26 results on '"Szyndralewiez C"'
Search Results
2. Die funktionelle Bedeutung der NADPH Oxidase 4 in der Mikroumgebung des Prostatakarzinoms
- Author
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Brunner, E, Puhr, M, Schäfer, G, Szyndralewiez, C, Klocker, H, and Sampson, N
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Hintergrund: Tumor-assoziierte Fibroblasten (engl. cancer associated fibroblasts, CAFs) spielen eine zentrale Rolle in der Entstehung, Progression und Therapieresistenz des Prostatakarzinoms. Durch Interaktionen mit Tumorzellen und die Ausschüttung parakriner Faktoren haben sie einen entscheidenden[zum vollständigen Text gelangen Sie über die oben angegebene URL], 46. Gemeinsame Tagung der Bayerischen Urologenvereinigung und der Österreichischen Gesellschaft für Urologie und Andrologie
- Published
- 2020
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3. Therapeutic potential of NADPH oxidase 1/4 inhibitors
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Teixeira, G, Szyndralewiez, C, Molango, S, Carnesecchi, S, Heitz, F, Wiesel, P, and Wood, J M
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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
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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
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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
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- 2016
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6. Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic Apoe (-/-) mice
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Di Marco, E., Di Marco, E., Gray, S. P., Chew, P., Koulis, C., Ziegler, A., Szyndralewiez, C., Touyz, R. M., Schmidt, H. H. H. W., Cooper, M. E., Slattery, R., Jandeleit-Dahm, K. A., Di Marco, E., Di Marco, E., Gray, S. P., Chew, P., Koulis, C., Ziegler, A., Szyndralewiez, C., Touyz, R. M., Schmidt, H. H. H. W., Cooper, M. E., Slattery, R., and Jandeleit-Dahm, K. A.
- Published
- 2014
7. 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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8. Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune–inflammatory responses in diabetic Apoe −/− mice
- Author
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Di Marco, E., primary, Gray, S. P., additional, Chew, P., additional, Koulis, C., additional, Ziegler, A., additional, Szyndralewiez, C., additional, Touyz, R. M., additional, Schmidt, H. H. H. W., additional, Cooper, M. E., additional, Slattery, R., additional, and Jandeleit-Dahm, K. A., additional
- Published
- 2013
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9. Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic Apoe mice.
- Author
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Marco, E., Gray, S., Chew, P., Koulis, C., Ziegler, A., Szyndralewiez, C., Touyz, R., Schmidt, H., Cooper, M., Slattery, R., and Jandeleit-Dahm, K.
- Abstract
Aims/hypothesis: Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis. Methods: Diabetes was induced in male Apoe mice with five daily doses of streptozotocin (55 mg kg day). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe mice for 10 weeks. Results: Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFNγ. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area. Conclusions/interpretation: Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe mice. [ABSTRACT FROM AUTHOR]
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- 2014
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10. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy.
- Author
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Sedeek, M., Callera, G., Montezano, A., Gutsol, A., Heitz, F., Szyndralewiez, C., Page, P., Kennedy, C. R. J., Burns, K. D., Touyz, R. M., and Hébert, R. L.
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OXIDASES ,OXIDATIVE stress ,DIABETIC nephropathies ,GLUCOSE ,OXIDATION-reduction reaction - Abstract
Molecular mechanisms underlying renal complications of diabetes remain unclear. We tested whether renal NADPH oxidase (Nox) 4 contributes to increased reactive oxygen species (ROS) generation and hyperactivation of redox-sensitive signaling pathways in diabetic nephropathy. Diabetic mice (db/db) (20 wk) and cultured mouse proximal tubule (MPT) cells exposed to high glucose (25 mmol/l, d-glucose) were studied. Expression (gene and protein) of Nox4, p22
phox , and p47phox , but not Nox1 or Nox2, was increased in kidney cortex, but not medulla, from db/db vs. control mice (db/m) (P < 0.05). ROS generation, p38 mitogen-activated protein (MAP) kinase phosphorylation, and content of fibronectin and transforming growth factor (TGF)-β1/2 were increased in db/db vs. db/m (P < 0.01). High glucose increased expression of Nox4, but not other Noxes vs. normal glucose (P < 0.05). This was associated with increased NADPH oxidase activation and enhanced ROS production. Nox4 downregulation by small-interfering RNA and inhibition of Nox4 activity by GK-136901 (Nox1/4 inhibitor) attenuated d-glucose-induced NADPH oxidase-derived ROS generation. High d-glucose, but not l-glucose, stimulated phosphorylation of p38MAP kinase and increased expression of TGF-β1/2 and fibronectin, effects that were inhibited by SB-203580 (p38MAP kinase inhibitor). GK-136901 inhibited d-glucose-induced actions. Our data indicate that, in diabetic conditions: 1) renal Nox4 is upregulated in a cortex-specific manner, 2) MPT cells possess functionally active Nox4-based NADPH, 3) Nox4 is a major source of renal ROS, and 4) activation of profibrotic processes is mediated via Nox4-sensitive, p38MAP kinase-dependent pathways. These findings implicate Nox4-based NADPH oxidase in molecular mechanisms underlying fibrosis in type 2 diabetic nephropathy. [ABSTRACT FROM AUTHOR]- Published
- 2010
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11. 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.)
