20 results on '"Szyndralewiez C"'
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2. Pharmacological inhibition of NADPH oxidase 4 abrogates stromal activation associated with prostate cancer
- Author
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Sampson, N., primary, Brunner, E., additional, Puhr, M., additional, Szyndralewiez, C., additional, and Klocker, H., additional
- Published
- 2018
- Full Text
- View/download PDF
3. Therapeutic potential of NADPH oxidase 1/4 inhibitors
- Author
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Teixeira, G, Szyndralewiez, C, Molango, S, Carnesecchi, S, Heitz, F, Wiesel, P, and Wood, J M
- Subjects
Inflammation ,Pyridines ,Pyridones ,NADPH Oxidase 2 ,Anti-Inflammatory Agents ,NADPH Oxidase 1 ,Animals ,Humans ,Pyrazoles ,Enzyme Inhibitors ,Pyrazolones ,Themed Section: Review Articles ,Fibrosis - Abstract
The NADPH oxidase (NOX) family of enzymes produces ROS as their sole function and is becoming recognized as key modulators of signal transduction pathways with a physiological role under acute stress and a pathological role after excessive activation under chronic stress. The seven isoforms differ in their regulation, tissue and subcellular localization and ROS products. The most studied are NOX1, 2 and 4. Genetic deletion of NOX1 and 4, in contrast to NOX2, has revealed no significant spontaneous pathologies and a pathogenic relevance of both NOX1 and 4 across multiple organs in a wide range of diseases and in particular inflammatory and fibrotic diseases. This has stimulated interest in NOX inhibitors for therapeutic application. GKT136901 and GKT137831 are two structurally related compounds demonstrating a preferential inhibition of NOX1 and 4 that have suitable properties for in vivo studies and have consequently been evaluated across a range of disease models and compared with gene deletion. In contrast to gene deletion, these inhibitors do not completely suppress ROS production, maintaining some basal level of ROS. Despite this and consistent with most gene deletion studies, these inhibitors are well tolerated and slow or prevent disease progression in a range of models of chronic inflammatory and fibrotic diseases by modulating common signal transduction pathways. Clinical trials in patients with GKT137831 have demonstrated excellent tolerability and reduction of various markers of chronic inflammation. NOX1/4 inhibition may provide a safe and effective therapeutic strategy for a range of inflammatory and fibrotic diseases.This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
- Published
- 2016
4. 672 Therapeutic potential of the Nox1/4 inhibitor GKT137831 in Systemic sclerosis
- Author
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Dosoki, H., primary, Taha, M., additional, Schnittler, H., additional, Szyndralewiez, C., additional, Luger, T.A., additional, and Böhm, M., additional
- Published
- 2017
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5. Therapeutic potential of NADPH oxidase 1/4 inhibitors
- Author
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Teixeira, G, primary, Szyndralewiez, C, additional, Molango, S, additional, Carnesecchi, S, additional, Heitz, F, additional, Wiesel, P, additional, and Wood, J M, additional
- Published
- 2016
- Full Text
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6. Therapeutic potential of NADPH oxidase 1/4 inhibitors.
