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1
Han, Jin, Donghwi Park, Ji Young Park, and Seungwoo Han. "Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis." Antioxidants 11, no. 12 (November 27, 2022): 2346. http://dx.doi.org/10.3390/antiox11122346.
Повний текст джерелаАнотація:
Increased oxidative stress in osteoarthritis (OA) cartilage mediates catabolic signal transduction leading to extracellular matrix degradation and chondrocyte apoptosis. This study aimed to explore the contribution of NADPH oxidase (NOX), a major source of cellular reactive oxygen species (ROS), to the catabolic process of chondrocytes and to OA. The inhibition of NOX isoforms with a pan-NOX inhibitor, APX-115, significantly decreased IL-1β-induced ROS production in primary chondrocytes and, most potently, suppressed the expression of oxidative stress marker genes and catabolic proteases compared with the inhibition of other ROS sources. Catabolic stimuli by IL-1β treatment and in post-traumatic OA conditions upregulated the expression of NOX2 and NOX4 in chondrocytes. In the post-traumatic OA model, the pharmacologic inhibition of NOX protected mice against OA by modulating the oxidative stress and the expression of MMP-13 and Adamts5 in chondrocytes. Mechanistically, NOX inhibition suppresses Rac1, p38, and JNK MAPK signaling consistently and restores oxidative phosphorylation in IL-1β-treated chondrocytes. In conclusion, NOX inhibition prevented the development of OA by attenuating the catabolic signaling and restoring the mitochondrial metabolism and can thus be a promising class of drug for OA.
2
Coby, Aaron J., and Flynn W. Picardal. "Inhibition of NO3− and NO2− Reduction by Microbial Fe(III) Reduction: Evidence of a Reaction between NO2− and Cell Surface-Bound Fe2+." Applied and Environmental Microbiology 71, no. 9 (September 2005): 5267–74. http://dx.doi.org/10.1128/aem.71.9.5267-5274.2005.
Повний текст джерелаАнотація:
ABSTRACT A recent study (D. C. Cooper, F. W. Picardal, A. Schimmelmann, and A. J. Coby, Appl. Environ. Microbiol. 69:3517-3525, 2003) has shown that NO3 − and NO2 − (NOx −) reduction by Shewanella putrefaciens 200 is inhibited in the presence of goethite. The hypothetical mechanism offered to explain this finding involved the formation of a Fe(III) (hydr)oxide coating on the cell via the surface-catalyzed, abiotic reaction between Fe2+ and NO2 −. This coating could then inhibit reduction of NOx − by physically blocking transport into the cell. Although the data in the previous study were consistent with such an explanation, the hypothesis was largely speculative. In the current work, this hypothesis was tested and its environmental significance explored through a number of experiments. The inhibition of ∼3 mM NO3 − reduction was observed during reduction of a variety of Fe(III) (hydr)oxides, including goethite, hematite, and an iron-bearing, natural sediment. Inhibition of oxygen and fumarate reduction was observed following treatment of cells with Fe2+ and NO2 −, demonstrating that utilization of other soluble electron acceptors could also be inhibited. Previous adsorption of Fe2+ onto Paracoccus denitrificans inhibited NOx − reduction, showing that Fe(II) can reduce rates of soluble electron acceptor utilization by non-iron-reducing bacteria. NO2 − was chemically reduced to N2O by goethite or cell-sorbed Fe2+, but not at appreciable rates by aqueous Fe2+. Transmission and scanning electron microscopy showed an electron-dense, Fe-enriched coating on cells treated with Fe2+ and NO2 −. The formation and effects of such coatings underscore the complexity of the biogeochemical reactions that occur in the subsurface.
3
Kampschreur, M. J., N. C. G. Tan, C. Picioreanu, M. S. M. Jetten, I. Schmidt, and M. C. M. van Loosdrecht. "Role of nitrogen oxides in the metabolism of ammonia-oxidizing bacteria." Biochemical Society Transactions 34, no. 1 (January 20, 2006): 179–81. http://dx.doi.org/10.1042/bst0340179.
Повний текст джерелаАнотація:
Ammonia-oxidizing bacteria (AOB) can use oxygen and nitrite as electron acceptors. Nitrite reduction by Nitrosomonas is observed under three conditions: (i) hydrogen-dependent denitrification, (ii) anoxic ammonia oxidation with nitrogen dioxide (NO2) and (iii) NOx-induced aerobic ammonia oxidation. NOx molecules play an important role in the conversion of ammonia and nitrite by AOB. Absence of nitric oxide (NO), which is generally detectable during ammonia oxidation, severely impairs ammonia oxidation by AOB. The lag phase of recovery of aerobic ammonia oxidation was significantly reduced by NO2 addition. Acetylene inhibition tests showed that NO2-dependent and oxygen-dependent ammonia oxidation can be distinguished. Addition of NOx increased specific activity of ammonia oxidation, growth rate and denitrification capacity. Together, these findings resulted in a hypothetical model on the role of NOx in ammonia oxidation: the NOx cycle.
4
Gaspar, Renato Simões, Tanya Sage, Gemma Little, Neline Kriek, Giordano Pula, and Jonathan M. Gibbins. "Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors." Antioxidants 10, no. 3 (March 23, 2021): 497. http://dx.doi.org/10.3390/antiox10030497.
Повний текст джерелаАнотація:
Background: Protein disulphide isomerase (PDI) and NADPH oxidase 1 (Nox-1) regulate platelet function and reactive oxygen species (ROS) generation, suggesting potentially interdependent roles. Increased platelet reactivity and ROS production have been correlated with cardiometabolic disease risk factors. Objectives: To establish whether PDI and Nox-1 cooperate to control platelet function. Methods: Immunofluorescence microscopy was utilised to determine expression and localisation of PDI and Nox-1. Platelet aggregation, fibrinogen binding, P-selectin exposure, spreading and calcium mobilization were measured as markers of platelet function. A cross-sectional population study (n = 136) was conducted to assess the relationship between platelet PDI and Nox-1 levels and cardiometabolic risk factors. Results: PDI and Nox-1 co-localized upon activation induced by the collagen receptor GPVI. Co-inhibition of PDI and Nox-1 led to additive inhibition of GPVI-mediated platelet aggregation, activation and calcium flux. This was confirmed in murine Nox-1−/− platelets treated with PDI inhibitor bepristat, without affecting bleeding. PDI and Nox-1 together contributed to GPVI signalling that involved the phosphorylation of p38 MAPK, p47phox, PKC and Akt. Platelet PDI and Nox-1 levels were upregulated in obesity, with platelet Nox-1 also elevated in hypertensive individuals. Conclusions: We show that PDI and Nox-1 cooperate to control platelet function and are associated with cardiometabolic risk factors.
5
Chen, Hai, Yun Seon Song, and Pak H. Chan. "Inhibition of NADPH Oxidase is Neuroprotective after Ischemia—Reperfusion." Journal of Cerebral Blood Flow & Metabolism 29, no. 7 (May 6, 2009): 1262–72. http://dx.doi.org/10.1038/jcbfm.2009.47.
Повний текст джерелаАнотація:
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is well known as a major source for superoxide radical generation in leukocytes. Superoxide radicals play a significant role in brain ischemia–reperfusion (I/R) injury. Recent data have also shown expression of NOX in the brain. However, the manner by which NOX is involved in pathologic processes after cerebral ischemia remains unknown. Therefore, we subjected mice deficient in the NOX subunit, gp91phox (gp91phox-/-), those treated with the NOX inhibitor, apocynin, and wild-type (WT) mice to 75 mins of focal ischemia followed by reperfusion. At 24 h of reperfusion, the gp91phox-/- and apocynin-treated mice showed 50% less brain infarction and 70% less cleaved spectrin compared with WT mice. The levels of 4-hydroxy-2-nonenal, malondialdehyde, and 8-hydroxy-2‘-deoxyguanosine increased significantly after I/R, indicating oxidative brain injury. NADPH oxidase inhibition reduced biomarker generation. Furthermore, NOX was involved in postischemic inflammation in the brains, as less intercellular adhesion molecule-1 upregulation and less neutrophil infiltration were found in the NOX-inhibited mice after I/R. Moreover, gp91phox expression increased after ischemia, and was further aggravated by genetic copper/zinc-superoxide dismutase (SOD1) ablation, but ameliorated in SOD1-overexpressing mice. This study suggests that NOX plays a role in oxidative stress and inflammation, thus contributing to ischemic brain injury.
6
Wu, Tian Hua, and Ren Zhang Qian. "Study of NOx Inhibition Technology Based on Water-Gas Reaction." Applied Mechanics and Materials 737 (March 2015): 584–87. http://dx.doi.org/10.4028/www.scientific.net/amm.737.584.
Повний текст джерелаАнотація:
Pulverized coal combustion is one of the main NOx emission sources. The existing low NOx combustion technology can not meet the requirements of environment conservation. In this paper, a new low NOx combustion technology, the NOx inhibition method based on water-gas reaction, is presented, in which steam is injected into the anoxic flame of pulverized coal to bring water-gas reaction and produce CO and H2 which will inhibit the production of NOx. The produced H2 is especially very active. Water-gas reaction is endothermic, which has an effect of reducing the peak temperature of the flame and is very propitious to the inhibition of thermal type NOx. As the water-gas reaction is also an interim process, the heat absorbed in it will be released when burning with oxygen so that the whole amount of heat inside the furnace is not affected. The principle of the method is proved correct by experiments and industrial scale of 420 t/h boiler tests in which the effect of NOx reduction is obvious. The technology is consistent with that of air-staged combustion.
