of ammonium sulfate fractionation, GTP-agarose, DEAE Sepharose, and Ultragel AcA 34 chromatography. The purified enzyme gave a single band for a protein estimated to be 32 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The molecular mass of the native enzyme was estimated to be 253 kDa by gel filtration, indicating that the active enzyme is a homo-octamer. The enzyme follows Michaelis-Menten kinetics, with a Km for GTP of 6.5μ M. Nocardia GTPCH possessed a unique N-terminal amino acid sequence. The pH and temperature optima for the enzyme were 7.8 and 56°C, respectively. The enzyme was heat stable and slightly activated by potassium ion but was inhibited by calcium, copper, zinc, and mercury, but not magnesium. BH4 inhibited enzyme activity by 25% at a concentration of 100 μM. 2,4-Diamino-6-hydroxypyrimidine (DAHP) appeared to competitively inhibit the enzyme, with a Ki of 0.23 mM. With Nocardia cultures, DAHP decreased medium levels of NO2 − plus NO3 −. Results suggest that in Nocardia cells, NOS synthesis of nitric oxide is indirectly decreased by reducing the biosynthesis of an essential reducing cofactor, BH4.
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Brown, Amy, Jennifer Danielsson, Elizabeth A. Townsend, Yi Zhang, Jose F. Perez-Zoghbi, Charles W. Emala, and George Gallos. "Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 8 (April 15, 2016): L747—L758. http://dx.doi.org/10.1152/ajplung.00215.2015.
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Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond β-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo ( n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo ( n = 6–8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine ( n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) ( n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCβ enzymes ( n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium ( n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation ( n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCβ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.
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Shim, Seunghwan, and Yongseok Choi. "대표적인 NADPH oxidase 저해제: 저해 방법, 효능, 그리고 다양한 질병에 대한 쓰임새." Institute of Life Science and Natural Resources 30 (December 31, 2022): 33–39. http://dx.doi.org/10.33147/lsnrr.2022.30.1.33.
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NADPH Oxidase(NOX) induced reactive oxygen species(ROS) generation found on several types of cells including in leukocytes, artery wall, and brain. The human isoform complex comprises NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2. Each NOX isoforms consists of multi-subunit complex including membrane-associated enzymes and cytosolic subunits. NOX activation is step-by-step process where cytosolic subunits are assembled and translocated to the membrane, leading to transport electrons to oxygen, and finally to produce superoxide. Abnormal production of superoxide via NOX has been shown to play an important role in various diseases related to inflammation, cell growth, and progressive degenerative in cells. So, developing NOX inhibitors has been thought to be promising treatment and published many small molecules. This review will focus on representative NOX inhibitors with their chemical properties, potency on NOX, mechanisms, and limitation of use as a drug.
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Guichard, Cécile, Richard Moreau, Dominique Pessayre, Terry Kay Epperson, and Karl-Heinz Krause. "NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes?" Biochemical Society Transactions 36, no. 5 (September 19, 2008): 920–29. http://dx.doi.org/10.1042/bst0360920.
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The incidence of obesity and non-esterified (‘free’) fatty acid-associated metabolic disorders such as the metabolic syndrome and diabetes is increasing dramatically in most countries. Although the pathogenesis of these metabolic disorders is complex, there is emerging evidence that ROS (reactive oxygen species) are critically involved in the aberrant signalling and tissue damage observed in this context. Indeed, it is now widely accepted that ROS not only play an important role in physiology, but also contribute to cell and tissue dysfunction. Inappropriate ROS generation may contribute to tissue dysfunction in two ways: (i) dysregulation of redox-sensitive signalling pathways, and (ii) oxidative damage to biological structures (DNA, proteins, lipids, etc.). An important source of ROS is the NOX family of NADPH oxidases. Several NOX isoforms are expressed in the liver and pancreatic β-cells. There is now evidence that inappropriate activation of NOX enzymes may damage the liver and pancreatic β-cells. In the context of the metabolic syndrome, the emerging epidemic of non-alcoholic steatohepatitis is thought to be NOX/ROS-dependent and of particular medical relevance. NOX/ROS-dependent β-cell damage is thought to be involved in glucolipotoxicity and thereby leads to progression from the metabolic syndrome to Type 2 diabetes. Thus understanding the role of NOX enzymes in liver and β-cell damage should lead to an increased understanding of pathomechanisms in the metabolic syndrome and diabetes and may identify useful targets for novel therapeutic strategies.
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Teuber, James P., Kobina Essandoh, Scott L. Hummel, Nageswara R. Madamanchi, and Matthew J. Brody. "NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction." Antioxidants 11, no. 9 (September 16, 2022): 1822. http://dx.doi.org/10.3390/antiox11091822.
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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.
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Hu, Aihua, Sumbul Fatma, Jing Cao, Judith S. Grunstein, Gustavo Nino, Yael Grumbach, and Michael M. Grunstein. "Th2 cytokine-induced upregulation of 11β-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 5 (May 2009): L790—L803. http://dx.doi.org/10.1152/ajplung.90572.2008.