- Author
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Teixeira, G, Szyndralewiez, C, Molango, S, Carnesecchi, S, Heitz, F, Wiesel, P, and Wood, J M
- Subjects
- *
NADPH oxidase , *INFLAMMATION treatment , *OXYGEN in the body , *CELLULAR signal transduction , *DELETION mutation ,PREVENTION of disease progression - Abstract
The NADPH oxidase (NOX) family of enzymes produces ROS as their sole function and is becoming recognized as key modulators of signal transduction pathways with a physiological role under acute stress and a pathological role after excessive activation under chronic stress. The seven isoforms differ in their regulation, tissue and subcellular localization and ROS products. The most studied are NOX1, 2 and 4. Genetic deletion of NOX1 and 4, in contrast to NOX2, has revealed no significant spontaneous pathologies and a pathogenic relevance of both NOX1 and 4 across multiple organs in a wide range of diseases and in particular inflammatory and fibrotic diseases. This has stimulated interest in NOX inhibitors for therapeutic application. GKT136901 and GKT137831 are two structurally related compounds demonstrating a preferential inhibition of NOX1 and 4 that have suitable properties for in vivo studies and have consequently been evaluated across a range of disease models and compared with gene deletion. In contrast to gene deletion, these inhibitors do not completely suppress ROS production, maintaining some basal level of ROS. Despite this and consistent with most gene deletion studies, these inhibitors are well tolerated and slow or prevent disease progression in a range of models of chronic inflammatory and fibrotic diseases by modulating common signal transduction pathways. Clinical trials in patients with GKT137831 have demonstrated excellent tolerability and reduction of various markers of chronic inflammation. NOX1/4 inhibition may provide a safe and effective therapeutic strategy for a range of inflammatory and fibrotic diseases.
Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]- Published
- 2017
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7. P-23 - Pharmacological inhibition of NADPH oxidase 4 abrogates stromal activation associated with prostate cancer.
- Author
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Sampson, N., Brunner, E., Puhr, M., Szyndralewiez, C., and Klocker, H.
- Subjects
- *
PROSTATE cancer , *NADPH oxidase , *FIBROBLASTS , *PROSTATE-specific antigen , *EXOCRINE glands - Published
- 2018
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8. Pre-clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver, kidney and lung fibrosis.
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Thannickal VJ, Jandeleit-Dahm K, Szyndralewiez C, and Török NJ
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- Humans, NADPH Oxidase 1, Reactive Oxygen Species, Hepatic Stellate Cells, Liver pathology, NADPH Oxidases, Kidney pathology, NADPH Oxidase 4, Pulmonary Fibrosis pathology
- Abstract
Fibrosis describes a dysregulated tissue remodelling response to persistent cellular injury and is the final pathological consequence of many chronic diseases that affect the liver, kidney and lung. Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) enzymes produce reactive oxygen species (ROS) as their primary function. ROS derived from NOX1 and NOX4 are key mediators of liver, kidney and lung fibrosis. Setanaxib (GKT137831) is a first-in-class, dual inhibitor of NOX1/4 and is the first NOX inhibitor to progress to clinical trial investigation. The anti-fibrotic effects of setanaxib in liver, kidney and lung fibrosis are supported by multiple lines of pre-clinical evidence. However, despite advances in our understanding, the precise roles of NOX1/4 in fibrosis require further investigation. Additionally, there is a translational gap between the pre-clinical observations of setanaxib to date and the applicability of these to human patients within a clinical setting. This narrative review critically examines the role of NOX1/4 in liver, kidney and lung fibrosis, alongside the available evidence investigating setanaxib as a therapeutic agent in pre-clinical models of disease. We discuss the potential clinical translatability of this pre-clinical evidence, which provides rationale to explore NOX1/4 inhibition by setanaxib across various fibrotic pathologies in clinical trials involving human patients., (© 2023 Calliditas Therapeutics AB. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2023
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9. NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.
- Author
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Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, Wood O, Machado M, Lopez MA, Ganesan AP, Wang C, Chakravarthy A, Fenton TR, King EV, Vijayanand P, Ottensmeier CH, Al-Shamkhani A, Savelyeva N, and Thomas GJ
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Humans, Immunotherapy, Mice, NADPH Oxidase 4, Reactive Oxygen Species, Cancer-Associated Fibroblasts, Neoplasms
- Abstract
Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8
+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg. See related commentary by Hayward, p. 1799 ., (©2020 American Association for Cancer Research.)- Published
- 2020
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10. Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice.