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- 2023
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12. 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
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- 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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13. Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice.
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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
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- 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.)
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- 2020
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14. Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy.
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Stalin J, Garrido-Urbani S, Heitz F, Szyndralewiez C, Jemelin S, Coquoz O, Ruegg C, and Imhof BA
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- 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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15. 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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16. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4.
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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
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- 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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17. 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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18. 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
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- 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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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
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20. Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes.
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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.
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- 2015
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21. Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy.
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Jha JC, Gray SP, Barit D, Okabe J, El-Osta A, Namikoshi T, Thallas-Bonke V, Wingler K, Szyndralewiez C, Heitz F, Touyz RM, Cooper ME, Schmidt HH, and Jandeleit-Dahm KA
- Subjects
- Albuminuria drug therapy, Albuminuria enzymology, Albuminuria genetics, Animals, Apolipoproteins E genetics, Apolipoproteins E metabolism, Cell Line, Transformed, Disease Models, Animal, Enzyme Inhibitors pharmacology, Extracellular Matrix metabolism, Gene Silencing, Glucose pharmacology, Humans, Macrophages metabolism, Male, Mice, Mice, Knockout, NADH, NADPH Oxidoreductases antagonists & inhibitors, NADH, NADPH Oxidoreductases genetics, NADH, NADPH Oxidoreductases metabolism, NADPH Oxidase 1, NADPH Oxidase 4, NADPH Oxidases genetics, NADPH Oxidases metabolism, Podocytes cytology, Pyrazolones, Pyridones, Reactive Oxygen Species metabolism, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental enzymology, Diabetes Mellitus, Experimental genetics, Diabetic Nephropathies drug therapy, Diabetic Nephropathies enzymology, Diabetic Nephropathies genetics, NADPH Oxidases antagonists & inhibitors, Podocytes enzymology, Pyrazoles pharmacology, Pyridines pharmacology
- Abstract
Diabetic nephropathy may occur, in part, as a result of intrarenal oxidative stress. NADPH oxidases comprise the only known dedicated reactive oxygen species (ROS)-forming enzyme family. In the rodent kidney, three isoforms of the catalytic subunit of NADPH oxidase are expressed (Nox1, Nox2, and Nox4). Here we show that Nox4 is the main source of renal ROS in a mouse model of diabetic nephropathy induced by streptozotocin administration in ApoE(-/-) mice. Deletion of Nox4, but not of Nox1, resulted in renal protection from glomerular injury as evidenced by attenuated albuminuria, preserved structure, reduced glomerular accumulation of extracellular matrix proteins, attenuated glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 and NF-κB in streptozotocin-induced diabetic ApoE(-/-) mice. Importantly, administration of the most specific Nox1/4 inhibitor, GKT137831, replicated these renoprotective effects of Nox4 deletion. In human podocytes, silencing of the Nox4 gene resulted in reduced production of ROS and downregulation of proinflammatory and profibrotic markers that are implicated in diabetic nephropathy. Collectively, these results identify Nox4 as a key source of ROS responsible for kidney injury in diabetes and provide proof of principle for an innovative small molecule approach to treat and/or prevent chronic kidney failure., (Copyright © 2014 by the American Society of Nephrology.)
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- 2014
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22. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis.