7
Djerdjev, Alex M., Pramith Priyananda, Jeff Gore, James K. Beattie, Chiara Neto, and Brian S. Hawkett. "Safer emulsion explosives resulting from NOx inhibition." Chemical Engineering Journal 403 (January 2021): 125713. http://dx.doi.org/10.1016/j.cej.2020.125713.
Повний текст джерела
8
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.
Повний текст джерелаАнотація:
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.
9
Shin, Kyong-Oh, Sungeun Kim, Bokyung Kim, Hye-Yoon Park, Eunhee Jung, Garyun Kim, Donghee Kim, Hwang Eui Cho, Yoshikazu Uchida, and Kyungho Park. "Euphorbia supina Extracts Block NADPH Oxidase-Mediated, Ceramide-Induced Apoptosis Initiated by Diesel Particulate Matter." Pharmaceuticals 15, no. 4 (March 31, 2022): 431. http://dx.doi.org/10.3390/ph15040431.
Повний текст джерелаАнотація:
Air pollutants contribute to the development of diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary cancer, cardiovascular problems, and some skin diseases. We recently found that a major air pollutant, diesel particulate matter (DPM), induces apoptosis in human keratinocytes by increasing a proapoptotic lipid mediator, ceramide. DPM activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which stimulates sphingomyelinase, leading to an increased conversion of sphingomyelin to ceramide. Interestingly, we characterized that although NOX is a reactive oxygen species (ROS) generator, the activation of sphingomyelinases by NOX is an ROS-independent mechanism. A Korean weed, prostrate spurge Euphorbia supina Rafin (ESR), has been used for centuries as a folk medicine to treat bronchitis, hepatitis, hemorrhage, and skin inflammation. Flavonoids, terpenes and tannins are enriched in ESR, and although ESR has proven antioxidative activity, its biological activities are largely unknown. Here, we investigate whether and how ESR protects keratinocytes against DPM-mediated apoptosis. We found that ESR-extracts (ESR-Ex) protect keratinocytes from DPM-induced apoptosis by inhibiting NOX activation in keratinocytes in response to DPM. We also demonstrated that ESR-Ex suppresses NOX activation via a blockage of the aryl hydrocarbon receptor (AhR) activation-mediated transcription of neutrophil cytosolic factor 1 (NCF1)/p47phox, a subunit of NOX. Our study reveals previously uncharacterized biological activity of ESR-Ex; i.e., its inhibition of Ahr and NOX activation. Thus, because the inhibition of NOX has already been developed to treat NOX-mediated diseases, including various types of cardiovascular diseases and cancers, initiated by air pollutants and because AhR activation contributes to the development of chronic inflammatory diseases, our study provides further advantages for the medical use of ESR.
10
Teng, Ru-Jeng, Jianhai Du, Scott Welak, Tongju Guan, Annie Eis, Yang Shi, and Girija G. Konduri. "Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 7 (April 1, 2012): L651—L663. http://dx.doi.org/10.1152/ajplung.00177.2011.
Повний текст джерелаАнотація:
Autophagy is a process for cells to degrade proteins or entire organelles to maintain a balance in the synthesis, degradation, and subsequent recycling of cellular products. Increased reactive oxygen species formation is known to induce autophagy. We previously reported that increased NADPH oxidase (NOX) activity in pulmonary artery endothelial cells (PAEC) from fetal lambs with persistent pulmonary hypertension (PPHN) contributes to impaired angiogenesis in PPHN-PAEC compared with normal PAEC. We hypothesized that increased NOX activity in PPHN-PAEC is associated with increased autophagy, which, in turn, contributes to impaired angiogenesis in PPHN-PAEC. In the present study, we detected increased autophagy in PPHN-PAEC as shown by increased ratio of the microtubule-associated protein 1 light chain (LC3)-II to LC3-I and increased percentage of green fluorescent protein-LC3 punctate positive cells. Inhibiting autophagy by 3-methyladenine, chloroquine, and beclin-1 knockdown in PPHN-PAEC has led to decreased autophagy and increased in vitro angiogenesis. Inhibition of autophagy also decreased the association between gp91phox and p47phox, NOX activity, and superoxide generation. A nonspecific antioxidant N-acetylcysteine and a NOX inhibitor apocynin decreased autophagy in PPHN-PAEC. In conclusion, autophagy may contribute to impaired angiogenesis in PPHN-PAEC through increasing NOX activity. Our results suggest that, in PPHN-PAEC, a positive feedback relationship between autophagy and NOX activity may regulate angiogenesis.
11
Cheng, Xinliang, Liqiang Wang, Lijuan Fang, Shiyan Chen, Xin Zhou, Jingjun Ma, Yuqing Pan, and Pengfei Li. "Potential Strong Inhibition on Ozone Production Sensitivity by Particle Uptake." Atmosphere 13, no. 10 (September 23, 2022): 1558. http://dx.doi.org/10.3390/atmos13101558.
Повний текст джерелаАнотація:
The accurate identification of ozone (O3) production sensitivity is central to developing O3 pollution control policies. It is determined by the relative ratio of the radical loss to the total primary radical production. However, such radical losses in the traditional sensitivity analysis typically rely on nitrogen oxide (NOx) sinks while ignoring particle uptake (collisions between compounds in the gas phase and condensed phases that result in irreversible uptake due to chemical reactions). Therefore, we combine NOx and particle uptakes to optimize peroxy radical loss estimates and thus analyze the relative sensitivity. We also assess the absolute responses of precursor reduction to O3 production. Such relative and absolute sensitivity analysis is applied to measurements in Chun’an, a county in China, where volatile organic compounds (VOCs) and NOx are both rich. Consequently, the relative sensitivity analysis presents that the dominant precursor for O3 production sensitivity shifts from volatile organic compounds (VOCs) in the morning and evening to NOx in the afternoon, the main driver of which is related to NO depletion. In contrast, the absolute sensitivity analysis confirms that VOCs persistently determine the diurnal ozone production sensitivity. Moreover, they both show that particle uptake does not change the regime classification of O3 production sensitivity (i.e., VOC- or NOx-sensitive regime) but potentially has a strong inhibition on the sensitivity magnitude (within 16% and 38% for VOC- or NOx-sensitive regimes, respectively). Our results partly explain more insensitive O3 production measurements than those suggested by traditional sensitivity analyses, which has important implications for synergistic controls on O3 and fine particulate matter pollution.
12
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.
Повний текст джерелаАнотація:
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.
13
Menden, Heather, Everett Tate, Neil Hogg та Venkatesh Sampath. "LPS-mediated endothelial activation in pulmonary endothelial cells: role of Nox2-dependent IKK-β phosphorylation". American Journal of Physiology-Lung Cellular and Molecular Physiology 304, № 6 (15 березня 2013): L445—L455. http://dx.doi.org/10.1152/ajplung.00261.2012.
Повний текст джерелаАнотація:
Lipopolysaccharide (LPS)-mediated endothelial activation contributes to lung inflammation and alveolar remodeling seen in premature infants with bronchopulmonary dysplasia (BPD). The mechanisms underlying LPS-mediated oxidative stress and proinflammatory signaling in human pulmonary microvascular endothelial cells (HPMEC) remain unclear. We hypothesized that NADPH oxidase (Nox) mediates LPS-induced endothelial activation in HPMEC by regulating phosphorylation of Toll-like receptor (TLR) pathway proteins. LPS-induced expression of intercellular adhesion molecule 1 (ICAM-1) was associated with increased 2-OH-E+ (marker for superoxide formation) levels and was attenuated by apocynin and the Nox inhibitor, VAS2870. LPS triggered membrane translocation of p67 phox, suggesting activation of Nox2. Silencing Nox2, but not Nox4, suppressed LPS-induced ICAM-1 expression in HPMEC. Immunoprecipitation studies showed that inhibitor of κ-B kinase-β (IKK-β) serine phosphorylation induced by LPS was inhibited by Nox2 silencing. We examined whether Nox2-dependent, LPS-mediated IKK-β phosphorylation was regulated by protein phosphatase 2A (PP2A) or TGF-β associated kinase-1 (TAK1) in HPMEC. LPS increased PP2A activity in HPMEC, and inhibition of PP2A did not alter LPS-mediated ICAM-1 expression but attenuated IKK-β phosphorylation. TAK1 inhibition decreased LPS-induced ICAM-1 expression in HPMEC, and Nox2 silencing attenuated LPS-mediated TAK1 phosphorylation (Thr184/187). We demonstrate that Nox2 regulates LPS-mediated endothelial activation in pulmonary endothelial cells by modulating phosphorylation of key kinases in the TLR signaling cascade. Our data support a novel mechanism by which Nox-dependent signaling regulates proinflammatory signaling in pulmonary endothelial cells. Inhibition of vascular Nox may potentially limit lung injury and alveolar remodeling caused by infections in BPD.
14
Li, Ting-Bo, Jie-Jie Zhang, Bin Liu, Xiu-Ju Luo, Qi-Lin Ma, and Jun Peng. "Dysfunction of endothelial progenitor cells in hyperlipidemic rats involves the increase of NADPH oxidase derived reactive oxygen species production." Canadian Journal of Physiology and Pharmacology 95, no. 5 (May 2017): 474–80. http://dx.doi.org/10.1139/cjpp-2016-0142.