- Author
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Eid SA, El Massry M, Hichor M, Haddad M, Grenier J, Dia B, Barakat R, Boutary S, Chanal J, Aractingi S, Wiesel P, Szyndralewiez C, Azar ST, Boitard C, Zaatari G, Eid AA, and Massaad C
- Subjects
- Aged, Aged, 80 and over, Animals, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 2 complications, Diabetic Neuropathies etiology, Female, Humans, Hydrocarbons, Fluorinated pharmacology, Liver X Receptors agonists, Male, Mice, Myelin Proteins genetics, NADPH Oxidase 4 antagonists & inhibitors, Pyrazoles pharmacology, Pyrazolones, Pyridines pharmacology, Pyridones, Reactive Oxygen Species metabolism, Signal Transduction, Sulfonamides pharmacology, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 2 metabolism, Diabetic Neuropathies metabolism, Liver X Receptors metabolism, NADPH Oxidase 4 metabolism, Schwann Cells metabolism
- Abstract
Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach., (© 2019 by the American Diabetes Association.)
- Published
- 2020
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11. Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy.
- Author
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Stalin J, Garrido-Urbani S, Heitz F, Szyndralewiez C, Jemelin S, Coquoz O, Ruegg C, and Imhof BA
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Colonic Neoplasms immunology, Colonic Neoplasms metabolism, Endothelial Cells drug effects, Endothelial Cells metabolism, Humans, Immunotherapy, Interferon-gamma metabolism, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidases genetics, NADPH Oxidases metabolism, Natural Killer T-Cells drug effects, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Programmed Cell Death 1 Receptor immunology, Reactive Oxygen Species metabolism, Reactive Oxygen Species pharmacology, Tumor Microenvironment immunology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colonic Neoplasms drug therapy, NADPH Oxidase 1 antagonists & inhibitors, NADPH Oxidases antagonists & inhibitors, Programmed Cell Death 1 Receptor antagonists & inhibitors, Tumor Microenvironment drug effects
- Abstract
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., (© 2019 Stalin et al.)
- Published
- 2019
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12. Inhibition of Nox4-dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal-mediated protumorigenic interactions.
- Author
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Sampson N, Brunner E, Weber A, Puhr M, Schäfer G, Szyndralewiez C, and Klocker H
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- Cancer-Associated Fibroblasts cytology, Cancer-Associated Fibroblasts metabolism, Cell Line, Tumor, Cell Movement drug effects, Culture Media, Conditioned pharmacology, Humans, Male, Oxidative Stress drug effects, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Pyrazolones, Pyridones, Sequence Analysis, RNA, Signal Transduction drug effects, Stromal Cells cytology, Stromal Cells metabolism, Transforming Growth Factor beta1 metabolism, Cancer-Associated Fibroblasts drug effects, NADPH Oxidase 4 genetics, NADPH Oxidase 4 metabolism, Prostatic Neoplasms metabolism, Pyrazoles pharmacology, Pyridines pharmacology, Reactive Oxygen Species metabolism
- Abstract
Carcinoma-associated fibroblasts (CAFs) play a key onco-supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1-mediated activation of primary prostate human fibroblasts to a CAF-like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine-mediated PCa-relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri-tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFβ protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF-associated marker expression and migration of TGFβ1-activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA-mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFβ1-driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFβ1-activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFβ1 as conditioned media from PCa cell lines endogenously secreting high TGFβ1 levels induced fibroblast activation in a stromal Nox4- and TGFβ receptor-dependent manner. Importantly, GKT137831 also attenuated PCa cell-driven fibroblast activation. Collectively, these findings suggest the TGFβ-Nox4 signaling axis is a key interface to dysregulated reciprocal stromal-epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal-targeted approach to complement current PCa treatment modalities., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2018
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13. Nox4 is a Target for Tuberin Deficiency Syndrome.
