The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

Cifuentes-Pagano, Eugenia; Meijles, Daniel N.; Pagano, Patrick J.

doi:10.1089/ars.2013.5620

Cited by 74 publications

(60 citation statements)

References 175 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inhibition of AML-cell proliferation and attenuation of the development of a FLT3-ITD driven myeloproliferative disease in mice by compounds reported to inhibit NOX4 have been recent promising findings [28]. However, many currently available compounds for interference with ROS formation are not entirely specific or controversial with respect to their mechanism of action [86]. Given the importance of NOX mediated ROS formation not only in leukemia but many other pathological contexts, the improvement of compounds can be expected and their testing in leukemia models will be an exciting perspective.…”

Section: Future Directionsmentioning

confidence: 99%

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

Jayavelu

Moloney

Böhmer

et al. 2016

Experimental Hematology

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Section: Future Directionsmentioning

confidence: 99%

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

Jayavelu

Moloney

Böhmer

et al. 2016

Experimental Hematology

View full text Add to dashboard Cite

show abstract

“…1G. To demonstrate the relevance of LPS-induced superoxide to the expression of angiogenic markers, we conducted experiments with VAS2870 (a NOX inhibitor) and PEG-superoxide dismutase (a superoxide anion scavenger) (21,22). Pretreatment with VAS2870 (10 M) or PEG-superoxide dismutase (400 units/ml) for 1 h attenuated LPS-mediated induction of Ang2, VEGF-A, and Tie2 RNA at 3 h (Fig.…”

Section: Lps-induced Ang2 Tie2 and Vegf-a Expression In Hpmec Is Asmentioning

confidence: 99%

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

Menden

Welak

Cossette

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The mechanisms by which bacterial ligands alter angiogenesis remain unknown. Results: Lipopolysaccharide-mediated Angiopoietin-2-dependent autocrine angiogenesis in lung endothelial cells is regulated by NADPH oxidase 2. Conclusion: Endothelial Nox2 regulates Angiopoietin-2-dependent angiogenesis. Significance: This study presents new data regarding the regulation of proinflammatory angiogenesis.

show abstract

“…Pretreatment with gp91phox ds-tat decreased coimmunoprecipitation of p67phox with gp91phox, confirming inhibition of lung NOX2 activation with the peptide inhibitor. Although the mechanism and specificity of gp91phox ds-tat has been elucidated in vitro, these original data validate its function in vivo (31,53). Consistent with the inhibition of lung NOX2 assembly by gp91phox ds-tat, sepsisinduced cytokine and ICAM-1 expression were attenuated in mice treated with the peptide inhibitor.…”

Section: Original Researchmentioning

confidence: 86%

“…To investigate the therapeutic potential of NOX2 activity modulation in sepsisinduced lung inflammation, we tested intraperitoneal gp91phox ds-tat (NOX2-I, 10 mg/kg), a synthetic peptide that binds to gp91phox and inhibits NOX2 assembly in our model (31). First, we examined the assembly of NOX2 complex in the lung by immunoprecipitating gp91phox and probing for the cytosolic subunit p67phox.…”

Section: Effect Of Nox2 Ds-tat On Lps-induced Lung Inflammation and Tmentioning

confidence: 99%

“…To test the potential therapeutic benefits of NOX2 inhibition on sepsisinduced lung inflammation, we performed experiments with gp91phox ds-tat, a cellpermeable peptide that inhibits NOX2 activation by disrupting assembly of the active NOX2 complex (31,52). Data showing coimmunoprecipitation of p67phox with gp91phox 6 hours after systemic LPS demonstrate that an active NOX2 complex is assembled in the lung during sepsis.…”

Section: Original Researchmentioning

confidence: 99%

See 1 more Smart Citation

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Buonfiglio

Bagegni

Borcherding

et al. 2016

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsisinduced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2 1/1 and NOX2 2/2 mice were injected with intraperitoneal LPS to induce sepsis. Lung inflammation and canonical TLR signaling were assessed 24 hours after LPS. Alveolar development was examined in 15-day-old mice after LPS on Day 6. The in vivo efficacy of a NOX2 inhibitor (NOX2-I) on NOX2 complex assembly and sepsis-induced lung inflammation were examined. Lung cytokine expression and neutrophil influx induced with sepsis in NOX2 1/1 mice was decreased by .50% in NOX2 2/2 mice. LPS-induced TLR4 signaling evident by inhibitor of NF-kB kinase-b and mitogen-activated protein kinase phosphorylation, and nuclear factor-kB/AP-1 translocation were attenuated in NOX2 2/2 mice. LPS increased matrix metalloproteinase 9 while decreasing elastin and keratinocyte growth factor levels in NOX21/1 mice. An LPS-induced increase in matrix metalloproteinase 9 and decrease in fibroblast growth factor 7 and elastin were not evident in NOX22/2 mice. An LPS-induced reduction in radial alveolar counts and increased mean linear intercepts were attenuated in NOX2 2/2 mice. LPS-induced NOX2 assembly evident by p67phox/gp91phox coimmunoprecipitation was disrupted with NOX2-I. NOX2-I also mitigated LPS-induced cytokine expression, TLR pathway signaling, and alveolar simplification. In a mouse model of neonatal sepsis, NOX2 regulates proinflammatory TLR signaling and alveolar remodeling induced by a single dose of LPS. Our results provide mechanistic insight into the regulation of sepsis-induced alveolar remodeling in the developing lung.Keywords: nicotinamide adenine dinucleotide phosphate oxidase; sepsis; Toll-like receptor signaling; neonatal lung injury; bronchopulmonary dysplasia Postnatal inflammation and tissue injury in the developing lung contribute to the disrupted alveolar development observed in premature infants with bronchopulmonary dysplasia (BPD) (1, 2). Risk factors associated with BPD, such as hyperoxia, barotrauma, and sepsis, trigger the production of reactive oxygen species (ROS) in the premature lung, which contributes to lung inflammation and matrix degradation (3-5). Multiple investigators have shown that markers of oxidant-mediated lung injury, such as 8-Oxo-29-deoxyguanosine, oxidized surfactant phospholipids, F2-isoprostanes, and nitrotyrosine, are elevated in the bronchoalveolar lavage, serum, or urine of premature infants who subsequently develop BPD (4-7). Therapies to mitigate oxidant stress, such as recombinant superoxide dismutase and vitamin A, have been used in premature infants to decrease BPD, with limited succes...

show abstract

The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

Abstract: Significance: Numerous studies in animal models and human subjects corroborate that elevated levels of reactive oxygen species (ROS) play a pivotal role in the progression of multiple diseases. As a major source of ROS in many organ systems, the NADPH oxidase (Nox)

Cited by 74 publications

References 175 publications

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Contact Info

Product

Resources

About