Повний текст джерелаАнотація:
NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) in the body and it plays a key role in mediation of oxidative injury in the cardiovascular system. The purposes of this study are to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic rats and to determine whether NOX-derived ROS promotes the dysfunction of EPCs. The rats were fed on a high-fat diet for 8 weeks to establish a hyperlipidemic rat model, which showed the increased plasma lipids and the impaired functions of circulating EPCs (including the reduced abilities in migration and adhesion) accompanied by an increase in NOX activity and ROS production. Next, EPCs were isolated from normal rats and they were treated with oxidized low-density lipoprotein (ox-LDL) (100 μg/mL) for 24 h to induce a dysfunctional model in vitro. In agreement with our findings in vivo, ox-LDL treatment increased the dysfunctions of EPCs concomitant with an increase in NOX activity and ROS production; these phenomena were reversed by the NOX inhibitor. Based on these observations, we conclude that NOX-derived ROS involved in the dysfunctions of circulating EPCs in hyperlipidemic rats and inhibition of NOX might provide a novel strategy to improve EPC functions in hyperlipidemia.
15
Meyer, Matthias R., Thomas Rosemann, Matthias Barton, and Eric R. Prossnitz. "GPER Mediates Functional Endothelial Aging in Renal Arteries." Pharmacology 100, no. 3-4 (2017): 188–93. http://dx.doi.org/10.1159/000478732.
Повний текст джерелаАнотація:
Aging is associated with impaired renal artery function, which is partly characterized by arterial stiffening and a reduced vasodilatory capacity due to excessive generation of reactive oxygen species by NADPH oxidases (Nox). The abundance and activity of Nox depends on basal activity of the heptahelical transmembrane receptor GPER; however, whether GPER contributes to age-dependent functional changes in renal arteries is unknown. This study investigated the effect of aging and Nox activity on renal artery tone in wild-type and GPER-deficient (Gper-/-) mice (4 and 24 months old). In wild-type mice, aging markedly impaired endothelium-dependent, nitric oxide (NO)-mediated relaxations to acetylcholine, which were largely preserved in renal arteries of aged Gper-/- mice. The Nox inhibitor gp91ds-tat abolished this difference by greatly enhancing relaxations in wild-type mice, while having no effect in Gper-/- mice. Contractions to angiotensin II and phenylephrine in wild-type mice were partly sensitive to gp91ds-tat but unaffected by aging. Again, deletion of GPER abolished effects of Nox inhibition on contractile responses. In conclusion, basal activity of GPER is required for the age-dependent impairment of endothelium-dependent, NO-mediated relaxation in the renal artery. Restoration of relaxation by a Nox inhibitor in aged wild-type but not Gper-/- mice strongly supports a role for Nox-derived reactive oxygen species as the underlying cause. Pharmacological blockers of GPER signaling may thus be suitable to inhibit functional endothelial aging of renal arteries by reducing Nox-derived oxidative stress and, possibly, the associated age-dependent deterioration of kidney function.
16
Perim, Raphael R., Daryl P. Fields, and Gordon S. Mitchell. "Cross-talk inhibition between 5-HT2B and 5-HT7 receptors in phrenic motor facilitation via NADPH oxidase and PKA." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 314, no. 5 (May 1, 2018): R709—R715. http://dx.doi.org/10.1152/ajpregu.00393.2017.
Повний текст джерелаАнотація:
Intermittent spinal serotonin receptor activation elicits phrenic motor facilitation (pMF), a form of spinal respiratory motor plasticity. Episodic activation of either serotonin type 2 (5-HT2) or type 7 (5-HT7) receptors elicits pMF, although they do so via distinct cellular mechanisms known as the Q (5-HT2) and S (5-HT7) pathways to pMF. When coactivated, these pathways interact via mutual cross-talk inhibition. Although we have a rudimentary understanding of mechanisms mediating cross-talk interactions between spinal 5-HT2 subtype A (5-HT2A) and 5-HT7 receptor activation, we do not know if similar interactions exist between 5-HT2 subtype B (5-HT2B) and 5-HT7 receptors. We confirmed that either spinal 5-HT2B or 5-HT7 receptor activation alone elicits pMF and tested the hypotheses that 1) concurrent activation of both receptors suppresses pMF due to cross-talk inhibition; 2) 5-HT7 receptor inhibition of 5-HT2B receptor-induced pMF requires protein kinase A (PKA) activity; and 3) 5-HT2B receptor inhibition of 5-HT7 receptor-induced pMF requires NADPH oxidase (NOX) activity. Selective 5-HT2B and 5-HT7 receptor agonists were administered intrathecally at C4 (3 injections, 5-min intervals) to anesthetized, paralyzed, and ventilated rats. Whereas integrated phrenic nerve burst amplitude increased after selective spinal 5-HT2B or 5-HT7 receptor activation alone (i.e., pMF), pMF was no longer observed with concurrent 5-HT2B and 5-HT7 receptor agonist administration. With concurrent receptor activation, pMF was rescued by inhibiting either NOX or PKA activity, demonstrating their roles in cross-talk inhibition between these pathways to pMF. This report demonstrates cross-talk inhibition between 5-HT2B- and 5-HT7 receptor-induced pMF and that NOX and PKA activity are necessary for that cross-talk inhibition.
17
Sato, Koichi, David M. Rodman, and Ivan F. McMurtry. "Hypoxia inhibits increased ETB receptor-mediated NO synthesis in hypertensive rat lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 4 (April 1, 1999): L571—L581. http://dx.doi.org/10.1152/ajplung.1999.276.4.l571.
Повний текст джерелаАнотація:
Although hypertensive lungs of chronically hypoxic rats express increased levels of nitric oxide (NO) synthases (NOSs) and produce increased amounts of NO-containing compounds (NOx) during normoxic ventilation, the level of NO production during hypoxic exposure is unclear. Because hypoxia inhibits NO synthesis in normotensive lungs, we investigated whether hypoxic ventilation inhibited NO synthesis in isolated hypertensive lungs and chronically hypoxic rats. Measurement of perfusate NOx concentration in hypertensive lungs from male rats exposed to 4 wk of hypobaric hypoxia showed that basal NOx production was reduced during hypoxic (0% O2) vs. normoxic (21% O2) ventilation. Similarly, plasma NOxconcentration was lower in chronically hypoxic rats breathing 10% O2 than in those breathing 21% O2. Hypoxic inhibition of lung NOx production was not prevented by supplementaryl-arginine or tetrahydrobiopterin and was not mimicked by inhibition of Ca2+ influx. However, it was mimicked by inhibition of constitutive NOS with N G-monomethyl-l-arginine and chelation of intracellular Ca2+. The endothelin type B-receptor antagonist BQ-788 prevented the increases in NOx production associated with normoxic ventilation in both isolated hypertensive lungs and intact chronically hypoxic rats. These results suggest that a reduced supply of the cosubstrate molecular O2 to NOS counteracts an endothelin type B receptor-mediated stimulation of NO synthesis in hypertensive rat lungs. Thus, despite increased NOS protein in the lungs and pulmonary arteries of chronically hypoxic rats, direct hypoxic inhibition of NO production may contribute to the development of pulmonary hypertension.
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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.
Повний текст джерелаАнотація:
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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Lee, Hyun-Seok, Hye Yoon Park, Sung Pil Kwon, Bogyeong Kim, Yerin Lee, Seongeun Kim, Kyong-Oh Shin, and Kyungho Park. "NADPH Oxidase-Mediated Activation of Neutral Sphingomyelinase Is Responsible for Diesel Particulate Extract-Induced Keratinocyte Apoptosis." International Journal of Molecular Sciences 21, no. 3 (February 3, 2020): 1001. http://dx.doi.org/10.3390/ijms21031001.
Повний текст джерелаАнотація:
Human epidermis is positioned at the interface with the external environment, protecting our bodies against external challenges, including air pollutants. Emerging evidence suggests that diesel particulate extract (DPE), a major component of air pollution, leads to impairment of diverse cellular functions in keratinocytes (KC). In this study, we investigated the cellular mechanism underlying DPE-induced KC apoptosis. We first addressed cell death occurring in KC exposed to DPE, paralleled by increased activation of NADPH oxidases (NOXs) and subsequent ROS generation. Blockade of NOX activation with a specific inhibitor attenuated the expected DPE-induced KC apoptosis. In contrast, pre-treatment with a specific inhibitor of reactive oxygen species (ROS) generation did not reverse DPE/NOX-mediated increase in KC apoptosis. We next noted that NOX-mediated KC apoptosis is mainly attributable to neutral sphingomyelinase (SMase)-mediated stimulation of ceramides, which is a well-known pro-apoptotic lipid. Moreover, we found that inhibition of NOX activation significantly attenuated DPE-mediated increase in the ratio of ceramide to its key metabolite sphingosine-1-phosphate (S1P), an important determinant of cell fate. Together, these results suggest that activation of neutral SMase serves as a key downstream signal for the DPE/NOX activation-mediated alteration in ceramide and S1P productions, and subsequent KC apoptosis.
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Dorman, Robert B., Christian Wunder, Hamida Saba, Jennifer L. Shoemaker, Lee Ann MacMillan-Crow, and Robert W. Brock. "NAD(P)H oxidase contributes to the progression of remote hepatic parenchymal injury and endothelial dysfunction, but not microvascular perfusion deficits." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G1025—G1032. http://dx.doi.org/10.1152/ajpgi.00246.2005.