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Shi Q, Viswanadhapalli S, Friedrichs WE, Velagapudi C, Szyndralewiez C, Bansal S, Bhat MA, Choudhury GG, and Abboud HE
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- Angiomyolipoma complications, Angiomyolipoma metabolism, Animals, Case-Control Studies, Humans, Kidney metabolism, Kidney Diseases complications, Kidney Diseases metabolism, Male, Mice, Mice, Nude, NADPH Oxidase 4 genetics, Reactive Oxygen Species metabolism, Syndrome, Tuberous Sclerosis complications, Tuberous Sclerosis metabolism, Tuberous Sclerosis Complex 2 Protein genetics, Xenograft Model Antitumor Assays, Angiomyolipoma pathology, Kidney pathology, Kidney Diseases pathology, NADPH Oxidase 4 metabolism, Tuberous Sclerosis pathology, Tuberous Sclerosis Complex 2 Protein metabolism
- Abstract
The mechanism by which TSC2 inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex from Tsc2+/- mice exhibit elevated levels of reactive oxygen species (ROS). Downregulation of tuberin (protein encoded by TSC2 gene) in renal proximal tubular epithelial cells significantly increased ROS concomitant with enhanced Nox4. Similarly, we found elevated levels of Nox4 in the renal cortex of Tsc2+/- mice and in the renal angiomyolipomas from TSC patients. Tuberin deficiency is associated with activation of mTORC1. Rapamycin, shRNAs targeting raptor, or inhibition of S6 kinase significantly inhibited the expression of Nox4, resulting in attenuation of production of ROS in tuberin-downregulated proximal tubular epithelial cells. In contrast, activation of mTORC1 increased Nox4 and ROS. These results indicate that Nox4 may be a potential target for tuberin-deficiency-derived diseases. Using a xenograft model from tuberin-null tubular cells in nude mice, both anti-sense Nox4 and GKT137831, a specific inhibitor of Nox1/4, significantly inhibited the tumor growth. Thus, our results demonstrate the presence of an antagonistic relationship between tuberin and Nox4 to drive oncogenesis in the tuberin deficiency syndrome and identify Nox4 as a target to develop a therapy for TSC.
- Published
- 2018
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14. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4.
- Author
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Hanley CJ, Mellone M, Ford K, Thirdborough SM, Mellows T, Frampton SJ, Smith DM, Harden E, Szyndralewiez C, Bullock M, Noble F, Moutasim KA, King EV, Vijayanand P, Mirnezami AH, Underwood TJ, Ottensmeier CH, and Thomas GJ
- Subjects
- Actins analysis, Adenocarcinoma chemistry, Adenocarcinoma genetics, Adult, Aged, Aged, 80 and over, Animals, Cancer-Associated Fibroblasts chemistry, Cancer-Associated Fibroblasts physiology, Carcinoma, Non-Small-Cell Lung chemistry, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell chemistry, Carcinoma, Squamous Cell genetics, Cell Count, Cell Transdifferentiation drug effects, Cell Transdifferentiation genetics, Colorectal Neoplasms pathology, Disease Progression, Esophageal Neoplasms chemistry, Esophageal Neoplasms genetics, Female, Head and Neck Neoplasms chemistry, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Humans, Lung Neoplasms chemistry, Lung Neoplasms genetics, Male, Mice, Middle Aged, Mouth Neoplasms pathology, Myofibroblasts chemistry, NADPH Oxidase 4, NADPH Oxidases analysis, NADPH Oxidases genetics, Neoplasm Transplantation, Oropharyngeal Neoplasms pathology, Phenotype, Pyrazoles therapeutic use, Pyrazolones, Pyridines therapeutic use, Pyridones, RNA Interference, Reactive Oxygen Species metabolism, Survival Rate, Up-Regulation, Adenocarcinoma drug therapy, Cancer-Associated Fibroblasts pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Colorectal Neoplasms chemistry, Esophageal Neoplasms drug therapy, Lung Neoplasms drug therapy, Mouth Neoplasms chemistry, Myofibroblasts pathology, NADPH Oxidases antagonists & inhibitors, Oropharyngeal Neoplasms chemistry
- Abstract
Background: Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed., Methods: CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided., Results: Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04)., Conclusions: These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types., (© The Author 2017. Published by Oxford University Press.)
- Published
- 2018
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15. Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease.
