scholarly journals Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia

2021 ◽  
Author(s):  
Halina Leung ◽  
Jose Perdomo ◽  
Zohra Ahmadi ◽  
Feng Yan ◽  
Steven E. McKenzie ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Ros Production ◽  
Oxygen Species ◽  
Fresh Blood ◽  
Antithrombotic Treatment ◽  
Heparin Induced Thrombocytopenia ◽  
Activated Neutrophils ◽  
Thrombotic Complications

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and NADPH oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant NETs and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis and thrombosis using human blood. Inhibition of NOX2 with diphenyleneiodonium chloride or GSK2795039 abrogated HIT-induced thrombi in vivo using FcγRIIa+/hPF4+ transgenic mice. Thrombocytopenia in mice remained unaffected by ROS inhibition. Increased ROS production in activated neutrophils were also confirmed using fresh blood from patients with active HIT. Our findings show that ROS and NOX2 play a crucial role in NETosis and thrombosis in HIT. This enhances our understanding of the processes driving thrombosis in HIT and identifies NOX2 as a potential new therapeutic target for antithrombotic treatment for HIT.

scholarly journals Apocynin: Molecular Aptitudes

2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
J. Stefanska ◽  
R. Pawliczak
Keyword(s):  
Nadph Oxidase ◽  
Inflammatory Diseases ◽  
Experimental Models ◽  
Ros Production ◽  
Oxygen Species ◽  
Naturally Occurring ◽  
Activated Neutrophils ◽  
Anti Inflammatory ◽  
Insight Into

Apocynin is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of NADPH-oxidase. It can decrease the production of superoxide (O2−) from activated neutrophils and macrophages while the ability of phagocytosis remains unaffected. The anti-inflammatory activity of apocynin has been demonstrated in a variety of cell and animal models of inflammation. Apocynin, after metabolic conversion, inhibits the assembly of NADPH-oxidase that is responsible for reactive oxygen species (ROS) production. It is, therefore, extensively used to reveal the role of this enzyme in cell and experimental models. Although some of the ROS serve as signaling molecules in the cells, excessive production is damaging and has been implicated to play an important role in the progression of many disease processes. This is why in many studies apocynin presents a promising potential treatment for some disorders; however, its utility with inflammatory diseases remains to be determined. Since its mode of action is not well defined, we tried to get a more precise insight into the mechanisms by which apocynin exerts its activity. Considering the anti-inflammatory activities of apocynin, we may conclude that this compound definitely deserves further study.

scholarly journals Effect of Staurosporine in the Morphology and Viability of Cerebellar Astrocytes: Role of Reactive Oxygen Species and NADPH Oxidase

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Mauricio Olguín-Albuerne ◽  
Guadalupe Domínguez ◽  
Julio Morán
Keyword(s):  
Cell Death ◽  
Nadph Oxidase ◽  
Morphological Changes ◽  
Critical Factor ◽  
Cytoskeletal Proteins ◽  
Ros Production ◽  
Oxygen Species ◽  
Morphological Alterations ◽  
Cerebellar Astrocytes

Cell death implies morphological changes that may contribute to the progression of this process. In astrocytes, the mechanisms involving the cytoskeletal changes during cell death are not well explored. Although NADPH oxidase (NOX) has been described as being a critical factor in the production of ROS, not much information is available about the participation of NOX-derived ROS in the cell death of astrocytes and their role in the alterations of the cytoskeleton during the death of astrocytes. In this study, we have evaluated the participation of ROS in the death of cultured cerebellar astrocytes using staurosporine (St) as death inductor. We found that astrocytes express NOX1, NOX2, and NOX4. Also, St induced an early ROS production and NOX activation that participate in the death of astrocytes. These findings suggest that ROS produced by St is generated through NOX1 and NOX4. Finally, we showed that the reorganization of tubulin and actin induced by St is ROS independent and that St did not change the level of expression of these cytoskeletal proteins. We conclude that ROS produced by a NOX is required for cell death in astrocytes, but not for the morphological alterations induced by St.

scholarly journals C-junInhibits Mammary Apoptosis In Vivo

2010 ◽  
Vol 21 (23) ◽  
pp. 4264-4274 ◽  
Author(s):  
Sanjay Katiyar ◽  
Mathew C. Casimiro ◽  
Luis Dettin ◽  
Xiaoming Ju ◽  
Erwin F. Wagner ◽  
...  
Keyword(s):  
Germ Line ◽  
Mammary Epithelial ◽  
Conditional Knockout ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Cellular Apoptosis ◽  
Laser Capture

c-jun, which is overexpressed in a number of human cancers encodes a critical component of the AP-1 complex. c-jun has been shown to either induce or inhibit cellular apoptosis. Germ line deletion of both c-jun alleles is embryonically lethal. To determine the role of the endogenous c-jun gene in apoptosis, we performed mammary epithelial cell–targeted somatic deletion using floxed c-jun (c-junf/f) conditional knockout mice. Laser capture microdissection demonstrated endogenous c-jun inhibits expression of apoptosis inducing genes and reactive oxygen species (ROS)-reducing genes (MnSOD, catalase). ROS have been implicated in apoptosis and undergo enzymatic elimination via MnSOD and CuZnSOD with further detoxification via catalase. c-jun–mediated survival was in part dependent on ROS production. c-jun–mediated repression of MnSOD and catalase occurred via mitochondrial complex I and NOX I. Collectively, these studies define a pivotal role of endogenous c-jun in promoting cell survival via maintaining mitochondrial integrity and expression of the key regulators of ROS production.