Повний текст джерелаАнотація:
Oxidative stress occurs in remote liver injury, but the origin of the oxidant generation has yet to be thoroughly delineated. Some reports suggest that the source of the distant oxidative stress originates from the site of initial insult [i.e., xanthine oxidase (XO)]; however, it could also be derived from sources such as phagocytic and/or vascular NAD(P)H oxidase (Nox) enzymes. With a murine model of bilateral hindlimb ischemia-reperfusion, we describe here a mechanism for Nox-dependent oxidant production that contributes, at least in part, to remote hepatic parenchymal injury and sinusoidal endothelial cell (SEC) dysfunction. To determine whether Nox enzymes were the source of oxidants, mice were treated immediately after the onset of hindlimb ischemia with specific inhibitors to XO (50 mg/kg ip allopurinol) or Nox (10 mg/kg ip gp91ds-tat and 3 mg/kg ip apocynin). After 1 h of ischemia, hindlimbs were reperfused for either 3 or 6 h. Inhibition of XO failed to provide any improvement in parenchymal injury, SEC dysfunction, neutrophil accumulation, or microvascular dysfunction. In contrast, the inhibition of Nox enzymes prevented the progression (6 h) of parenchymal injury, significantly protected against SEC dysfunction, and completely prevented signs of neutrophil-derived oxidant stress. At the same time, however, inhibition of Nox failed to protect against the early parenchymal injury and microvascular dysfunction at 3 h of reperfusion. These data confirm that microvascular perfusion deficits are not essential for the pathogenesis of remote hepatic parenchymal injury. The data also suggest that Nox enzymes, not XO, are involved in the progression of compromised hepatic parenchymal and endothelial integrity during a systemic inflammatory response.
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Zhu, Xiaolong, R. Davis Manning, Deyin Lu, Celso E. Gomez-Sanchez, Yiling Fu, Luis A. Juncos, and Ruisheng Liu. "Aldosterone stimulates superoxide production in macula densa cells." American Journal of Physiology-Renal Physiology 301, no. 3 (September 2011): F529—F535. http://dx.doi.org/10.1152/ajprenal.00596.2010.
Повний текст джерелаАнотація:
Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O2−) and nitric oxide (NO) by macula densa (MD) cells. MD O2− inactivates NO; however, among the factors that increase MD O2− release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O2− production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10−8 mol/l for 30 min) doubled MMDD1 cell O2− production, and this was completely blocked by MR inhibition with 10−5 mol/l eplerenone. RT-PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O2− production to the same degree. These data suggest that aldosterone-stimulated MD O2− production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small-interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O2− production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O2− production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O2−. The resulting balance between O2− and NO in the MD is important in modulating TGF.
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Kim, Taeshin, and Mark A. Lawson. "GnRH Regulates Gonadotropin Gene Expression Through NADPH/Dual Oxidase-Derived Reactive Oxygen Species." Endocrinology 156, no. 6 (June 1, 2015): 2185–99. http://dx.doi.org/10.1210/en.2014-1709.
Повний текст джерелаАнотація:
Abstract The appropriate control of synthesis and secretion of the gonadotropin hormones LH and FSH by pituitary gonadotropes is essential for the regulation of reproduction. The hypothalamic neuropeptide GnRH is the central regulator of both processes, coordinating secretion with transcription and translation of the gonadotropin hormone subunit genes. The MAPK family of second messengers is strongly induced in gonadotropes upon GnRH stimulation, and multiple pathways activate these kinases. Intracellular reactive oxygen species participate in signaling cascades that target MAPKs, but also participate in signaling events indicative of cell stress. The NADPH oxidase (NOX)/dual oxidase (DUOX) family is a major enzymatic source of intracellular reactive oxygen, and we show that GnRH stimulation of mouse primary pituitary cells and the LβT2 gonadotrope cell line elevates intracellular reactive oxygen via NOX/DUOX activity. Mouse pituitary and LβT2 cells abundantly express NOX/DUOX and cofactor mRNAs. Pharmacological inhibition of NOX/DUOX activity diminishes GnRH-stimulated activation of MAPKs, immediate-early gene expression, and gonadotropin subunit gene expression. Inhibitor studies implicate the calcium-activated DUOX family as a major, but not exclusive, participant in GnRH signaling. Knockdown of DUOX2 in LβT2 cells reduces GnRH-induced Fshb, but not Lhb mRNA levels, suggesting differential sensitivity to DUOX activity. Finally, GnRH pulse-stimulated FSH and LH secretion are suppressed by inhibition of NOX/DUOX activity. These results indicate that reactive oxygen is a potent signaling intermediate produced in response to GnRH stimulation and further suggest that reactive oxygen derived from other sources may influence the gonadotrope response to GnRH stimulation.
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Johnson, M. D., S. Korcek, and M. J. Rokosz. "Effects of NOX on inhibition of oxidation by ZDTPS." Lubrication Science 6, no. 3 (April 1994): 247–66. http://dx.doi.org/10.1002/ls.3010060304.
Повний текст джерела
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Yatime, Laure, Christian Maasch, Kai Hoehlig, Sven Klussmann, Axel Vater, and Gregers Andersen. "Structural basis for inhibition of complement C5a by an L-RNA aptamer." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C202. http://dx.doi.org/10.1107/s2053273314097976.
Повний текст джерелаАнотація:
Complement is a central component of innate immunity providing a first line of defense against invading pathogens. It also bridges the innate and adaptive immunity, initiates the inflammatory response, and participates in immune surveillance. The anaphylatoxin C5a, generated during complement activation, is a potent inflammatory mediator which induces chemotaxis, oxidative burst, histamine release and increased vasodilatation, through G-protein coupled receptor signaling. Although inflammation is an integral part of the healing process following tissue damage and infection, excessive levels of C5a correlate with the onset of various inflammatory disorders including sepsis, rheumatoid arthritis, acute lung injury, ischemia-reperfusion injury, allergy, transplantation and asthma. Therapeutical targeting of the C5a:receptor axis is considered a promising strategy to down-regulate complement-mediated inflammation. The L-aptamer NOX-D20, fully composed of non-natural mirror-image nucleotides (a so called Spiegelmer), has been identified as a potent C5a inhibitor. NOX-D20 has already shown encouraging efficacy in an experimental model of sepsis [1]. Here, we present the first crystallographic structure of an active Spiegelmer®, NOX-D20, bound to its physiological target, the mouse C5a anaphylatoxin, determined at 1.8 Å resolution. The structure reveals a complex 3D-architecture for the L-RNA molecule that wraps around C5a, including an intramolecular G-quadruplex stabilized by a Ca2+ ion as validated through anomalous diffraction data. The aptamer:C5a binding mode observed in the structure was validated through mutational studies using SPR. Our structure provides a molecular basis for NOX-D20 inhibitory properties and allows us to rationalize NOX-D20 selectivity towards human and mouse C5a
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Valdés, Álvaro, Adriana Treuer, Guillermo Barrios, Nikol Ponce, Roberto Fuentealba, Raul Dulce та Daniel González. "NOX Inhibition Improves β-Adrenergic Stimulated Contractility and Intracellular Calcium Handling in the Aged Rat Heart". International Journal of Molecular Sciences 19, № 8 (15 серпня 2018): 2404. http://dx.doi.org/10.3390/ijms19082404.
Повний текст джерелаАнотація:
Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca2+]i) homeostasis. It has been suggested that oxidative stress may be involved in this process. We and others have reported that in cardiomyopathies the NADPH oxidase (NOX)-derived superoxide is increased, with a negative impact on [Ca2+]i and contractility. We tested the hypothesis that in the aged heart, [Ca2+]i handling and contractility are disturbed by NOX-derived superoxide. For this we used adults (≈5 month-old) and aged (20–24 month-old) rats. Contractility was evaluated in isolated hearts, challenged with isoproterenol. To assess [Ca2+]i, isolated cardiac myocytes were field-stimulated and [Ca2+]i was monitored with fura-2. Cardiac concentration-response to isoproterenol was depressed in aged compared to adults hearts (p < 0.005), but was restored by NOX inhibitors apocynin and VAS2870. In isolated cardiomyocytes, apocynin increased the amplitude of [Ca2+]i in aged myocytes (p < 0.05). Time-50 [Ca2+]i decay was increased in aged myocytes (p < 0.05) and reduced towards normal by NOX inhibition. In addition, we found that myofilaments Ca2+ sensitivity was reduced in aged myocytes (p < 0.05), and was further reduced by apocynin. NOX2 expression along with NADPH oxidase activity was increased in aged hearts. Phospholamban phosphorylation (Ser16/Thr17) after isoproterenol treatment was reduced in aged hearts compared to adults and was restored by apocynin treatment (p < 0.05). In conclusion, β-adrenergic-induced contractility was depressed in aged hearts, and NOX inhibition restored back to normal. Moreover, altered Ca2+ handling in aged myocytes was also improved by NOX inhibition. These results suggest a NOX-dependent effect in aged myocytes at the level of Ca2+ handling proteins and myofilaments.
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MOHD ZAIN, ZETTY NADIA. "Synergistic inhibition of platelet function by NADPH oxidase inhibitors and clopidogrel." Malaysian Journal of Science Health & Technology 7, no. 2 (October 1, 2021): 65–69. http://dx.doi.org/10.33102/mjosht.v7i2.144.
Повний текст джерелаАнотація:
Previous studies have shown platelets play an important role in prothrombotic complications due to several factors such as hyperglycemia, oxidative stress, and hypercholesterolemia, which affected platelets reactivity. Platelets activation involves ADP stimulation via P2Y12 receptor, whereas reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide (H2O2) produced by NADPH oxidase (Nox) act as the second messenger, which involved in platelets activation and may contribute to thrombus formation. The aim of the present study was to investigate the influence of Nox on the purinergic receptor (P2Y12 receptor) in activation of human platelets function stimulated by platelets agonist. This research explored the effects of Nox inhibitors and clopidogrel either alone or in combination, on various agonist-stimulated human platelets, including platelets aggregation and adhesion measured by modified LTA, expression of platelets activation markers, and calcium mobilization using flow cytometry, and ROS formation, NADPH oxidase activity, as well as cAMP levels by chemiluminescence assay. Taken together, findings from these experiments suggest that the combination of clopidogrel and Nox inhibitors synergistically reduced platelets aggregation, platelets adhesion, and expression of platelets activation marker during late activation, ROS formation, NADPH oxidase activity, calcium mobilization and increased cAMP levels in vitro. This combination showed that P2Y12receptor reactivity was influenced by the activation of NADPH oxidase. Thus, these data demonstrated a potential combination therapy to reduce the risk of thrombosis formation.