- Author
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Gray SP, Jha JC, Kennedy K, van Bommel E, Chew P, Szyndralewiez C, Touyz RM, Schmidt HHHW, Cooper ME, and Jandeleit-Dahm KAM
- Subjects
- Animals, Atherosclerosis metabolism, Atherosclerosis prevention & control, Diabetes Mellitus, Experimental genetics, Diabetic Nephropathies metabolism, Diabetic Nephropathies prevention & control, Mice, Mice, Knockout, NADH, NADPH Oxidoreductases antagonists & inhibitors, NADH, NADPH Oxidoreductases deficiency, NADH, NADPH Oxidoreductases genetics, NADPH Oxidase 1, NADPH Oxidase 4, NADPH Oxidases antagonists & inhibitors, NADPH Oxidases deficiency, NADPH Oxidases genetics, Oxidative Stress drug effects, Pyrazolones, Pyridones, Diabetes Complications metabolism, Diabetes Complications prevention & control, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism, NADH, NADPH Oxidoreductases metabolism, NADPH Oxidases metabolism, Pyrazoles therapeutic use, Pyridines therapeutic use
- Abstract
Aims/hypothesis: Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications., Methods: GKT137831 was administered at two doses, 30 mg kg
-1 day-1 and 60 mg kg-1 day-1 , to ApoE-/- mice 10 weeks after diabetes induction with streptozotocin (STZ), for a period of 10 weeks., Results: Consistent with Nox4-/- mouse data, GKT137831 was protective in a model of diabetic nephropathy at both the 30 mg kg-1 day-1 and 60 mg kg-1 day-1 doses, through suppression of proinflammatory and profibrotic processes. Conversely, in diabetic atherosclerosis, where Nox1-/y and Nox4-/- mice have yielded qualitatively opposing results, the net effect of pharmacological NOX1/4 inhibition was protection, albeit to a lower extent and only at the lower 30 mg kg-1 day-1 dose., Conclusions/interpretation: As dose-dependent and tissue-specific effects of the dual NOX1/4 inhibitor GKT137831 were observed, it is critical to define in further studies the relative balance of inhibiting NOX4 vs NOX1 in the micro- and macrovasculature in diabetes.- Published
- 2017
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16. NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis.
- Author
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Di Marco E, Gray SP, Kennedy K, Szyndralewiez C, Lyle AN, Lassègue B, Griendling KK, Cooper ME, Schmidt HHHW, and Jandeleit-Dahm KAM
- Subjects
- Animals, Aorta metabolism, Aorta pathology, Atherosclerosis etiology, Atherosclerosis pathology, Becaplermin, Cell Proliferation, Cells, Cultured, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental pathology, Fibrosis, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, NADPH Oxidase 1 metabolism, NADPH Oxidase 4 genetics, Osteopontin genetics, Osteopontin metabolism, Proto-Oncogene Proteins c-sis genetics, Proto-Oncogene Proteins c-sis metabolism, Superoxides metabolism, Atherosclerosis enzymology, Diabetes Mellitus, Experimental enzymology, Myocytes, Smooth Muscle physiology, NADPH Oxidase 4 metabolism, Reactive Oxygen Species metabolism
- Abstract
Smooth muscle cell (SMC) proliferation and fibrosis contribute to the development of advanced atherosclerotic lesions. Oxidative stress caused by increased production or unphysiological location of reactive oxygen species (ROS) is a known major pathomechanism. However, in atherosclerosis, in particular under hyperglycaemic/diabetic conditions, the hydrogen peroxide-producing NADPH oxidase type 4 (NOX4) is protective. Here we aim to elucidate the mechanisms underlying this paradoxical atheroprotection of vascular smooth muscle NOX4 under conditions of normo- and hyperglycaemia both in vivo and ex vivo. Following 20-weeks of streptozotocin-induced diabetes, Apoe(-/-) mice showed a reduction in SM-alpha-actin and calponin gene expression with concomitant increases in platelet-derived growth factor (PDGF), osteopontin (OPN) and the extracellular matrix (ECM) protein fibronectin when compared to non-diabetic controls. Genetic deletion of Nox4 (Nox4(-/)(-)Apoe(-/-)) exacerbated diabetes-induced expression of PDGF, OPN, collagen I, and proliferation marker Ki67. Aortic SMCs isolated from NOX4-deficient mice exhibited a dedifferentiated phenotype including loss of contractile gene expression, increased proliferation and ECM production as well as elevated levels of NOX1-associated ROS. Mechanistic studies revealed that elevated PDGF signalling in NOX4-deficient SMCs mediated the loss of calponin and increase in fibronectin, while the upregulation of NOX1 was associated with the increased expression of OPN and markers of proliferation. These findings demonstrate that NOX4 actively regulates SMC pathophysiological responses in diabetic Apoe(-/-) mice and in primary mouse SMCs through the activities of PDGF and NOX1., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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17. Airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD.