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The anti-inflammatory actions of endogenous glucocorticoids (GCs) are regulated by the activities of the GC-activating and -inactivating enzymes, 11β-hydroxysteroid dehydrogenase (11β-HSD)-1 and 11β-HSD2, respectively, that catalyze the interconversion of the inert GC, cortisone, and its bioactive derivative, cortisol. Proinflammatory cytokines regulate 11β-HSD1 expression in various cell types and thereby modulate the bioavailability of cortisol to the glucocorticoid receptor (GR). Since endogenous GCs reportedly attenuate the airway asthmatic response to allergen exposure, we investigated whether airway smooth muscle (ASM) exhibits cytokine-induced changes in 11β-HSD1 expression that enable the ASM to regulate its own bioavailability of GC and, accordingly, the protective effect of GR signaling on airway function under proasthmatic conditions. Human ASM cells exposed to the primary proasthmatic T helper type 2 (Th2) cytokine, IL-13, exhibited upregulated expression of 11β-HSD1, an effect that was attributed to activation of the transcription factor, AP-1, coupled to MAPK signaling via the ERK1/2 and JNK pathways. The induction of 11β-HSD1 expression and its oxoreductase activity by IL-13 (also IL-4) served to amplify the conversion of cortisone to cortisol by the cytokine-exposed ASM and, hence, heighten GR-mediated transcriptional activation. Extended studies demonstrated that this amplified 11β-HSD1-dependent GC activation enabled physiologically relevant concentrations of cortisone to exert enhanced protection of ASM tissues from the proasthmatic effects of IL-13 on ASM constrictor and relaxation responsiveness. Collectively, these novel findings identify a Th2 cytokine-driven homeostatic feedback mechanism in ASM that enhances its responsiveness to endogenous GCs by upregulating 11β-HSD1 activity, thereby curtailing the adverse effects of the proasthmatic cytokine on airway function.
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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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Pascual, Rodolfo M., Elizabeth M. Carr, Michael C. Seeds, Manhong Guo, Reynold A. Panettieri, Stephen P. Peters, and Raymond B. Penn. "Regulatory features of interleukin-1β-mediated prostaglandin E2 synthesis in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 3 (March 2006): L501—L508. http://dx.doi.org/10.1152/ajplung.00420.2005.
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Exposure of airway smooth muscle (ASM) cells to the cytokine IL-1β results in an induction of PGE2 synthesis that affects numerous cell functions. Current dogma posits induction of COX-2 protein as the critical, obligatory event in cytokine-induced PGE2 production, although PGE2 induction can be inhibited without a concomitant inhibition of COX-2. To explore other putative regulatory features we examined the role of phospholipase A2 (PLA2) and PGE synthase (PGES) enzymes in IL-1β-induced PGE2 production. Treatment of human ASM cultures with IL-1β caused a time-dependent induction of both cytosolic PLA2 (cPLA2) and microsomal PGES (mPGES) similar to that observed for COX-2. Regulation of COX-2 and mPGES induction was similar, being significantly reduced by inhibition of p42/p44 or p38, whereas cPLA2 induction was only minimally reduced by inhibition of p38 or PKC. COX-2 and mPGES induction was subject to feed-forward regulation by PKA, whereas cPLA2 induction was not. SB-202474, an SB-203580 analog lacking the ability to inhibit p38 but capable of inhibiting IL-1β-induced PGE2 production, was effective in inhibiting mPGES but not COX-2 or cPLA2 induction. These data suggest that although COX-2, cPLA2, and mPGES are all induced by IL-β in human ASM cells, regulatory features of cPLA2 are dissociated, whereas those of COX-2 and mPGES are primarily associated, with regulation of PGE2 production. mPGES induction and, possibly, cPLA2 induction appear to cooperate with COX-2 to determine IL-1β-mediated PGE2 production in human ASM cells.
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Syabbalo, Nightingale. "The role of airway remodeling in the pathogenesis and treatment of chronic obstructive pulmonary disease." Journal of Lung, Pulmonary & Respiratory Research 8, no. 3 (July 22, 2021): 96–102. http://dx.doi.org/10.15406/jlprr.2021.08.00259.
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Chronic obstructive pulmonary disease (COPD) is currently considered the third leading cause of death in the world. COPD represents an important public health challenge and a socio-economical problem that is preventable and treatable. The main cause of COPD is chronic inhalation of cigarette smoke, and other harmful constituents of air pollution, which cause epithelial injury, chronic inflammation and airway remodeling. Airway remodeling is most prominent in small airways. It is due to infiltration of the airways by inflammatory cells, such as neutrophils, eosinophils, macrophages, and immune cells, including CD8+ T-cells, Th1, Th17 lymphocytes, and innate lymphoid cells group 3. Fibroblasts, myofibroblasts, and airway smooth muscle (ASM) cells also contribute to airway remodeling by depositing extracellular matrix (ECM) proteins, which increase the thickness of the airway wall. Activated inflammatory cells, and structural cells secrete cytokines, chemokines, growth factors, and enzymes which propagate airway remodeling. Airway remodeling is an active process which leads to thickness of the reticular basement membrane, subepithelial fibrosis, peribronchiolar fibrosis, and ASM cells hyperplasia and hypertrophy. It is also accompanied by submucosal glands and goblet cells hypertrophy and mucus hypersecretion, and angiogenesis. Epithelial mesenchymal transmission (EMT) plays a key role in airway remodeling. In patients with COPD and smokers, cellular reprograming in epithelial cells leads to EMT, whereby epithelial cells assume a mesencymal phenotype. Additionally, COPD is associated with increased parasympathetic cholinergic activity, which leads to ASM cells hypercontractility, increased mucus secretion, and vasodilatation. Treatment of COPD is intricate because of the heterogeneous nature of the disease, which requires specific treatment of the pathophysiological pathways, such as airway inflammation, ASM cell hypercontractility, and parasympathetic cholinergic hyperreactivity. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 strategy report recommends personalized approach for the treatment of COPD. However, some patients with COPD are unresponsive to the standards of care. They may require a triple combination of LABA/LAMA/ICS. Single-inhaler triple therapy (SITT), such as fluticasone fuorate/vilanterol/umeclidinium has been shown to significantly improve symptoms and asthma control, reduce moderate and severe exacerbations, and to improve lung function.
