scholarly journals NOX Inhibitors: From Bench to Naxibs to Bedside

2020 ◽  
Author(s):  
Mahmoud H. Elbatreek ◽  
Hermann Mucke ◽  
Harald H. H. W. Schmidt
Keyword(s):  
Nox Inhibitors

Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors

2016 ◽  
Vol 24 (18) ◽  
pp. 4144-4151 ◽  
Author(s):  
Yun Soo Bae ◽  
Sun Choi ◽  
Jung Jae Park ◽  
Jung Hee Joo ◽  
Minghua Cui ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Biological Evaluation ◽  
Nox Inhibitors ◽  
Synthesis And Biological Evaluation

scholarly journals VAS2870 Inhibits Histamine-Induced Calcium Signaling and vWF Secretion in Human Umbilical Vein Endothelial Cells

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 196 ◽  
Author(s):  
Pavel Avdonin ◽  
Elena Rybakova ◽  
Piotr Avdonin ◽  
Sergei Trufanov ◽  
Galina Mironova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Calcium Concentration ◽  
Umbilical Vein ◽  
Rat Aorta ◽  
Human Umbilical Vein ◽  
Nox Inhibitors ◽  
Umbilical Vein Endothelial Cells ◽  
Von Willebrand ◽  
Willebrand Factor

In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([Ca2+]i) and the secretion of von Willebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs) and on relaxation of rat aorta in response to histamine. At 10 μM concentration, VAS2870 suppressed the [Ca2+]i rise induced by histamine. Inhibition was not competitive, with IC50 3.64 and 3.22 μM at 1 and 100 μM concentrations of histamine, respectively. There was no inhibition of [Ca2+]i elevation by VAS2870 in HUVECs in response to the agonist of type 1 protease-activated receptor SFLLRN. VAS2870 attenuated histamine-induced secretion of vWF and did not inhibit basal secretion. VAS2870 did not change the degree of histamine-induced relaxation of rat aortic rings constricted by norepinephrine. We suggest that NOX inhibitors might be used as a tool for preventing thrombosis induced by histamine release from mast cells without affecting vasorelaxation.

scholarly journals High-Throughput Screening of NOX Inhibitors

2019 ◽  
pp. 429-446 ◽  
Author(s):  
Jacek Zielonka ◽  
Monika Zielonka ◽  
Gang Cheng ◽  
Micael Hardy ◽  
Balaraman Kalyanaraman
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Nox Inhibitors

NOX Inhibitors as a Therapeutic Strategy for Stroke and Neurodegenerative Disease

2012 ◽  
Vol 13 (2) ◽  
pp. 199-206 ◽  
Author(s):  
Belinda Cairns ◽  
Jong Youl Kim ◽  
Xian Nan Tang ◽  
Midori A. Yenari
Keyword(s):  
Neurodegenerative Disease ◽  
Therapeutic Strategy ◽  
Nox Inhibitors

scholarly journals The role of NOX inhibitors in neurodegenerative diseases

IBRO Reports ◽  
2019 ◽  
Vol 7 ◽  
pp. 59-69 ◽  
Author(s):  
Sumit Barua ◽  
Jong Youl Kim ◽  
Midori A. Yenari ◽  
Jong Eun Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Nox Inhibitors

Small-Molecule NOX Inhibitors: ROS-Generating NADPH Oxidases as Therapeutic Targets

2009 ◽  
Vol 11 (10) ◽  
pp. 2535-2552 ◽  
Author(s):  
Vincent Jaquet ◽  
Leonardo Scapozza ◽  
Robert A. Clark ◽  
Karl-Heinz Krause ◽  
J. David Lambeth
Keyword(s):  
Small Molecule ◽  
Therapeutic Targets ◽  
Nadph Oxidases ◽  
Nox Inhibitors

scholarly journals P03.27 Role of NOX2 for hypoxia-induced chemoresistance in acute myeloid leukemia

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A33.2-A34
Author(s):  
S Paul ◽  
H Grauers Wiktorin ◽  
R Kiffin ◽  
K Hellstrand ◽  
A Martner
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Intellectual Property ◽  
Stock Options ◽  
Myeloid Leukemia ◽  
Oxygen Sensors ◽  
Hypoxic Environment ◽  
Nox Inhibitors ◽  
Acute Myeloid