- Author
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Hollins F, Sutcliffe A, Gomez E, Berair R, Russell R, Szyndralewiez C, Saunders R, and Brightling C
- Subjects
- Bronchi drug effects, Bronchi physiopathology, Case-Control Studies, Cells, Cultured, Enzyme Inhibitors pharmacology, Humans, Muscle, Smooth drug effects, Muscle, Smooth physiopathology, Myocytes, Smooth Muscle drug effects, NADPH Oxidase 4 antagonists & inhibitors, Pulmonary Disease, Chronic Obstructive etiology, Pulmonary Disease, Chronic Obstructive physiopathology, Smoking adverse effects, Tumor Necrosis Factor-alpha pharmacology, Up-Regulation, Bronchi enzymology, Muscle, Smooth enzymology, Myocytes, Smooth Muscle enzymology, NADPH Oxidase 4 metabolism, Pulmonary Disease, Chronic Obstructive enzymology, Reactive Oxygen Species metabolism
- Abstract
The burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD). However, whether the intra-cellular mechanisms controlling the oxidant/anti-oxidant balance in structural airway cells such as airway smooth muscle in COPD is altered is unclear. We sought to determine whether the expression of the NADPH oxidase (NOX)-4 is increased in airway smooth muscle in COPD both in vivo and primary cells in vitro and its role in hydrogen peroxide-induced reactive oxygen species generation. We found that in vivo NOX4 expression was up-regulated in the airway smooth muscle bundle in COPD (n = 9) and healthy controls with >20 pack year history (n = 4) compared to control subjects without a significant smoking history (n = 6). In vitro NOX4 expression was increased in airway smooth muscle cells from subjects with COPD (n = 5) compared to asthma (n = 7) and upregulated following TNF-α stimulation. Hydrogen peroxide-induced reactive oxygen species generation by airway smooth muscle cells in COPD (n = 5) was comparable to healthy controls (n = 9) but lower than asthma (n = 5); and was markedly attenuated by NOX4 inhibition. Our findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and although we did not observe an intrinsic increase in oxidant-induced reactive oxygen species generation in COPD, it was reduced markedly by NOX4 inhibition supporting a potential therapeutic role for NOX4 in COPD.
- Published
- 2016
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18. NADPH Oxidase-4 Overexpression Is Associated With Epithelial Ciliary Dysfunction in Neutrophilic Asthma.