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Andersson, Karl-Erik. "Oxidative Stress and Its Relation to Lower Urinary Tract Symptoms." International Neurourology Journal 26, no. 4 (December 30, 2022): 261–67. http://dx.doi.org/10.5213/inj.2244190.095.
Повний текст джерелаАнотація:
The aim of this review is to discuss how to link lower urinary tract symptoms (LUTS) and oxidative stress (OS) and to define relevant targets for therapeutic intervention. Narrative review based on published literature. Many of the multifactorial pathophysiological mechanisms behind LUTS can initiate reactive oxygen species (ROS) generation. Assuming that OS is a consequence rather than a primary cause of LUTS it seems reasonable to identify both the disease mechanism initiating LUTS, and the source of ROS involved. There are many possible sources of ROS overproduction, but the NADPH oxidase (NOX) family of enzymes is the primary source; NOX activation in turn, may result in the activation of secondary ROS sources, i.e., ROS-dependent ROS production. Selective NOX inhibition therefore seems an attractive therapeutic strategy in LUTS treatment. The finding of NOX2 localization to centers in the brain associated with micturition control, opens up for further studies of NOX involvement in the central control of micturition, normally and in disease. Further information on the localization of the different isoforms of NOX in the LUT e.g., the bladder wall and its components and the prostate, is desirable. To optimize treatment, the pathophysiological mechanism initiating LUTS, and the activated isoform of NOX, should be identified. Unfortunately, in most cases of LUTS this is currently not possible. Even if selective NOX inhibitors have entered the clinical trial stage for treatment of disorders other than LUT dysfunction, their efficacy for LUTS treatment has to be demonstrated. If this can be achieved, an attractive approach would be combination of selective NOX inhibition with established drug therapies.
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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.
Повний текст джерелаАнотація:
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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Chen, Ying-Hua, Zhang-Wei Chen, Hong-Mei Li, Xin-Feng Yan, and Bo Feng. "AGE/RAGE-Induced EMP Release via the NOX-Derived ROS Pathway." Journal of Diabetes Research 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/6823058.
Повний текст джерелаАнотація:
Objective. Diabetes is associated with accelerated formation of advanced glycation end products (AGEs) that are extensively found in circulating endothelial microparticles (EMPs). This study aimed to investigate whether AGEs have a direct effect on EMP formation and the possible underlying mechanism. Methods. In vitro, cultured human umbilical vein endothelial cells (HUVECs) were incubated with AGEs (200 and 400 μg/ml) for 24 hours with or without pretreatment with anti-RAGE antibody, NOX inhibitor, or ROS scavenger. The number of CD31-positive EMPs was assessed by flow cytometry. Results. The number of EMPs was significantly increased in HUVECs stimulated by AGEs in a dose-dependent manner. In addition, receptors for AGEs (RAGE), NAD(P)H oxidase (NOX), and reactive oxygen species (ROS) were increased by AGEs as compared to the control group. These changes could be reversed when HUVECs were pretreated with anti-RAGE antibody. Moreover, inhibition of NOX as well as antioxidant treatment reduced the release of EMPs induced by AGEs. Conclusion. Our study suggested that AGEs increased EMP generation, which was mediated by RAGE signaling through NOX-derived ROS.
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Li, Jian-Zhe, Shu-Yi Yu, Jian-Hua Wu, Qing-Rui Shao, and Xiao-Min Dong. "Paeoniflorin protects myocardial cell from doxorubicin-induced apoptosis through inhibition of NADPH oxidase." Canadian Journal of Physiology and Pharmacology 90, no. 12 (December 2012): 1569–75. http://dx.doi.org/10.1139/y2012-140.
Повний текст джерелаАнотація:
Increased intracellular reactive oxygen species (ROS) are involved in doxorubicin (DOX)-induced myocardial cell apoptosis, and paeoniflorin (PEF) has been shown to exert an antioxidant effect. The aim of the present study was to explore the protective effect of PEF on DOX-induced myocardial cell apoptosis and the underlying mechanisms. In cultured H9c2 cells, different concentrations (1, 10, or 100 μmol/L) of PEF was added for 2 h prior to exposure to DOX (5 μmol/L) for 24 h. Cell apoptosis was evaluated by hoechst 33342 staining, and caspase-3 expression and activity. The mRNA and protein expression of NADPH oxidase (NOX) 2 and NOX4 was determined by real-time polymerase chain reaction and Western blot, respectively. Intracellular ROS and NOX activity were measured by assay kit. The results showed that DOX significantly increased myocardial cell apoptosis, increased caspase-3 expression and activity concomitantly with enhanced ROS production, and increased NOX2, NOX4 mRNA and protein expression, and NOX activity. These effects were remarkably inhibited by pretreatment of PEF. Our results suggested that PEF has a protective effect against DOX-induced myocardial cell apoptosis through a mechanism involving a decrease in ROS production by inhibition of NOX2, NOX4 expression, and NOX activity.
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Hernandez, Isabelle, Audrey Chissey, Jean Guibourdenche, Roger Atasoy, Xavier Coumoul, Thierry Fournier, Jean-Louis Beaudeux та Amal Zerrad-Saadi. "Human Placental NADPH Oxidase Mediates sFlt-1 and PlGF Secretion in Early Pregnancy: Exploration of the TGF-β1/p38 MAPK Pathways". Antioxidants 10, № 2 (12 лютого 2021): 281. http://dx.doi.org/10.3390/antiox10020281.
Повний текст джерелаАнотація:
Preeclampsia, a hypertensive disorder occurring during pregnancy, is characterized by excessive oxidative stress and trophoblast dysfunction with dysregulation of soluble Fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) production. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase (Nox) is the major source of placental superoxide in early pregnancy and its activation with the subsequent formation of superoxide has been demonstrated for various agents including Transforming Growth Factor beta-1 (TGF-β1), a well-known p38 MAPK pathway activator. However, the bridge between Nox and sFlt-1 remains unknown. The purpose of this study was to explore the possible signaling pathway of TGF-β1/Nox/p38 induced sFlt-1 production in human chorionic villi (CV). Methods: Human chorionic villi from first trimester placenta (7–9 Gestational Weeks (GW)) were treated with TGF-β1 or preincubated with p38 inhibitor, SB203580. For NADPH oxidase inhibition, CV were treated with diphenyleneiodonium (DPI). The protein levels of phospho-p38, p38, phospho-Mothers Against Decapentaplegic homolog 2 (SMAD2), and SMAD2 were detected by Western blot. The secretion of sFlt-1 and PlGF by chorionic villi were measured with Electrochemiluminescence Immunologic Assays, and NADPH oxidase activity was monitored by lucigenin method. Results: We demonstrate for the first time that NADPH oxidase is involved in sFlt-1 and PlGF secretion in first trimester chorionic villi. Indeed, the inhibition of Nox by DPI decreases sFlt-1, and increases PlGF secretions. We also demonstrate the involvement of p38 MAPK in sFlt-1 secretion and Nox activation as blocking the p38 MAPK phosphorylation decreases both sFlt-1 secretion and superoxide production. Nevertheless, TGF-β1-mediated p38 activation do not seem to be involved in regulation of the first trimester placental angiogenic balance and no crosstalk was found between SMAD2 and p38 MAPK pathways. Conclusions: Thus, the placental NADPH oxidase play a major role in mediating the signal transduction cascade of sFlt-1 production. Furthermore, we highlight for the first time the involvement of p38 activation in first trimester placental Nox activity.
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Roccaro, Aldo M., Antonio Sacco, Marco Ungari, Patricia Maiso, Salomon Manier, Phong Quang, Yosra Aljaway, et al. "In Vivo Targeting of Stromal-Derived Factor-1 As a Strategy to Prevent Myeloma Cell Dissemination to Distant Bone Marrow Niches." Blood 120, no. 21 (November 16, 2012): 440. http://dx.doi.org/10.1182/blood.v120.21.440.440.