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Hernandes, Marina S., Qian Xu, and Kathy K. Griendling. "Role of NADPH Oxidases in Blood–Brain Barrier Disruption and Ischemic Stroke." Antioxidants 11, no. 10 (September 30, 2022): 1966. http://dx.doi.org/10.3390/antiox11101966.
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NADPH oxidases (Nox) are one of the main sources of reactive oxygen species (ROS) in the central nervous system (CNS). While these enzymes have been shown to be involved in physiological regulation of cerebral vascular tone, excessive ROS produced by Nox1-5 play a critical role in blood–brain barrier (BBB) dysfunction in numerous neuropathologies. Nox-derived ROS have been implicated in mediating matrix metalloprotease (MMP) activation, downregulation of junctional complexes between adjacent brain endothelial cells and brain endothelial cell apoptosis, leading to brain microvascular endothelial barrier dysfunction and consequently, increases in BBB permeability. In this review, we will highlight recent findings on the role played by these enzymes in BBB disruption induced by ischemic stroke.
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Murayama, Hirotada, Ayumi Eguchi, Misato Nakamura, Masahi Kawashima, Rei Nagahara, Sayaka Mizukami, Masayuki Kimura, et al. "Spironolactone in Combination with α-glycosyl Isoquercitrin Prevents Steatosis-related Early Hepatocarcinogenesis in Rats through the Observed NADPH Oxidase Modulation." Toxicologic Pathology 46, no. 5 (May 29, 2018): 530–39. http://dx.doi.org/10.1177/0192623318778508.
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Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.
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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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Shen, Garry X. "Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidaseThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease." Canadian Journal of Physiology and Pharmacology 88, no. 3 (March 2010): 241–48. http://dx.doi.org/10.1139/y10-018.
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Cardiovascular diseases are the predominant cause of death in patients with diabetes mellitus. Underlying mechanism for the susceptibility of diabetic patients to cardiovascular diseases remains unclear. Elevated oxidative stress was detected in diabetic patients and in animal models of diabetes. Hyperglycemia, oxidatively modified atherogenic lipoproteins, and advanced glycation end products are linked to oxidative stress in diabetes. Mitochondria are one of major sources of reactive oxygen species (ROS) in cells. Mitochondrial dysfunction increases electron leak and the generation of ROS from the mitochondrial respiratory chain (MRC). High levels of glucose and lipids impair the activities of MRC complex enzymes. NADPH oxidase (NOX) generates superoxide from NADPH in cells. Increased NOX activity was detected in diabetic patients. Hyperglycemia and hyperlipidemia increased the expression of NOX in vascular endothelial cells. Accumulated lines of evidence indicate that oxidative stress induced by excessive ROS production is linked to many processes associated with diabetic cardiovascular complications. Overproduction of ROS resulting from mitochondrial dysfunction or NOX activation is associated with uncoupling of endothelial nitric oxide synthase, which leads to reduced production of nitric oxide and endothelial-dependent vasodilation. Gene silence or inhibitor of NOX reduced oxidized or glycated LDL-induced expression of plasminogen activator inhibitor-1 in endothelial cells. Statins, hypoglycemic agents, and exercise may reduce oxidative stress in diabetic patients through the reduction of NOX activity or the improvement of mitochondrial function, which may prevent or postpone the development of cardiovascular complications.
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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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Hickman-Davis, Judy M., J. Russell Lindsey, and Sadis Matalon. "Cyclophosphamide Decreases Nitrotyrosine Formation and Inhibits Nitric Oxide Production by Alveolar Macrophages in Mycoplasmosis." Infection and Immunity 69, no. 10 (October 1, 2001): 6401–10. http://dx.doi.org/10.1128/iai.69.10.6401-6410.2001.