- Author
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Wan WY, Hollins F, Haste L, Woodman L, Hirst RA, Bolton S, Gomez E, Sutcliffe A, Desai D, Chachi L, Mistry V, Szyndralewiez C, Wardlaw A, Saunders R, O'Callaghan C, Andrew PW, and Brightling CE
- Subjects
- Adult, Animals, Dual Oxidases, Female, Humans, Inflammation metabolism, Male, Mice, Middle Aged, NADPH Oxidase 4, Neutrophils, Oxidative Stress, Statistics as Topic, Asthma metabolism, Asthma pathology, Asthma physiopathology, Cilia metabolism, NADPH Oxidases metabolism, Respiratory Mucosa metabolism, Respiratory Mucosa pathology, Respiratory Mucosa physiopathology
- Abstract
Background: Bronchial epithelial ciliary dysfunction is an important feature of asthma. We sought to determine the role in asthma of neutrophilic inflammation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in ciliary dysfunction., Methods: Bronchial epithelial ciliary function was assessed by using video microscopy in fresh ex vivo epithelial strips from patients with asthma stratified according to their sputum cell differentials and in culture specimens from healthy control subjects and patients with asthma. Bronchial epithelial oxidative damage was determined by 8-oxo-dG expression. Nicotinamide adenine dinucleotide phosphate oxidase (NOX)/dual oxidase (DUOX) expression was assessed in bronchial epithelial cells by using microarrays, with NOX4 and DUOX1/2 expression assessed in bronchial biopsy specimens. Ciliary dysfunction following NADPH oxidase inhibition, using GKT137831, was evaluated in fresh epithelial strips from patients with asthma and a murine model of ovalbumin sensitization and challenge., Results: Ciliary beat frequency was impaired in patients with asthma with sputum neutrophilia (n = 11) vs those without (n = 10) (5.8 [0.6] Hz vs 8.8 [0.5] Hz; P = .003) and was correlated with sputum neutrophil count (r = -0.70; P < .001). Primary bronchial epithelial cells expressed DUOX1/2 and NOX4. Levels of 8-oxo-dG and NOX4 were elevated in patients with neutrophilic vs nonneutrophilic asthma, DUOX1 was elevated in both, and DUOX2 was elevated in nonneutrophilic asthma in vivo. In primary epithelial cultures, ciliary dysfunction did not persist, although NOX4 expression and reactive oxygen species generation was increased from patients with neutrophilic asthma. GKT137831 both improved ciliary function in ex vivo epithelial strips (n = 13), relative to the intensity of neutrophilic inflammation, and abolished ciliary dysfunction in the murine asthma model with no reduction in inflammation., Conclusions: Ciliary dysfunction is increased in neutrophilic asthma associated with increased NOX4 expression and is attenuated by NADPH oxidase inhibition., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
19. Hepatocyte Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity During Development of Steatohepatitis in Mice.
- Author
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Bettaieb A, Jiang JX, Sasaki Y, Chao TI, Kiss Z, Chen X, Tian J, Katsuyama M, Yabe-Nishimura C, Xi Y, Szyndralewiez C, Schröder K, Shah A, Brandes RP, Haj FG, and Török NJ
- Subjects
- Animals, Biomarkers metabolism, Biopsy, Diet methods, Disease Models, Animal, Fatty Liver chemically induced, Fatty Liver genetics, Fatty Liver metabolism, Hepatocytes metabolism, Humans, Lipid Peroxidation drug effects, Liver cytology, Liver pathology, Liver Cirrhosis pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, NADP administration & dosage, NADPH Oxidase 4, Obesity drug therapy, Obesity metabolism, Protein Phosphatase 1 metabolism, Pyrazoles metabolism, Pyrazolones, Pyridines metabolism, Pyridones, Stress, Physiological drug effects, Fatty Liver drug therapy, Hepatocytes drug effects, Insulin Resistance, Liver Cirrhosis drug therapy, NADP pharmacology, NADPH Oxidases metabolism, Oxidative Stress drug effects
- Abstract