Повний текст джерелаАнотація:
Abstract Abstract 440 Background. Multiple myeloma (MM) patients present with multiple lytic lesions at diagnosis, indicating the presence of continuous dissemination of MM cells from the primary site of tumor development to multiple distant bone marrow (BM) niches. We hypothesized that stromal-derived factor-1 (SDF-1) may represent a target for preventing transition from MGUS (micrometastatic stage) to active-MM (macrometastatic stage); thus resulting in inhibition of MM progression. We therefore evaluated SDF-1 expression in the BM of patients with MGUS, MM, compared to healthy individuals; and tested NOX-A12, a high affinity l-oligonucleotide (Spiegelmer) binder to SDF-1 in MM, looking at its ability to modulate MM cell tumor growth and MM cell homing to the BM in vitro and in vivo . Methods. SDF-1 levels were evaluated by immunohistochemistry on BM specimens obtained from patients with MGUS, active-MM, or healthy individuals; and confirmed by ELISA, using conditioned-medium of BM-mesenchymal stromal cells obtained from MGUS, active-MM and healthy individuals. BM metastatic lesions from primary epithelial tumors were also considered. Co-localization of MM tumor cells (MM.1S-GFP+) with SDF-1 was tested in vivo by in vivo confocal microscopy, using both AlexaFluor633-conjugated-anti-SDF-1 monoclonal antibody and AlexaFluor647-conjugated-NOX-A12 oligonucleotide. Effect of NOX-A12 on modulating MM cell dissemination was tested in vivo, by using in vivo confocal microscopy. In vivo homing and in vivo tumor growth of MM cells (MM.1S-GFP+/luc+) were assessed by using in vivo confocal microscopy and in vivo bioluminescence, in SCID mice treated with 1) vehicle; 2) NOX-A12; 3) bortezomib; 4) NOX-A12+bortezomib. Detection of mobilized MM-GFP+ cells ex vivo was performed by flow cytometry. Effects of drug combination on dissemination of MM cells to distant BM niches was evaluated ex vivo by immunofluorescence on femurs obtained from each cohort of mice. DNA synthesis and adhesion of MM cells in the context of NOX-A12 (50–100nM) treated primary MM BM stromal cells (BMSCs) in presence or absence of bortezomib (2.5–5nM) were tested by thymidine uptake and adhesion in vitro assay, respectively. Synergism was calculated by using CalcuSyn software. NOX-A12-dependent-modulation of signaling was evaluated by western blot on MM cells exposed or not to primary BM-MSCs. Results. Patients with active-MM present with higher BM SDF-1 expression vs. MGUS patients and healthy individuals. Similarly, BM presenting with metastasis from epithelial primary malignancies had higher SDF-1 levels compared to healthy subjects, thus suggesting the importance of SDF-1 in favoring tumor cell metastasis to BM niches. SDF-1 co-localized at BM level with MM tumor cells in vivo. In vitro, NOX-A12 induced a dose-dependent de-adhesion of MM cells from the BMSCs supported by inhibition of BM-MSC-mediated phosphorylation of ERK1/2 and cofilin. These findings were corroborated and validated in vivo: NOX-A12 induced MM cell mobilization from the BM to the peripheral blood as shown ex vivo, by reduced percentage of MM cells in the BM and increased number of MM cells within the peripheral blood of mice treated with NOX-A12 vs. control (BM: 57% vs. 45%; PB: 2.7% vs. 15%). This was supported by inhibited homing of MM cells to the BM of those mice pre-treated with NOX-A12. We next showed that NOX-A12-dependent de-adhesion of MM cells from BMSCs lead to enhanced MM cell sensitivity to bortezomib, as shown in vitro, where a synergistic effect between NOX-A12 and bortezomib was observed (C.I.: .57-.76). These findings were validated in vivo: tumor burden was similar between NOX-A12- and control mice whereas bortezomib-treated mice showed significant reduction in tumor progression compared to the control (P<.05); importantly, significant reduction of tumor burden in those mice treated with sequential administration of NOX-A12 and bortezomib was observed, compared to bortezomib alone-treated mice (P <.05). Similarly, NOX-A12+bortezomib combination induced significant inhibition of MM cell homing, as shown by in vivo confocal microscopy. Conclusion. SDF-1 represents a valid target for inhibiting MM cell dissemination to distant BM niches, thus providing the evidence for using the SDF-1 inhibiting Spiegelmer NOX-A12 to target MM cells at the stage of micrometastasis (MGUS), thus preventing development of symptomatic macrometastatic MM. Disclosures: Zboralski: NOXXON Pharma AG, Berlin, Germany: Employment. Kruschinski:NOXXON Pharma AG, Berlin, Germany: Employment. Ghobrial:Novartis: Advisory Board Other; Onyx: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Bristol Myers Squibb: Advisory Board, Advisory Board Other.
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Rauen, Ursula, Tongju Li, Iosif Ioannidis, and Herbert de Groot. "Nitric oxide increases toxicity of hydrogen peroxide against rat liver endothelial cells and hepatocytes by inhibition of hydrogen peroxide degradation." American Journal of Physiology-Cell Physiology 292, no. 4 (April 2007): C1440—C1449. http://dx.doi.org/10.1152/ajpcell.00366.2006.
Повний текст джерелаАнотація:
Nitric oxide (NO) and hydrogen peroxide (H2O2) show cooperativity in their cytotoxic action. The present study was performed to decipher the mechanisms underlying this phenomenon. In cultured liver endothelial cells and in cultured, glutathione-depleted hepatocytes, the combined exposure to NO (released by spermine NONOate, 1 mM) and H2O2 (released by glucose oxidase) induced cell injury that was far higher than the injury elicited by NO or H2O2 alone. In both cell types, the addition of the NO donor increased H2O2 steady-state levels, although with different kinetics: in hepatocytes, the increase in H2O2 levels was already evident at early time points while in liver endothelial cells it became evident after ≥2 h of incubation. NO exposure inhibited H2O2 degradation, assessed after addition of 50 μM, 200 μM, or 4 mM authentic H2O2, significantly in both cell types. However, again, early and delayed inhibition was observed. The late inhibition of H2O2 degradation in endothelial cells was paralleled by a decrease in glutathione peroxidase activity. Glutathione peroxidase inactivation was prevented by hypoxia or by ascorbate, suggesting inactivation by reactive nitrogen oxide species (NOx). Early inhibition of H2O2 degradation by NO, in contrast, could be mimicked by the catalase inhibitor azide. Together, these results suggest that the cooperative effect of NO and H2O2 is due to inhibition of H2O2 degradation by NO, namely to inhibition of catalase by NO itself (predominant in hepatocytes) and/or to inhibition of glutathione peroxidase by NOx (prevailing in endothelial cells).
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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.
Повний текст джерелаАнотація:
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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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.
Повний текст джерелаАнотація:
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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Seredenina, Tamara, Stefania Schiavone, Ghassan Maghzal, Olivier Basset, Laetitia Fioraso-Cartier, Zahia Mahiout, Olivier Plastre, et al. "Inhibition of NOX NADPH oxidases as a potentialtreatment for neuroinflammation." Free Radical Biology and Medicine 65 (September 2013): S14. http://dx.doi.org/10.1016/j.freeradbiomed.2013.08.137.
Повний текст джерела
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Stalin, Jimmy, Sarah Garrido-Urbani, Freddy Heitz, Cédric Szyndralewiez, Stephane Jemelin, Oriana Coquoz, Curzio Ruegg, and Beat A. Imhof. "Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor–based immunotherapy." Life Science Alliance 2, no. 4 (June 27, 2019): e201800265. http://dx.doi.org/10.26508/lsa.201800265.
Повний текст джерелаАнотація:
NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.
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Kuchan, M. J., H. Jo, and J. A. Frangos. "Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells." American Journal of Physiology-Cell Physiology 267, no. 3 (September 1, 1994): C753—C758. http://dx.doi.org/10.1152/ajpcell.1994.267.3.c753.
Повний текст джерелаАнотація:
Exposure of cultured endothelial cells to shear stress resulting from well-defined fluid flow stimulates the production of nitric oxide (NO). We have established that an initial burst in production is followed by sustained steady-state NO production. The signal transduction events leading to this stimulation are not well understood. In the present study, we examined the role of regulatory guanine nucleotide binding proteins (G proteins) in shear stress-mediated NO production. In endothelial cells not exposed to shear stress, AIF4-, a general activator of G proteins, markedly elevated the production of guanosine 3',5'-cyclic monophosphate (cGMP). Pretreatment with NO synthase inhibitor N omega-nitro-L-arginine completely blocked this stimulation. Incubation with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), a general G protein inhibitor, blocked the flow-mediated burst in cGMP production in a dose-dependent manner. Likewise, GDP beta S inhibited NOx (NO2 + NO3) production for the 1st h. However, inhibition was not detectable between 1 and 3 h. Pertussis toxin (PTx) had no effect on the shear response at any time point. The burst in NO production caused by a change in shear stress appears to be dependent on a PTx-refractory G protein. Sustained shear-mediated production is independent of G protein activation.
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Avdonin, Pavel, Elena Rybakova, Piotr Avdonin, Sergei Trufanov, Galina Mironova, Alexandra Tsitrina, and Nikolay Goncharov. "VAS2870 Inhibits Histamine-Induced Calcium Signaling and vWF Secretion in Human Umbilical Vein Endothelial Cells." Cells 8, no. 2 (February 23, 2019): 196. http://dx.doi.org/10.3390/cells8020196.
Повний текст джерелаАнотація:
In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([Ca2+]i) and the secretion of von Willebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs) and on relaxation of rat aorta in response to histamine. At 10 μM concentration, VAS2870 suppressed the [Ca2+]i rise induced by histamine. Inhibition was not competitive, with IC50 3.64 and 3.22 μM at 1 and 100 μM concentrations of histamine, respectively. There was no inhibition of [Ca2+]i elevation by VAS2870 in HUVECs in response to the agonist of type 1 protease-activated receptor SFLLRN. VAS2870 attenuated histamine-induced secretion of vWF and did not inhibit basal secretion. VAS2870 did not change the degree of histamine-induced relaxation of rat aortic rings constricted by norepinephrine. We suggest that NOX inhibitors might be used as a tool for preventing thrombosis induced by histamine release from mast cells without affecting vasorelaxation.
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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.
Повний текст джерелаАнотація:
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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Pérez-Girón, Jose V., Roberto Palacios, Angela Martín, Raquel Hernanz, Andrea Aguado, Sonia Martínez-Revelles, María T. Barrús, Mercedes Salaices, and María J. Alonso. "Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 11 (June 1, 2014): H1582—H1593. http://dx.doi.org/10.1152/ajpheart.00924.2013.
Повний текст джерелаАнотація:
Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg−1·day−1, 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2·− production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-κB subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-κB inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-κB and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones.