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ABSTRACT We previously reported that congenic C57BL/6 inducible nitric oxide synthase−/− (iNOS−/−) mice infected withMycoplasma pulmonis developed higher bacterial numbers and lung lesion scores than C57BL/6 iNOS+/+ controls but had similar lung nitrotyrosine levels. The present studies investigated the role of inflammatory cells in nitrotyrosine formation during mycoplasmal infection. iNOS+/+ and iNOS−/−mice were injected with cyclophosphamide (CYP) and inoculated with 107 CFU of M. pulmonis. CYP pretreatment ofM. pulmonis-infected iNOS+/+ and iNOS−/− mice reduced polymorphonuclear cells (PMNs) within bronchoalveolar lavages (BALs) by 88 and 72%, respectively, and whole-lung myeloperoxidase levels by 80 and 78%, respectively, at 72 h postinfection but did not alter the number of alveolar macrophages (AMs) in BALs. CYP treatment also significantly decreased nitrate and nitrite (NOx) levels in BALs and plasma of infected iNOS+/+ mice, whereas neither CYP nor mycoplasmal infection altered NOx in iNOS−/− mice. CYP reduced lung nitrotyrosine levels in both iNOS+/+ and iNOS−/− mice to uninfected-control levels as shown by immunohistochemical staining and enzyme-linked immunosorbent assay and inhibited mycoplasmal killing by iNOS+/+ mice in vivo. CYP inhibited the production of gamma interferon-inducible NOx by iNOS+/+ AMs in vitro but did not alter the number of iNOS-positive AMs, as detected by immunocytochemistry. In addition, AMs from CYP-treated iNOS+/+ mice had significantly decreased ability to kill mycoplasmas in vitro. These results demonstrate that reactive species generated by inflammatory cells as well as PMN myeloperoxidase are important contributors to nitrotyrosine formation during mycoplasmal infection and that treatment with CYP decreases NO⋅ production by AMs and inhibits mycoplasmal killing.
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Fan Gaskin, Jennifer C., Manisha H. Shah, and Elsa C. Chan. "Oxidative Stress and the Role of NADPH Oxidase in Glaucoma." Antioxidants 10, no. 2 (February 4, 2021): 238. http://dx.doi.org/10.3390/antiox10020238.
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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.
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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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He, L., X. Liu, J. Chen, B. Dinger, L. Stensaas, and S. Fidone. "Modulation of chronic hypoxia-induced chemoreceptor hypersensitivity by NADPH oxidase subunits in rat carotid body." Journal of Applied Physiology 108, no. 5 (May 2010): 1304–10. http://dx.doi.org/10.1152/japplphysiol.00766.2009.
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Previous studies in our laboratory established that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) facilitate the open state of a subset of K+ channels in oxygen-sensitive type I cells of the carotid body. Thus pharmacological inhibition of NOX or deletion of a NOX gene resulted in enhanced chemoreceptor sensitivity to hypoxia. The present study tests the hypothesis that chronic hypoxia (CH)-induced hypersensitivity of chemoreceptors is modulated by increased NOX activity and elevated levels of ROS. Measurements of dihydroethidium fluorescence in carotid body tissue slices showed that increased ROS production following CH (14 days, 380 Torr) was blocked by the specific NOX inhibitor 4-(2-amino-ethyl)benzenesulfonyl fluoride (AEBSF, 3 μM). Consistent with these findings, in normal carotid body AEBSF elicited a small increase in the chemoreceptor nerve discharge evoked by an acute hypoxic challenge, whereas after 9 days of CH the effect of the NOX inhibitor was some threefold larger ( P < 0.001). Evaluation of gene expression after 7 days of CH showed increases in the isoforms NOX2 (∼1.5-fold) and NOX4 (∼3.8-fold) and also increased presence of the regulatory subunit p47phox (∼4.2-fold). Involvement of p47phox was further implicated in studies of isolated type I cells that demonstrated an ∼8-fold and an ∼11-fold increase in mRNA after 1 and 3 days, respectively, of hypoxia in vivo. These findings were confirmed in immunocytochemical studies of carotid body tissue that showed a robust increase of p47phox in type I cells after 14 days of CH. Our findings suggest that increased ROS production by NOX enzymes in type I cells dampens CH-induced hypersensitivity in carotid body chemoreceptors.
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Wojewodzka-Zelezniakowicz, Marzena, Anna Gromotowicz-Poplawska, Wioleta Kisiel, Emilia Konarzewska, Janusz Szemraj, Jerzy Robert Ladny, and Ewa Chabielska. "Angiotensin-converting enzyme inhibitors attenuate propofol-induced pro-oxidative and antifibrinolytic effect in human endothelial cells." Journal of the Renin-Angiotensin-Aldosterone System 18, no. 1 (January 2017): 147032031668719. http://dx.doi.org/10.1177/1470320316687197.
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Introduction: The aim of this study was to investigate the effects of plasma and tissue angiotensin-converting enzyme inhibitors (ACE-Is) against propofol-induced endothelial dysfunction and to elucidate the involved mechanisms in vitro. Materials and methods: We examined the effects of propofol (50 μM), quinaprilat and enalaprilat (10−5 M) on fibrinolysis (t-PA, PAI-1, TAFI antigen levels), oxidative stress parameters (H2O2 and MDA antigen levels and SOD and NADPH oxidase mRNA levels) and nitric oxide bioavailability (NO2/NO3 concentration and NOS expression at the level of mRNA) in human umbilical vein endothelial cells (HUVECs). Results: We found that both ACE-Is promoted similar endothelial fibrinolytic properties and decreased oxidative stress in vitro. Propofol alone increased the release of antifibrinolytic and pro-oxidative factors from the endothelium and increased mRNA iNOS expression. We also found that the incubation of HUVECs in the presence of propofol following ACE-Is pre-incubation caused weakness of the antifibrinolytic and pro-oxidative potential of propofol and this effect was similar after both ACE-Is. Conclusions: This observation suggests that the studied ACE-Is exerted protective effects against endothelial cell dysfunction caused by propofol, independently of hemodynamics.