BackgroundRelapse of acute myeloid leukemia (AML) may arise from residual chemoresistant leukemic cells. A hypoxic tumor microenvironment, such as the bone marrow, is known to enhance chemoresistance in various forms of cancer, including AML. Hypoxia inducible factor 1 alpha (HIF-1α) is an important mediator of cellular adaptation to hypoxia. HIF-1α is a constitutively expressed transcription factor that is rapidly degraded under normoxic conditions after hydroxylation by oxygen sensors, such as the HIF prolyl hydroxylases (PHDs). However, under hypoxic conditions the oxygen sensors lose the ability to induce the degradation of HIF-1α resulting in its stabilization and translocation to the nucleolus where it induces the transcription of genes associated with glucose metabolism, angiogenesis, and cell survival. This may result in proliferation of malignant cells, impaired tumor cell differentiation and chemoresistance. Reactive oxygen species (ROS) have been shown to inhibit PHDs and may thereby stabilize HIF-1α, and may thus contribute to chemoresistance. AML cells may generate ROS via the myeloid NADPH oxidase NOX2. We therefore hypothesized that NOX inhibitors would decrease chemoresistance in a hypoxic environment.Materials and MethodsThe wild type (WT) AML cell line PLB-985 and its NOX2 knocked out (KO) counterpart were cultured for five days in hypoxia (1% oxygen) or normoxia (21% oxygen) in the presence or absence of the NOX inhibitors histamine dihydrochloride (HDC), diphenyleneiodonium (DPI) and GSK2795039. Thereafter cells were exposed to the chemotherapeutic agent daunorubicin for 48 hours (in hypoxia or normoxia) and cell death was determined using the XTT assay. Stabilization of HIF-1α was measured either by western blot or flow cytometry. Differentiation of cells was quantified by measuring the expression of CD14 and CD11b by flow cytometry.ResultsHypoxia reduced the sensitivity of WT PLB-985 cells to daunorubicin induced cell death (P < 0.05, n=4) whereas NOX2 KO cells were equally sensitive to daunorubicin in hypoxia and normoxia (P > 0.5, n=4). Furthermore, NOX2 KO AML cells displayed increased sensitivity to daunorubicin induced killing compared with PLB WT cells in a hypoxic environment (P < 0.05, n=4). Preliminary results show that pharmacological NOX inhibition using DPI enhanced the sensitivity of WT AML cells to daunorubicin induced killing. These results suggests that functional NOX2 contributes to chemoresistance in a hypoxic environment. As expected, hypoxia stabilized the expression of HIF-1α in AML cells. Preliminary results suggest that HIF-1α expression was reduced in the presence of NOX inhibitors.ConclusionsGenetic deletion or pharmacological inhibition of NOX2 sensitized AML cells to daunorubicin induced killing in hypoxic environments. NOX2 may thus be a target for overcoming chemoresistance in AML cells in the hypoxic bone marrow environment.SupportThis work was supported by Assar Gabrielsson’s Foundation( FB19-64) and other grants used by the research group.Disclosure InformationS. Paul: None. H. Grauers Wiktorin: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Patent. R. Kiffin: None. K. Hellstrand: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Patent. A. Martner: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Patent.

Synergistic inhibition of platelet function by NADPH oxidase inhibitors and clopidogrel

2021 ◽  
Vol 7 (2) ◽  
pp. 65-69
Author(s):  
ZETTY NADIA MOHD ZAIN
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Human Platelets ◽  
Calcium Mobilization ◽  
P2y12 Receptor ◽  
Activation Markers ◽  
Nadph Oxidase Activity ◽  
Nox Inhibitors ◽  
Ros Formation ◽  
Camp Levels

Previous studies have shown platelets play an important role in prothrombotic complications due to several factors such as hyperglycemia, oxidative stress, and hypercholesterolemia, which affected platelets reactivity. Platelets activation involves ADP stimulation via P2Y12 receptor, whereas reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide (H2O2) produced by NADPH oxidase (Nox) act as the second messenger, which involved in platelets activation and may contribute to thrombus formation. The aim of the present study was to investigate the influence of Nox on the purinergic receptor (P2Y12 receptor) in activation of human platelets function stimulated by platelets agonist. This research explored the effects of Nox inhibitors and clopidogrel either alone or in combination, on various agonist-stimulated human platelets, including platelets aggregation and adhesion measured by modified LTA, expression of platelets activation markers, and calcium mobilization using flow cytometry, and ROS formation, NADPH oxidase activity, as well as cAMP levels by chemiluminescence assay. Taken together, findings from these experiments suggest that the combination of clopidogrel and Nox inhibitors synergistically reduced platelets aggregation, platelets adhesion, and expression of platelets activation marker during late activation, ROS formation, NADPH oxidase activity, calcium mobilization and increased cAMP levels in vitro. This combination showed that P2Y12receptor reactivity was influenced by the activation of NADPH oxidase. Thus, these data demonstrated a potential combination therapy to reduce the risk of thrombosis formation.  

Platelet NOX, a novel target for anti-thrombotic treatment

2014 ◽  
Vol 111 (05) ◽  
pp. 817-823 ◽  
Author(s):  
Pasquale Pignatelli ◽  
Francesco Violi
Keyword(s):  
Platelet Activation ◽  
Platelet Adhesion ◽  
Second Messengers ◽  
Catalytic Core ◽  
Thrombotic Risk ◽  
Nox Inhibitors ◽  
Ros Formation ◽  
Reactive Oxidant ◽  
Novel Target ◽  
Specific Inhibitors

SummaryThere is a growing body of evidence to suggest that reactive oxidant species (ROS) including O2 −, OH− or H2O2 act as second messengers to activate platelets via 1) calcium mobilisation, 2) nitric oxide (NO) inac-tivation, and 3) interaction with arachidonic to give formation of isoprostanes. Among the enzymes generating ROS formation NOX2, the catalytic core of NADPH oxidase (NOX), plays a prominent role as shown by the almost absent ROS production by platelets taken from patients with hereditary deficiency of NOX2. Experimental and clinical studies provided evidence that NOX2 is implicated in platelet activation. Thus, impaired platelet activation has been detected in patients with NOX2 hereditary deficiency. Similarly, normal platelets added with NOX2 specific inhibitors disclosed impaired platelet activation along with ROS down-regulation. Accordingly, animals prone to atherosclerosis treated with apocynin, a NOX inhibitor, showed reduced platelet adhesion and atherosclerotic plaque. Furthermore, a significant association between NOX2 up-regulation and platelet activation has been detected in patients at athero-thrombotic risk, but a cause-effect relationship needs to be established. These findings may represent a rationale to plan interventional trials with NOX inhibitors to establish if blocking NOX2 or other NOX isoforms may represent a novel anti-platelet approach.

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