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Deliyanti, Devy, Saeed F. Alrashdi, Rhian M. Touyz, Christopher R. Kennedy, Jay C. Jha, Mark E. Cooper, Karin A. Jandeleit-Dahm, and Jennifer L. Wilkinson-Berka. "Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy." Hypertension 75, no. 4 (April 2020): 1091–101. http://dx.doi.org/10.1161/hypertensionaha.119.14100.
Повний текст джерелаАнотація:
Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase) isoforms, Nox1 and Nox4, contributes to vasculopathy in diabetic retinopathy; however, if Nox1/4 inhibition is beneficial in hypertensive diabetic retinopathy is unknown. Here, we determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats. GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events in diabetic Wistar Kyoto rats and spontaneously hypertensive rats. Retinal neovascularization does not develop in diabetic rodents, and therefore, the oxygen-induced retinopathy model is used to evaluate this pathology. We previously demonstrated that Nox1/4 inhibition reduced retinal neovascularization in oxygen-induced retinopathy. However, although Nox5 is expressed in human retina, its contribution to retinopathy has not been studied in vivo, largely due to its absence from the rodent genome. We generated transgenic mice with inducible human Nox5 expressed in endothelial cells (vascular endothelial-cadherin + Nox5 + mice). In vascular endothelial-cadherin + Nox5 + mice with oxygen-induced retinopathy, retinal vascular permeability and neovascularization, as well as the expression of angiogenic and inflammatory factors, were increased compared with wild-type littermates. In bovine retinal endothelial cells, which express Nox1, Nox4, and Nox5, Nox1/4 inhibition, as well as Nox5 silencing RNA, reduced the high glucose–induced upregulation of oxidative stress, angiogenic, and inflammatory factors. Collectively, these data indicate the potential of Nox1, Nox4, and Nox5 inhibition to reduce vision-threatening damage to the retinal vasculature.
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Oliveira, Luis, Anton Rückel, Lisa Nordgauer, Patric Schlumprecht, Elina Hutter, and Dirk Weuster-Botz. "Comparison of Syngas-Fermenting Clostridia in Stirred-Tank Bioreactors and the Effects of Varying Syngas Impurities." Microorganisms 10, no. 4 (March 22, 2022): 681. http://dx.doi.org/10.3390/microorganisms10040681.
Повний текст джерелаАнотація:
In recent years, syngas fermentation has emerged as a promising means for the production of fuels and platform chemicals, with a variety of acetogens efficiently converting CO-rich gases to ethanol. However, the feasibility of syngas fermentation processes is related to the occurrence of syngas impurities such as NH3, H2S, and NOX. Therefore, the effects of defined additions of NH4+, H2S, and NO3− were studied in autotrophic batch processes with C. autoethanogenum, C. ljungdahlii, and C. ragsdalei while applying continuously gassed stirred-tank bioreactors. Any initial addition of ammonium and nitrate curbed the cell growth of the Clostridia being studied and reduced the final alcohol concentrations. C. ljungdahlii showed the highest tolerance to ammonium and nitrate, whereas C. ragsdalei was even positively influenced by the presence of 0.1 g L−1 H2S. Quantitative goals for the purification of syngas were identified for each of the acetogens studied in the used experimental setup. Syngas purification should in particular focus on the NOX impurities that caused the highest inhibiting effect and maintain the concentrations of NH3 and H2S within an acceptable range (e.g., NH3 < 4560 ppm and H2S < 108 ppm) in order to avoid inhibition through the accumulation of these impurities in the bioreactor.
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Xiang, Lusha, Silu Lu, Peter N. Mittwede, John S. Clemmer, and Robert L. Hester. "Inhibition of NADPH oxidase prevents acute lung injury in obese rats following severe trauma." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 5 (March 1, 2014): H684—H689. http://dx.doi.org/10.1152/ajpheart.00868.2013.
Повний текст джерелаАнотація:
Lung capillary filtration coefficient (Kf) and impacts of oxidative stress have not been determined in the setting of severe trauma, especially in obese patients who exhibit increased lung injury. We hypothesized that severe trauma leads to a greater increase in lung Kf in obesity due to exacerbated production of and/or vulnerability to oxidative stress. Severe trauma was induced in lean and obese Zucker rats by muscle injury, fibula fracture, and bone component injection to both hindlimbs, with or without 24-h treatments of apocynin, a NADPH oxidase (NOX) inhibitor. Lung wet/dry weight ratios, lung vascular Kf, lung neutrophil counts, lung NOX and myeloperoxidase (MPO) activity, and plasma IL-6 levels were measured 24 h after trauma. In an additional study, lungs were isolated from nontrauma lean and obese rats to determine the acute effect of phenazime methosulfate, a superoxide donor, on pulmonary vascular Kf. After trauma, compared with lean rats, obese rats exhibited greater increases in lung capillary Kf, neutrophil accumulation, NOX and MPO activity, and plasma IL-6. The lung wet/dry weight ratio was increased in obese rats but not in lean rats. Apocynin treatment decreased lung Kf, neutrophil counts, NOX and MPO activities, wet/dry weight ratio, and plasma IL-6 in obese rats. Phenazime methosulfate treatment resulted in a greater increase in lung Kf in nontrauma obese rats compared with nontrauma lean rats. These results suggest that obese rats are susceptible to lung injury following severe trauma due to increased production of and responsiveness to pulmonary oxidative stress.
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Zeng, Si-yu, Qiu-jiang Yan, Li Yang, Qing-hua Mei, and Hui-qin Lu. "Inhibition of the ROS-EGFR Pathway Mediates the Protective Action of Nox1/4 Inhibitor GKT137831 against Hypertensive Cardiac Hypertrophy via Suppressing Cardiac Inflammation and Activation of Akt and ERK1/2." Mediators of Inflammation 2020 (August 4, 2020): 1–14. http://dx.doi.org/10.1155/2020/1078365.
Повний текст джерелаАнотація:
Oxidative stress, inflammation, and hypertension constitute a self-perpetuating vicious circle to exacerbate hypertension and subsequent hypertensive cardiac hypertrophy. NADPH oxidase (Nox) 1/4 inhibitor GKT137831 alleviates hypertensive cardiac hypertrophy in models of secondary hypertension; however, it remains unclear about its effect on hypertensive cardiac hypertrophy in models of essential hypertension. This study is aimed at determining the beneficial role of GKT137831 in hypertensive cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and its mechanisms of action. Treating with GKT137831 prevented cardiac hypertrophy in SHRs. Likewise, decreasing production of reactive oxygen species (ROS) with GKT137831 reduced epidermal growth factor receptor (EGFR) activity in the left ventricle of SHRs. Additionally, EGFR inhibition also reduced ROS production in the left ventricle and blunted hypertensive cardiac hypertrophy in SHRs. Moreover, inhibition of the ROS-EGFR pathway with Nox1/4 inhibitor GKT137831 or selective EGFR inhibitor AG1478 reduced protein and mRNA levels of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), as well as the activities of Akt and extracellular signal-regulated kinase (ERK) 1/2 in the left ventricle of SHRs. In summary, GKT137831 prevents hypertensive cardiac hypertrophy in SHRs, Nox-deprived ROS regulated EGFR activation through positive feedback in the hypertrophic myocardium, and inhibition of the ROS-EGFR pathway mediates the protective role of GKT137831 in hypertensive cardiac hypertrophy via repressing cardiac inflammation and activation of Akt and ERK1/2. This research will provide additional details for GKT137831 to prevent hypertensive cardiac hypertrophy.
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Chow, Shu-Er, Ya-Ching Hshu, Jong-Shyan Wang, and Jan-Kan Chen. "Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages." Journal of Applied Physiology 102, no. 4 (April 2007): 1520–27. http://dx.doi.org/10.1152/japplphysiol.00881.2006.
Повний текст джерелаАнотація:
trans-Resveratrol (RSV) has been shown to have cardioprotective effect during ischemia-reperfusion through reactive oxygen species (ROS)-scavenging activity. Elevated ROS has been implicated in the initiation and progression of atherosclerosis. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a major source of vascular ROS formation. In the present study, we show that exposure of vascular endothelial cells (EC) to oxidized low-density lipoproteins (oxLDL) results in elevations of NOX activity and cellular ROS levels. The oxLDL effects are effectively suppressed by RSV or astringinin (AST), either before or after oxLDL exposure. In this study, we show that RSV or AST treatment appears to suppress NOX activity by reducing the membrane association of gp91 phox and Rac1, two protein species required for the assembly of active NOX complex. Exposure to RSV or AST protects EC from oxidative functional damages, including antiplatelet activity and mononucleocyte adhesion. In addition, ANG II-induced NOX activation is also attenuated. These results suggest that RSV or AST protects EC from oxLDL-induced oxidative stress by both direct ROS scavenging and inhibition of NOX activity.
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Roccaro, Aldo M., Antonio Sacco, Phong Quang, AbdelKareem Azab, Patricia Maiso, Feda Azab, Yong Zhang, et al. "L-Stereoisomer RNA Oligonucleotide Anti-SDF-1 (Nox-A12) Disrupts the Interaction of Multiple Myeloma Cells with the Bone Marrow Milieu In Vivo, Leading to Enhanced Sensitivity to Bortezomib." Blood 118, no. 21 (November 18, 2011): 887. http://dx.doi.org/10.1182/blood.v118.21.887.887.