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Gray SP, Di Marco E, Okabe J, Szyndralewiez C, Heitz F, Montezano AC, de Haan JB, Koulis C, El-Osta A, Andrews KL, Chin-Dusting JP, Touyz RM, Wingler K, Cooper ME, Schmidt HH, and Jandeleit-Dahm KA
- Subjects
- Animals, Atherosclerosis pathology, Cells, Cultured, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental pathology, Endothelial Cells enzymology, Endothelial Cells pathology, Humans, Inflammation Mediators physiology, Male, Mice, Mice, Knockout, Mice, Transgenic, NADPH Oxidase 1, Organ Culture Techniques, Protein Isoforms physiology, Reactive Oxygen Species metabolism, Atherosclerosis enzymology, Atherosclerosis etiology, Diabetes Mellitus, Experimental enzymology, NADH, NADPH Oxidoreductases physiology, NADPH Oxidases physiology
- Abstract
Background: In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis., Methods and Results: Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E-deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E-deficient mice with GKT137831 attenuated atherosclerosis development., Conclusions: These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis.
- Published
- 2013
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23. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation.
- Author
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Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, and Hart CM
- Subjects
- Animals, Cell Hypoxia, Cells, Cultured, Endothelial Cells enzymology, Endothelial Cells physiology, Endothelium, Vascular pathology, Gene Expression drug effects, Gene Knockdown Techniques, Humans, Hydrogen Peroxide metabolism, Hypertension, Pulmonary drug therapy, Hypertension, Pulmonary enzymology, Hypertension, Pulmonary pathology, Lung drug effects, Lung metabolism, Mice, Mice, Inbred C57BL, Myocytes, Smooth Muscle enzymology, Myocytes, Smooth Muscle physiology, NADPH Oxidase 4, NADPH Oxidases genetics, NADPH Oxidases metabolism, PPAR gamma genetics, PPAR gamma metabolism, Proliferating Cell Nuclear Antigen metabolism, Pyrazoles therapeutic use, Pyrazolones, Pyridines therapeutic use, Pyridones, RNA Interference, Rosiglitazone, Thiazolidinediones pharmacology, Thiazolidinediones therapeutic use, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Ventricular Remodeling drug effects, Cell Proliferation drug effects, Endothelial Cells drug effects, Myocytes, Smooth Muscle drug effects, NADPH Oxidases antagonists & inhibitors, Pulmonary Artery pathology, Pyrazoles pharmacology, Pyridines pharmacology
- Abstract
Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) contribute to hypoxia-induced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxia-exposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O(2)) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPARγ, and transforming growth factor (TGF)β1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O(2)) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPARγ and TGF-β1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H(2)O(2) release, proliferation, and TGF-β1 expression and blunted reductions in PPARγ in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-β1 and reductions in PPARγ expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxia-induced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis.
- Published
- 2012
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24. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.
- Author
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Garrido-Urbani S, Jemelin S, Deffert C, Carnesecchi S, Basset O, Szyndralewiez C, Heitz F, Page P, Montet X, Michalik L, Arbiser J, Rüegg C, Krause KH, and Imhof BA
- Subjects
- Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Animals, Cells, Cultured, Endothelial Cells drug effects, Female, Gene Knockdown Techniques, Gene Targeting, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Molecular Targeted Therapy, NADH, NADPH Oxidoreductases antagonists & inhibitors, NADH, NADPH Oxidoreductases physiology, NADPH Oxidase 1, Neoplasms drug therapy, Neoplasms genetics, Neovascularization, Pathologic drug therapy, PPAR alpha genetics, Pyrazoles pharmacology, Pyrazoles therapeutic use, Pyridones pharmacology, Pyridones therapeutic use, RNA, Small Interfering pharmacology, Signal Transduction drug effects, Signal Transduction genetics, Endothelial Cells metabolism, NADH, NADPH Oxidoreductases genetics, Neoplasms blood supply, Neovascularization, Pathologic genetics, PPAR alpha physiology
- Abstract
Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.
- Published
- 2011
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25. NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis.