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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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Meza, Cesar A., Justin D. La Favor, Do-Houn Kim, and Robert C. Hickner. "Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?" International Journal of Molecular Sciences 20, no. 15 (August 2, 2019): 3775. http://dx.doi.org/10.3390/ijms20153775.
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NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.
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Lin, Hui, Jiayin Xu, Wenlian Sun, Wujia Hu, Huifang Gao, Kaihui Hu, Junzhi Qiu, Binbin Huang, and Liaoyuan Zhang. "Efficient 1-Hydroxy-2-Butanone Production from 1,2-Butanediol by Whole Cells of Engineered E. coli." Catalysts 11, no. 10 (September 28, 2021): 1184. http://dx.doi.org/10.3390/catal11101184.
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1-Hydroxy-2-butanone (HB) is a key intermediate for anti-tuberculosis pharmaceutical ethambutol. Commercially available HB is primarily obtained by the oxidation of 1,2-butanediol (1,2-BD) using chemical catalysts. In present study, seven enzymes including diol dehydrogenases, secondary alcohol dehydrogenases and glycerol dehydrogenase were chosen to evaluate their abilities in the conversion of 1,2-BD to HB. The results showed that (2R, 3R)- and (2S, 3S)-butanediol dehydrogenase (BDH) from Serratia sp. T241 could efficiently transform (R)- and (S)-1,2-BD into HB respectively. Furthermore, two biocatalysts co-expressing (2R, 3R)-/(2S, 3S)-BDH, NADH oxidase and hemoglobin protein in Escherichia coli were developed to convert 1,2-BD mixture into HB, and the transformation conditions were optimized. Maximum HB yield of 341.35 and 188.80 mM could be achieved from 440 mM (R)-1,2-BD and 360 mM (S)-1,2-BD by E. coli (pET-rrbdh-nox-vgb) and E. coli (pET-ssbdh-nox-vgb) under the optimized conditions. In addition, two biocatalysts showed the ability in chiral resolution of 1,2-BD isomers, and 135.68 mM (S)-1,2-BD and 112.43 mM (R)-1,2-BD with the purity of 100% could be obtained from 300 and 200 mM 1,2-BD mixture by E. coli (pET-rrbdh-nox-vgb) and E. coli (pET-ssbdh-nox-vgb), respectively. These results provided potential application for HB production from 1,2-BD mixture and chiral resolution of (R)-1,2-BD and (S)-1,2-BD.
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Schiavone, Stefania, Margherita Neri, Angela Maffione, Paolo Frisoni, Maria Morgese, Luigia Trabace, and Emanuela Turillazzi. "Increased iNOS and Nitrosative Stress in Dopaminergic Neurons of MDMA-Exposed Rats." International Journal of Molecular Sciences 20, no. 5 (March 12, 2019): 1242. http://dx.doi.org/10.3390/ijms20051242.
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Several mechanisms underlying 3,4-Methylenedioxy-N-methylamphetamine (MDMA) neurotoxicity have been proposed, including neurochemical alterations and excitotoxicity mediated by reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). However, ROS, NO, and RNS sources in the brain are not fully known. We aimed to investigate possible alterations in the expression of the ROS producer NOX enzymes (NOX2, NOX1, and NOX4), NO generators (iNOS, eNOS, and nNOS), markers of oxidative (8-hydroxy-2′-deoxyguanosine, 8OHdG), and nitrosative (3-nitrotyrosine, NT) stress, as well as the colocalization between cells positive for the dopamine transporter (DT1) and cells expressing the neuronal nuclei (NeuN) marker, in the frontal cortex of rats receiving saline or MDMA, sacrificed 6 h, 16 h, or 24 h after its administration. MDMA did not affect NOX2, NOX1, and NOX4 immunoreactivity, whereas iNOS expression was enhanced. The number of NT-positive cells was increased in MDMA-exposed animals, whereas no differences were detected in 8OHdG expression among experimental groups. MDMA and NT markers colocalized with DT1 positive cells. DT1 immunostaining was found in NeuN-positive stained cells. Virtually no colocalization was observed with microglia and astrocytes. Moreover, MDMA immunostaining was not found in NOX2-positive cells. Our results suggest that iNOS-derived nitrosative stress, but not NOX enzymes, may have a crucial role in the pathogenesis of MDMA-induced neurotoxicity, highlighting the specificity of different enzymatic systems in the development of neuropathological alterations induced by the abuse of this psychoactive compound.
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Patel, Jenish R., Bradley T. Christoph, Sakina F. Hussain, Keyur P. Vora, Priya Ranjan, Suryaprakash Sambhara, and Shivaprakash Gangappa. "Impact of NADPH Oxidase Inhibition on Influenza A Virus-induced Inflammation (134.80)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 134.80. http://dx.doi.org/10.4049/jimmunol.182.supp.134.80.