scholarly journals The role of reactive oxygen species in the immunity induced by nano-pulse stimulation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siqi Guo ◽  
Niculina I. Burcus ◽  
Megan Scott ◽  
Yu Jing ◽  
Iurii Semenov
Keyword(s):  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Ros Scavengers ◽  
Pulse Stimulation

AbstractReactive oxygen species (ROS) are byproducts of tumor cells treated with Nano-Pulse Stimulation (NPS). Recently, ROS have been suggested as a contributing factor in immunogenic cell death and T cell-mediated immunity. This research further investigated the role of NPS induced ROS in antitumor immunity. ROS production in 4T1-luc breast cancer cells was characterized using three detection reagents, namely, Amplex Red, MitoSox Red, and Dihydroethidium. The efficiency of ROS quenching was evaluated in the presence or absence of ROS scavengers and/or antioxidants. The immunogenicity of NPS treated tumor cells was assessed by ex vivo dendritic cell activation, in vivo vaccination assay and in situ vaccination with NPS tumor ablation. We found that NPS treatment enhanced the immunogenicity of 4T1-luc mouse mammary tumor, resulted in a potent in situ vaccination protection and induced long-term T cell immunity. ROS production derived from NPS treated breast cancer cells was an electric pulse dose-dependent phenomenon. Noticeably, the dynamic pattern of hydrogen peroxide production was different from that of superoxide production. Interestingly, regardless of NPS treatment, different ROS scavengers could either block or promote ROS production and stimulate or inhibit tumor cell growth. The activation of dendritic cells was not influenced by blocking ROS generation. The results from in vivo vaccination with NPS treated cancer cells suggests that ROS generation was not a prerequisite for immune protection.

scholarly journals The Role of Reactive Oxygen Species in the Immunity Induced by Nano-Pulse Stimulation

2021 ◽  
Author(s):  
Siqi Guo ◽  
Niculina I. Burcus ◽  
Megan Scott ◽  
Yu Jing ◽  
Iurii Semenov
Keyword(s):  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Ros Scavengers ◽  
Pulse Stimulation

Abstract Reactive oxygen species (ROS) are byproducts of tumor cells treated with Nano-Pulse Stimulation (NPS). Recently, ROS have been suggested as a contributing factor in immunogenic cell death and T cell-mediated immunity. This research further investigated the role of NPS induced ROS in antitumor immunity. ROS production in 4T1-luc breast cancer cells was characterized using three detection reagents, namely, Amplex Red, MitoSox Red, and Dihydroethidium. The efficiency of ROS quenching was evaluated in the presence or absence of ROS scavengers and/or antioxidants. The immunogenicity of NPS treated tumor cells was assessed by ex vivo dendritic cell activation, in vivo vaccination assay and in situ vaccination with NPS tumor ablation. We found that NPS treatment enhanced the immunogenicity of 4T1-luc mouse mammary tumor, resulted in a potent in situ vaccination protection and induced long-term T cell immunity. ROS production derived from NPS treated breast cancer cells was an electric pulse dose-dependent phenomenon. Noticeably, the dynamic pattern of hydrogen peroxide production was different from that of superoxide production. Interestingly, regardless of NPS treatment, different ROS scavengers could either block or promote ROS production and stimulate or inhibit tumor cell growth. The activation of dendritic cells was not influenced by blocking ROS generation. The results from in vivo vaccination with NPS treated cancer cells suggests that ROS generation was not a prerequisite for immune protection.

scholarly journals Multifunctional Role of Chitosan Edible Coatings on Antioxidant Systems in Fruit Crops: A Review

2021 ◽  
Vol 22 (5) ◽  
pp. 2633
Author(s):  
Giuseppina Adiletta ◽  
Marisa Di Matteo ◽  
Milena Petriccione
Keyword(s):  
State Of The Art ◽  
Antioxidant Systems ◽  
Edible Coatings ◽  
Ros Production ◽  
Oxygen Species ◽  
Fruit Crops ◽  
Oxidative Damages ◽  
Film Forming ◽  
Anti Oxidant

Chitosan-based edible coatings represent an eco-friendly and biologically safe preservative tool to reduce qualitative decay of fresh and ready-to-eat fruits during post-harvest life due to their lack of toxicity, biodegradability, film-forming properties, and antimicrobial actions. Chitosan-based coatings modulate or control oxidative stress maintaining in different manner the appropriate balance of reactive oxygen species (ROS) in fruit cells, by the interplay of pathways and enzymes involved in ROS production and the scavenging mechanisms which essentially constitute the basic ROS cycle. This review is carried out with the aim to provide comprehensive and updated over-view of the state of the art related to the effects of chitosan-based edible coatings on anti-oxidant systems, enzymatic and non-enzymatic, evaluating the induced oxidative damages during storage in whole and ready-to-eat fruits. All these aspects are broadly reviewed in this review, with particular emphasis on the literature published during the last five years.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Toshihiro Ichiki ◽  
Kotaro Takeda ◽  
Akira Takeshita
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Crucial Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Stimulation Of

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

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