- Author
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Vendrov AE, Madamanchi NR, Niu XL, Molnar KC, Runge M, Szyndralewiez C, Page P, and Runge MS
- Subjects
- Animals, Aorta, Atherosclerosis enzymology, Atherosclerosis metabolism, In Vitro Techniques, Mice, Mice, Knockout, Muscle, Smooth, Vascular cytology, Myocytes, Smooth Muscle enzymology, Reactive Oxygen Species, Thrombin pharmacology, Atherosclerosis etiology, Gene Expression Regulation, Hyaluronan Receptors genetics, Hyaluronic Acid genetics, Myocytes, Smooth Muscle metabolism, NADPH Oxidases physiology
- Abstract
The intracellular signaling events by which NADPH oxidase-generated reactive oxygen species (ROS) modulate vascular smooth muscle cell (VSMC) function and atherogenesis are yet to be entirely elucidated. We previously demonstrated that NADPH oxidase deficiency decreased atherosclerosis in apoE(-/-) mice and identified adhesion protein CD44 as an important ROS-sensitive gene expressed in VSMC and atherosclerotic lesions. Here, we examined the molecular mechanisms by which NADPH oxidase-generated ROS regulate the expression of CD44 and its principal ligand, hyaluronan (HA), and how CD44-HA interaction affects VSMC proliferation and migration and inflammatory gene expression in apoE(-/-) mice aortas. Thrombin-induced CD44 expression is mediated by transcription factor AP-1 in a NADPH oxidase-dependent manner. NADPH oxidase-mediated ROS generation enhanced thrombin-induced HA synthesis, and hyaluronan synthase 2 expression in VSMC. Hyaluronidase, which generates low molecular weight HA (LMW-HA), is induced in VSMC in a NADPH oxidase-dependent manner and LMW-HA stimulated ROS generation and cell proliferation in wild-type but not p47(phox-/-) VSMC, effects that were enhanced by thrombin pretreatment. Haptotactic VSMC migration toward HA was increased by thrombin in a CD44-dependent manner. HA expression in atherosclerotic lesions and plasma-soluble CD44 and HA levels were higher in apoE(-/-) compared with apoE(-/-)/p47(phox-/-) mice. HA-regulated pro-inflammatory gene expression was higher in apoE(-/-) than apoE(-/-)/p47(phox-/-) mouse aortas. GKT136901, a specific inhibitor of Nox1- and Nox4-containing NADPH oxidase activity, attenuated ROS generation and atherosclerosis and decreased CD44 and HA expression in atherosclerotic lesions. Together, these data suggest that increased CD44 and HA expression and CD44-HA-dependent gene regulation may play a role in atherosclerosis stimulated by NADPH oxidase activation.
- Published
- 2010
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26. GLEPP1/protein-tyrosine phosphatase phi inhibitors block chemotaxis in vitro and in vivo and improve murine ulcerative colitis.
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Gobert RP, van den Eijnden M, Szyndralewiez C, Jorand-Lebrun C, Swinnen D, Chen L, Gillieron C, Pixley F, Juillard P, Gerber P, Johnson-Léger C, Halazy S, Camps M, Bombrun A, Shipp M, Vitte PA, Ardissone V, Ferrandi C, Perrin D, Rommel C, and Hooft van Huijsduijnen R
- Subjects
- Animals, Colitis, Ulcerative drug therapy, Cytoskeleton metabolism, Female, In Vitro Techniques, Leukocytes metabolism, Macrophages metabolism, Mice, Mice, Inbred BALB C, Molecular Conformation, Monocytes metabolism, Phosphoric Monoester Hydrolases metabolism, Protein Tyrosine Phosphatases metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3 adverse effects, Signal Transduction, Thioglycolates pharmacology, Chemotaxis drug effects, Colitis, Ulcerative metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3 chemistry
- Abstract
We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase . Two previously described GLEPP1 substrates, paxillin and Syk, are both required for cytoskeletal rearrangement and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1 inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and block primary human monocyte and mouse bone marrow-derived macrophage chemotaxis in a gradient of monocyte chemotactic protein-1. In mice, the GLEPP1 inhibitors also reduce thioglycolate-induced peritoneal chemotaxis of neutrophils, lymphocytes, and macrophages. In murine disease models, the GLEPP1 inhibitors significantly reduce severity of contact hypersensitivity, a model for allergic dermatitis, and dextran sulfate sodium-induced ulcerative colitis, a model for inflammatory bowel disease. Taken together, our data provide confirmation that GLEPP1 plays an important role in controlling chemotaxis of multiple types of leukocytes and that pharmacological inhibition of this phosphatase may have therapeutic use.
- Published
- 2009
- Full Text
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