Background & Aims: Reactive oxidative species (ROS) are believed to be involved in the progression of nonalcoholic steatohepatitis (NASH). However, little is known about the sources of ROS in hepatocytes or their role in disease progression. We studied the effects of nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (NOX4) in liver tissues from patients with NASH and mice with steatohepatitis., Methods: Liver biopsy samples were obtained from 5 patients with NASH, as well as 4 patients with simple steatosis and 5 patients without steatosis (controls) from the University of California, Davis Cancer Center Biorepository. Mice with hepatocyte-specific deletion of NOX4 (NOX4(hepKO)) and NOX4(floxp+/+) C57BL/6 mice (controls) were given fast-food diets (supplemented with high-fructose corn syrup) or choline-deficient l-amino acid defined diets to induce steatohepatitis, or control diets, for 20 weeks. A separate group of mice were given the NOX4 inhibitor (GKT137831). Liver tissues were collected and immunoblot analyses were performed determine levels of NOX4, markers of inflammation and fibrosis, double-stranded RNA-activated protein kinase, and phospho-eIF-2α kinase-mediated stress signaling pathways. We performed hyperinsulinemic-euglycemic clamp studies and immunoprecipitation analyses to determine the oxidation and phosphatase activity of PP1C., Results: Levels of NOX4 were increased in patients with NASH compared with controls. Hepatocyte-specific deletion of NOX4 reduced oxidative stress, lipid peroxidation, and liver fibrosis in mice with diet-induced steatohepatitis. A small molecule inhibitor of NOX4 reduced liver inflammation and fibrosis and increased insulin sensitivity in mice with diet-induced steatohepatitis. In primary hepatocytes, NOX4 reduced the activity of the phosphatase PP1C, prolonging activation of double-stranded RNA-activated protein kinase and phosphorylation of extracellular signal-regulated kinase-mediated stress signaling. Mice with hepatocyte-specific deletion of NOX4 and mice given GKT137831 had increased insulin sensitivity., Conclusions: NOX4 regulates oxidative stress in the liver and its levels are increased in patients with NASH and mice with diet-induced steatohepatitis. Inhibitors of NOX4 reduce liver inflammation and fibrosis and increase insulin sensitivity, and might be developed for treatment of NASH., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
20. Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes.
- Author
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Gorin Y, Cavaglieri RC, Khazim K, Lee DY, Bruno F, Thakur S, Fanti P, Szyndralewiez C, Barnes JL, Block K, and Abboud HE
- Subjects
- Animals, Diabetes Mellitus, Experimental metabolism, Diabetic Nephropathies drug therapy, Diabetic Nephropathies metabolism, Kidney metabolism, Kidney pathology, Mice, NADPH Oxidase 1, NADPH Oxidase 4, NADPH Oxidases antagonists & inhibitors, Podocytes drug effects, Podocytes metabolism, Pyrazolones, Pyridones, Reactive Oxygen Species metabolism, Diabetes Mellitus, Type 1 metabolism, Enzyme Inhibitors pharmacology, NADH, NADPH Oxidoreductases antagonists & inhibitors, NADPH Oxidases metabolism, Pyrazoles pharmacology, Pyridines pharmacology
- Abstract
Reactive oxygen species (ROS) generated by Nox NADPH oxidases may play a critical role in the pathogenesis of diabetic nephropathy (DN). The efficacy of the Nox1/Nox4 inhibitor GKT137831 on the manifestations of DN was studied in OVE26 mice, a model of type 1 diabetes. Starting at 4-5 mo of age, OVE26 mice were treated with GKT137831 at 10 or 40 mg/kg, once-a-day for 4 wk. At both doses, GKT137831 inhibited NADPH oxidase activity, superoxide generation, and hydrogen peroxide production in the renal cortex from diabetic mice without affecting Nox1 or Nox4 protein expression. The increased expression of fibronectin and type IV collagen was reduced in the renal cortex, including glomeruli, of diabetic mice treated with GKT137831. GKT137831 significantly reduced glomerular hypertrophy, mesangial matrix expansion, urinary albumin excretion, and podocyte loss in OVE26 mice. GKT137831 also attenuated macrophage infiltration in glomeruli and tubulointerstitium. Collectively, our data indicate that pharmacological inhibition of Nox1/4 affords broad renoprotection in mice with preexisting diabetes and established kidney disease. This study validates the relevance of targeting Nox4 and identifies GKT137831 as a promising compound for the treatment of DN in type 1 diabetes.
- Published
- 2015
- Full Text
- View/download PDF
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