Повний текст джерелаАнотація:
Abstract Abstract 887 Background. Stomal-cell-derived factor 1 (SDF-1) is known to be involved in bone marrow (BM) engrafment for malignant tumor cells, including CXCR4 expressing multiple myeloma (MM) cells. We hypothesized that de-adhesion of MM cells from the surrounding BM milieu through SDF-1 inhibition will enhance MM sensitivity to therapeutic agents. We therefore tested NOX-A12, a high affinity l-oligonucleotide (Spiegelmer) binder to SDF-1in MM, looking at its ability to modulate MM cell tumor growth and MM cell homing to the BM in vivo and in vitro. Methods. Bone marrow (BM) co-localization of MM tumor cells with SDF-1 expressing BM niches has been tested in vivo by using immunoimaging and in vivo confocal microscopy. MM.1S/GFP+ cells and AlexaFluor633-conjugated anti-SDF-1 monoclonal antibody were used. Detection of mobilized MM-GFP+ cells ex vivo has been performed by flow cytometry. In vivo homing and in vivo tumor growth of MM cells (MM.1S-GFP+/luc+) were assessed by using in vivo confocal microscopy and in vivo bioluminescence detection, in SCID mice treated with 1) vehicle; 2) NOX-A12; 3) bortezomib; 4) NOX-A12 followed by bortezomib. DNA synthesis and adhesion of MM cells in the context of NOX-A12 (50–200nM) treated primary MM BM stromal cells (BMSCs), in presence or absence of bortezomib (2.5–5nM), were tested by thymidine uptake and adhesion in vitro assay, respectively. Synergism was calculated by using CalcuSyn software (combination index: C.I. according to Chou-Talalay method). Results. We first showed that SDF-1 co-localizes in the same bone marrow niches of growth of MM tumor cells in vivo. NOX-A12 induced a dose-dependent de-adhesion of MM cells from the BM stromal cells in vitro. These findings were corroborated and validated in vivo: NOX-A12 induced MM cell mobilization from the BM to the peripheral blood (PB) as shown ex vivo, by reduced percentage of MM cells in the BM and increased number of MM cells within the PB of mice treated with NOX-A12 vs. control (BM: 57% vs. 45%; PB: 2.7% vs. 15%). We next showed that NOX-A12-dependent de-adhesion of MM cells from BMSCs lead to enhanced MM cell sensitivity to bortezomib, as shown in vitro, where a synergistic effect between NOX-A12 (50–100 nM) and bortezomib (2.5–5 nM) was observed (C.I.: all between 0.57 and 0.76). These findings were validated in vivo: tumor burden detected by BLI was similar between NOX-A12- and control mice whereas bortezomib-treated mice showed significant reduction in tumor progression compared to the control (P<.05); importantly significant reduction of tumor burden in those mice treated with sequential administration of NOX-A12 followed by bortezomib was observed as compared to bortezomib alone treated mice (P <.05). Similarly, NOX-A12 + bortezomib combination induced significant inhibition of MM cell homing in vivo, as shown by in vivo confocal microscopy, as compared to bortezomib used as single agent. Conclusion. Our data demonstrate that the SDF-1 inhibiting Spiegelmer NOX-A12 disrupts the interaction of MM cells with the BM milieu both in vitro and in vivo, thus resulting in enhanced sensitivity to bortezomib. Disclosures: Roccaro: Roche:. Kruschinski:Noxxon Pharma AG: Employment. Ghobrial:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Advisory Board, Research Funding.
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Yang, Z. P., D. A. Turner, J. J. Zhang, Y. L. Wang, M. C. Chen, Q. Zhang, O. T. Denmead, D. Chen, and J. R. Freney. "Loss of nitrogen by ammonia volatilisation and denitrification after application of urea to maize in Shanxi Province, China." Soil Research 49, no. 5 (2011): 462. http://dx.doi.org/10.1071/sr11107.
Повний текст джерелаАнотація:
Much of the fertiliser nitrogen (N) used in agriculture is lost to the atmosphere as nitric oxide and nitrogen dioxide (collectively referred to as NOx), ammonia (NH3), and nitrous oxide (N2O). The lost N is not only an economic problem for the farmer; it also contaminates the environment and affects human health. Because the values obtained for NOx and NH3 loss to the atmosphere from agriculture in Monsoon Asia have been questioned, we quantitatively determined, using new techniques, the emission of these gases from a maize crop fertilised with urea in northern China. The fertiliser was deep-placed by traditional farmers’ practice and emissions of NOx and NH3were determined with a chemiluminescence analyser and a backward Lagrangian stochastic dispersion technique. The emission measurements indicate that 1.2% of the applied N was lost as NOx. This loss is far greater than measured or derived by other researchers, and we suggest that this is because our measurements were made continuously rather than as spot measurements with static chambers. The results for NH3 show that, although the fertiliser was placed below the soil surface, a small amount (7% of the applied N) was still lost to the atmosphere. Soil analyses indicate that the rate of nitrification in this soil was low, and the maximum nitrate (NO3–) concentration found in the soil (31.4 µg N/g) was only 3.9% of the fertiliser N added. Thus, there is little potential for NO3– to be leached down the profile. A study using soil cores and acetylene inhibition to measure denitrifying activity suggested that the rate of denitrification in this soil was also very low. The results suggest that in this soil with slow nitrification and denitrification rates and little potential for leaching, deep placement of the urea to limit NH3 volatilisation is an effective method for increasing fertiliser use efficiency.
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Krauß, P. L., F. Buttgereit, T. Gaber, M. Pfeiffenberger, Y. Chen, and T. Buttgereit. "AB0029 THE METABOLIC HIERARCHY OF IMMUNE PROCESSES IN HUMAN MONOCYTES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1048.2–1048. http://dx.doi.org/10.1136/annrheumdis-2021-eular.794.
Повний текст джерелаАнотація:
Background:At sites of inflammation, monocytes carry out specific immunological functions while facing challenging bioenergetic restrictions.Objectives:Here, we investigated the potential of human monocytes to adapt under conditions of reduced energy supply by gradually inhibiting oxidative phosphorylation (OXPHOS) under glucose free conditions.Methods:We modelled this reduced energy supply with myxothiazol, an inhibitor of mitochondrial respiration, at 0, 2 and 4 pmol/106 cells to decrease mitochondrial ATP production for 0%, 25% and 66% under glucose free conditions. For the three energy levels, we assessed (i) phagocytosis of FITC-labelled E.coli using flow cytometry, (i) production of reactive oxygen species (ROS) through NADPH oxidase (NOX) as determined by VAS2870-sensitive OCR using a Clark-type electrode, (iii) ATP generation and steady state level using a Clark-type electrode and luminometric assessment (iv) expression of surface activation markers CD16, CD80, CD11b, HLA-DR and (v) production of the inflammatory cytokines IL-1β, IL-6 and TNF-α using flow cytometry in peripheral blood-derived human monocytes with and without LPS-stimulation.Results:As a prerequisite for our study, we demonstrate that human monocytes survived strong inhibition of mitochondrial respiration without any sign of apoptosis as determined by flow cytometry. As a result of the inhibition of OXPHOS, we demonstrate a reduction of VAS2870-sensitive OCR (ROS production through NOX), ATPase-dependent OCR and ATP steady-state levels. Focusing on immune function, we observed that phagocytosis and the production of IL-6 were the least sensitive to reduced energy supply while surface expression of CD11b, HLA-DR, production of TNF-α and IL-1β were most affected by inhibition of OXPHOS.Conclusion:Our data demonstrate an energy-dependent hierarchy of immune functions in monocytes, which may represent a potential therapeutic target in monocyte-mediated inflammatory diseases.Disclosure of Interests:None declared
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Parsanathan, Rajesh, та Sushil K. Jain. "Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFβ/NADPH Oxidases/ROS Signaling Pathway". International Journal of Molecular Sciences 21, № 20 (10 жовтня 2020): 7474. http://dx.doi.org/10.3390/ijms21207474.
Повний текст джерелаАнотація:
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common genetic inherited trait among humans, affects ~7% of the global population, and is associated with excess risk of cardiovascular disease (CVD). Transforming growth factor-β (TGF-β) regulates immune function, proliferation, epithelial-mesenchymal transition, fibrosis, cancer, and vascular dysfunction. This study examined whether G6PD deficiencies can alter TGF-β-mediated NADPH oxidases (NOX) and cell adhesion molecules (CAM) in human aortic endothelial cells (HAEC). Results show that treatment with high glucose and the saturated free fatty acid palmitate significantly downregulated G6PD; in contrast, mRNA levels of TGF-β components, NOX and its activity, and reactive oxygen species (ROS) were significantly upregulated in HAEC. The expression levels of TGF-β and its receptors, NOX and its activity, and ROS were significantly higher in HG-exposed G6PD-deficient cells (G6PD siRNA) compared to G6PD-normal cells. The protein levels of adhesion molecules (ICAM-1 and VCAM-1) and inflammatory cytokines (MCP-1 and TNF) were significantly increased in HG-exposed G6PD-deficient cells compared to G6PD-normal cells. The adherence of monocytes (SC cells) to HAEC was significantly elevated in HG-treated G6PD-deficient cells compared to control cells. Pharmacological inhibition of G6PD enhances ROS, NOX and its activity, and endothelial monocyte adhesion; these effects were impeded by NOX inhibitors. The inhibition of TGF-β prevents NOX2 and NOX4 mRNA expression and activity, ROS, and adhesion of monocytes to HAEC. L-Cysteine ethyl ester (cell-permeable) suppresses the mRNA levels of TGF-β and its receptors, along with NOX2 and NOX4, and decreases NOX activity, ROS, and adhesion of monocytes to HAEC. This suggests that G6PD deficiency promotes TGF-β/NADPH oxidases/ROS signaling, the expression of ICAM-1 and VCAM-1, and the adhesion of leukocytes to the endothelial monolayer, which can contribute to a higher risk for CVD.