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Abstract Activation of innate immunity pathways in susceptible cell types is critical for host defense against influenza-A viruses (IAV). Based on studies signifying a role for NOX1 in inflammation, we hypothesized that IAV of seasonal and pandemic potential may induce different isoforms of NOX enzymes in the respiratory tract, and that attenuation of virus strain-specific NOX enzymes can be exploited to prevent and/or treat severity of disease. Using three respiratory tract-relevant cell lines (epithelial/A549, endothelial/HULEC, and monoctytic/THP1) and three strains of IAV (H1N1/PR8, H3N2/X31, H1N1/WSN), we found significant upregulation of NOX1 in all three cell lines (e.g.-A549: PR8/55 fold; X31/35 fold; WSN/12,250 fold). Furthermore, in contrast to the epithelial cell line showing NOX1 expression by 4h with peak levels at 16h, the monocytic cell line showed delayed (8h) and sustained (48h) levels of NOX1. Interestingly, inhibition of NOX-isoforms in IAV-infected epithelial cells by diphenyleneiodonium (DPI), at a concentration (25μM), which did not impact cell death, showed significant decrease (75%) in virus triggered NOX1 levels. In addition, NOX-inhibition led to significant decrease in virus-induced chemokines (MCP1, MIP3, MIP1β, RANTES, and IP10) and proinflammatory cytokines (IL1α, IL6, IL8, and TNFα). Furthermore, decline in NOX1 correlated with a modest increase in viral NS1. Taken together, in addition to showing definitive evidence for upregulation of NOX1 in response to subtypes of IAV, our results strongly support a role for NOX1 in IAV-driven inflammation.
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Rahman, Md Mizanur, Amina El Jamali, Ganesh V. Halade, Allal Ouhtit, Haissam Abou-Saleh, and Gianfranco Pintus. "Nox2 Activity Is Required in Obesity-Mediated Alteration of Bone Remodeling." Oxidative Medicine and Cellular Longevity 2018 (November 8, 2018): 1–10. http://dx.doi.org/10.1155/2018/6054361.
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Despite increasing evidence suggesting a role for NADPH oxidases (Nox) in bone pathophysiology, whether Nox enzymes contribute to obesity-mediated bone remodeling remains to be clearly elucidated. Nox2 is one of the predominant Nox enzymes expressed in the bone marrow microenvironment and is a major source of ROS generation during inflammatory processes. It is also well recognized that a high-fat diet (HFD) induces obesity, which negatively impacts bone remodeling. In this work, we investigated the effect of Nox2 loss of function on obesity-mediated alteration of bone remodeling using wild-type (WT) and Nox2-knockout (KO) mice fed with a standard lab chow diet (SD) as a control or a HFD as an obesity model. Bone mineral density (BMD) of mice was assessed at the beginning and after 3 months of feeding with SD or HFD. Our results show that HFD increased bone mineral density to a greater extent in KO mice than in WT mice without affecting the total body weight and fat mass. HFD also significantly increased the number of adipocytes in the bone marrow microenvironment of WT mice as compared to KO mice. The bone levels of proinflammatory cytokines and proosteoclastogenic factors were also significantly elevated in WT-HFD mice as compared to KO-HFD mice. Furthermore, the in vitro differentiation of bone marrow cells into osteoclasts was significantly increased when using bone marrow cells from WT-HFD mice as compared to KO-HFD mice. Our data collectively suggest that Nox2 is implicated in HFD-induced deleterious bone remodeling by enhancing bone marrow adipogenesis and osteoclastogenesis.
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Sinitsky, M. Yu, A. V. Sinitskaya, D. K. Shishkova, M. A. Asanov, M. V. Khutornaya, and A. V. Ponasenko. "Oxidative stress in the endothelial cell culture exposed to mitomycin C." Siberian Journal of Clinical and Experimental Medicine 37, no. 3 (October 20, 2022): 121–27. http://dx.doi.org/10.29001/2073-8552-2022-37-3-121-127.
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Background. Atherosclerosis is one of the leading cardiovascular pathologies. Evidence suggests that DNA damage caused by endothelial cell exposure to mitomycin C (MMC) leads to endothelial dysfunction and is the risk factor for this disease. MMC is an alkylating mutagen involved in the development of oxidative stress, which is also a risk factor for atherosclerosis. Aim. To access the levels of oxidative stress markers in the primary human endothelial cell culture exposed to alkylating mutagen MMC.Material and Methods. Commercially available primary cultures of endothelial cells obtained from human coronary artery (HCAEC) and human internal thoracic artery (HITAEC) were used in the study. The cells were cultivated in the presence of 500 ng/mL MMC (experimental group) and without mutagenic load (control group). The levels of reactive oxygen species, reactive nitrogen species, and 8-OH-deoxyguanosine (8-OHdG) in cell growth media were assessed by enzyme-linked immunosorbent assay. The relative telomere length and expression of TERT and POT1 genes were accessed in endothelial cells by quantitative polymerase chain reaction. Statistical analysis of data was performed using GraphPad Prism 9 software.Results. There were no diff erences in the concentrations of reactive oxygen species, reactive nitrogen species (NO2 -, NO3 -, NO2 -/NO3 -), and 8-OHdG in HCAEC and HITAEC cultures exposed to MMC compared to the corresponding parameters in the non-exposed controls. At the same time, HCAEC and HITAEC exposed to MMC were characterized by a decrease in the relative telomere length compared to control (10.97 vs. 27.03 in HCAEC, p = 0.002 and 9.12 vs. 25.64 in HITAEC, p = 0.001). Moreover, we discovered 1.75-fold increase in the expression of POT1 gene in the experimental HCAEC compared to control (p = 0.019). No expression of TERT gene was observed in study groups.Conclusions. Alkylating mutagen MMC did not induce any pronounced oxidative stress in the primary human endothelial cells in vitro. The development of endothelial dysfunction caused by MMC exposure was triggered mainly by DNA alkylation resulting in the genotoxic stress in the endothelial cells.
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Mortezaee, Keywan, Nasser Hashemi Goradel, Peyman Amini, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Masoud Najafi, and Bagher Farhood. "NADPH Oxidase as a Target for Modulation of Radiation Response; Implications to Carcinogenesis and Radiotherapy." Current Molecular Pharmacology 12, no. 1 (January 11, 2019): 50–60. http://dx.doi.org/10.2174/1874467211666181010154709.
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Background:Radiotherapy is a treatment modality for cancer. For better therapeutic efficiency, it could be used in combination with surgery, chemotherapy or immunotherapy. In addition to its beneficial therapeutic effects, exposure to radiation leads to several toxic effects on normal tissues. Also, it may induce some changes in genomic expression of tumor cells, thereby increasing the resistance of tumor cells. These changes lead to the appearance of some acute reactions in irradiated organs, increased risk of carcinogenesis, and reduction in the therapeutic effect of radiotherapy.Discussion:So far, several studies have proposed different targets such as cyclooxygenase-2 (COX-2), some toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) etc., for the amelioration of radiation toxicity and enhancing tumor response. NADPH oxidase includes five NOX and two dual oxidases (DUOX1 and DUOX2) subfamilies that through the production of superoxide and hydrogen peroxide, play key roles in oxidative stress and several signaling pathways involved in early and late effects of ionizing radiation. Chronic ROS production by NOX enzymes can induce genomic instability, thereby increasing the risk of carcinogenesis. Also, these enzymes are able to induce cell death, especially through apoptosis and senescence that may affect tissue function. ROS-derived NADPH oxidase causes apoptosis in some organs such as intestine and tongue, which mediate inflammation. Furthermore, continuous ROS production stimulates fibrosis via stimulation of fibroblast differentiation and collagen deposition. Evidence has shown that in contrast to normal tissues, the NOX system induces tumor resistance to radiotherapy through some mechanisms such as induction of hypoxia, stimulation of proliferation, and activation of macrophages. However, there are some contradictory results. Inhibition of NADPH oxidase in experimental studies has shown promising results for both normal tissue protection and tumor sensitization to ionizing radiation.Conclusion:In this article, we aimed to review the role of different subfamilies of NADPH oxidase in radiation-induced early and late normal tissue toxicities in different organs.
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de Araújo, Glaucy Rodrigues, Ana Carolina Silveira Rabelo, Janaína Serenato Meira, Joamyr Victor Rossoni-Júnior, William de Castro-Borges, Renata Guerra-Sá, Maurício Azevedo Batista, et al. "Baccharis trimera inhibits reactive oxygen species production through PKC and down-regulation p47phox phosphorylation of NADPH oxidase in SK Hep-1 cells." Experimental Biology and Medicine 242, no. 3 (October 7, 2016): 333–43. http://dx.doi.org/10.1177/1535370216672749.
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Baccharis trimera, popularly known as “carqueja”, is a native South-American plant possessing a high concentration of polyphenolic compounds and therefore high antioxidant potential. Despite the antioxidant potential described for B. trimera, there are no reports concerning the signaling pathways involved in this process. So, the aim of the present study was to assess the influence of B. trimera on the modulation of PKC signaling pathway and to characterize the effect of the nicotinamide adenine dinucleotide phosphate oxidase enzyme (NOX) on the generation of reactive oxygen species in SK Hep-1 cells. SK-Hep 1 cells were treated with B. trimera, quercetin, or rutin and then stimulated or not with PMA/ionomycin and labeled with carboxy H2DCFDA for detection of reactive oxygen species by flow cytometer. The PKC expression by Western blot and enzyme activity was performed to evaluate the influence of B. trimera and quercetin on PKC signaling pathway. p47 phox and p47 phox phosphorylated expression was performed by Western blot to evaluate the influence of B. trimera on p47 phox phosphorylation. The results showed that cells stimulated with PMA/ionomycin (activators of PKC) showed significantly increased reactive oxygen species production, and this production returned to baseline levels after treatment with DPI (NOX inhibitor). Both B. trimera and quercetin modulated reactive oxygen species production through the inhibition of PKC protein expression and enzymatic activity, also with inhibition of p47 phox phosphorylation. Taken together, these results suggest that B. trimera has a potential mechanism for inhibiting reactive oxygen species production through the PKC signaling pathway and inhibition subunit p47 phox phosphorylation of nicotinamide adenine dinucleotide phosphate oxidase.
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Jung, Hee-Yeon, Se-Hyun Oh, Ji-Sun Ahn, Eun-Joo Oh, You-Jin Kim, Chan-Duck Kim, Sun-Hee Park, Yong-Lim Kim, and Jang-Hee Cho. "NOX1 Inhibition Attenuates Kidney Ischemia-Reperfusion Injury via Inhibition of ROS-Mediated ERK Signaling." International Journal of Molecular Sciences 21, no. 18 (September 21, 2020): 6911. http://dx.doi.org/10.3390/ijms21186911.
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The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin–Darby Canine Kidney (MDCK) cells were incubated with H2O2 (1.4 mM) for 1 h to induce oxidative stress. ML171, a selective NOX1 inhibitor, and siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of reactive oxygen species (ROS), including intracellular H2O2 production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by ML171. H2O2 evoked the changes in oxidative stress enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by ML171. Treatment with ML171 and transfection with siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H2O2 in MDCK cells. ML171 decreased caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H2O2-treated MDCK cells. Among the MAPK pathways, ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling.
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Stepniak, Jan, Andrzej Lewinski, and Malgorzata Karbownik-Lewinska. "Sexual Dimorphism of NADPH Oxidase/H2O2 System in Rat Thyroid Cells; Effect of Exogenous 17β-Estradiol." International Journal of Molecular Sciences 19, no. 12 (December 15, 2018): 4063. http://dx.doi.org/10.3390/ijms19124063.
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It has long been observed that females are more susceptible to thyroid diseases than males. Epidemiological and experimental data show that actions of hormonal factors—especially estrogens—may explain such disparity. However, the exact cause and mechanisms of this sexual dimorphism remain so far unknown. Therefore, we aimed at evaluating the effect of 17β-estradiol on the redox balance in thyroids of male and female rats. Expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, i.e., dual oxidase 1 (DUOX1), dual oxidase 2 (DUOX2) and NADPH oxidase 4 (NOX4), and hydrogen peroxide (H2O2) levels were evaluated in the primary cell cultures derived from thyroid glands of adult male or female Wistar rats. The measurement was made before and after treatment with 17β-estradiol alone or with addition of one of its receptor antagonists. We found that under basal conditions female thyroid cells are exposed to higher concentrations of H2O2, most likely due to NOX/DUOX enzymes activity. Additionally, exogenous 17β-estradiol stimulated NOX/DUOX expression as well as H2O2 production, and this effect was mainly mediated through ERα. In conclusion, oxidative processes may constitute mechanisms responsible for sexual dimorphism of thyroid diseases. Exogenous 17β-estradiol may play a crucial pathogenic role in thyroid diseases via oxidative mechanisms, however without any gender differences.
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Takaishi, Kazumi, Hiroyuki Kinoshita, Shingo Kawashima, and Shinji Kawahito. "Human Vascular Smooth Muscle Function and Oxidative Stress Induced by NADPH Oxidase with the Clinical Implications." Cells 10, no. 8 (July 31, 2021): 1947. http://dx.doi.org/10.3390/cells10081947.
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Among reactive oxygen species, superoxide mediates the critical vascular redox signaling, resulting in the regulation of the human cardiovascular system. The reduced form of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) is the source of superoxide and relates to the crucial intracellular pathology and physiology of vascular smooth muscle cells, including contraction, proliferation, apoptosis, and inflammatory response. Human vascular smooth muscle cells express NOX1, 2, 4, and 5 in physiological and pathological conditions, and those enzymes play roles in most cardiovascular disorders caused by hypertension, diabetes, inflammation, and arteriosclerosis. Various physiologically active substances, including angiotensin II, stimulate NOX via the cytosolic subunits’ translocation toward the vascular smooth muscle cell membrane. As we have shown, some pathological stimuli such as high glucose augment the enzymatic activity mediated by the phosphatidylinositol 3-kinase-Akt pathway, resulting in the membrane translocation of cytosolic subunits of NOXs. This review highlights and details the roles of human vascular smooth muscle NOXs in the pathophysiology and clinical aspects. The regulation of the enzyme expressed in the vascular smooth muscle cells may lead to the prevention and treatment of human cardiovascular diseases.
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Chen, Kai, Michael T. Kirber, Hui Xiao, Yu Yang, and John F. Keaney. "Regulation of ROS signal transduction by NADPH oxidase 4 localization." Journal of Cell Biology 181, no. 7 (June 23, 2008): 1129–39. http://dx.doi.org/10.1083/jcb.200709049.
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Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.
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Alsharabasy, Amir M., Sharon A. Glynn, and Abhay Pandit. "The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants." Biochemical Society Transactions 48, no. 6 (November 5, 2020): 2539–55. http://dx.doi.org/10.1042/bst20200208.
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The extracellular matrix (ECM) dynamics in tumour tissue are deregulated compared to the ECM in healthy tissue along with disorganized architecture and irregular behaviour of the residing cells. Nitric oxide (NO) as a pleiotropic molecule exerts different effects on the components of the ECM driving or inhibiting augmented angiogenesis and tumour progression and tumour cell proliferation and metastasis. These effects rely on the concentration of NO within the tumour tissue, the nature of the surrounding microenvironment and the sensitivity of resident cells to NO. In this review article, we summarize the recent findings on the correlation between the levels of NO and the ECM components towards the modulation of tumour angiogenesis in different types of cancers. These are discussed principally in the context of how NO modulates the expression of ECM proteins resulting in either the promotion or inhibition of tumour growth via tumour angiogenesis. Furthermore, the regulatory effects of individual ECM components on the expression of the NO synthase enzymes and NO production were reviewed. These findings support the current efforts for developing effective therapeutics for cancers.