Apocynin prevents cyclooxygenase 2 expression in human monocytes through NADPH oxidase and glutathione redox-dependent mechanisms

Barbieri, Silvia Stella; Cavalca, Viviana; Eligini, Sonia; Brambilla, Marta; Caiani, Alessia; Tremoli, Elena; Colli, S.

doi:10.1016/j.freeradbiomed.2004.04.020

Cited by 147 publications

(86 citation statements)

References 47 publications

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“…6A, LTA stimulated a time-dependent increase in translocation of p47 phox from the cytosol to the membrane with a maximal response within 30 min. DPI (a flavoprotein inhibitor) and APO (an inhibitor of translocation of the oxidase subunits) have been shown to prevent p47 phox translocation to the membrane (31,32). This effect is confirmed by our observation that the LTA-stimulated p47 phox translocation was attenuated by pretreatment with DPI or APO (Fig.…”

Section: Involvement Of Nadph Oxidase and Ros Generation In Lta-inducsupporting

confidence: 86%

“…Pretreatment of human alveolar and bronchial epithelial cells with NAc attenuates the injurious effects of hydrogen peroxide (45). In addition, DPI (a flavoprotein inhibitor) and APO (an inhibitor of translocation of the oxidase subunits) have been shown to prevent p47 phox translocation to the membrane (31,32). Therefore, we further investigated the roles of NADPH oxidase and ROS associated with HO-1 expression in response to LTA in HTSMCs, using NAc, DPI, and APO.…”

Section: Discussionmentioning

confidence: 99%

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Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells

Lee¹,

Wang²,

Lee³

et al. 2008

The Journal of Immunology

132

153

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Heme oxygenase‐1 (HO‐1) is a stress‐inducible rate‐limiting enzyme in heme degradation, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Increasing reports have indicated that lipoteichoic acid (LTA) exerts as LPS as an immune system‐stimulating agent and plays a role in the pathogenesis of severe inflammatory responses induced by Gram‐positive bacteria infection. Here, we report that LTA is an inducer of HO‐1 and examine the signaling pathways by which LTA regulates HO‐1 expression in human tracheal smooth muscle cells (HTSMCs). LTA induced HO‐1 protein, mRNA expression, and HO‐1 promoter activity. LTA‐stimulated HO‐1 expression was attenuated by transfection with dominant negative mutants of Toll‐like receptor‐2 (TLR‐2) and MyD88, the NADPH oxidase inhibitor (DPI), the ROS scavenger (NAC), and transfection with siRNAs of Src and NF‐E2‐related factor 2 (Nrf2). LTA‐stimulated c‐Src phosphorylation, translocation of p47phox and Nrf2, and ROS production were attenuated by transfection with dominant negative mutants of TLR‐2, MyD88, and c‐Src, and by pretreatment with DPI or NAC. Further studies revealed that LTA induced TLR‐2, MyD88, c‐Src, and p47phox complex formation. These results demonstrated that in HTSMCs, LTA induced ROS generation through the TLR‐2/MyD88/c‐Src/NADPH oxidase pathway, in turn initiates the activation of Nrf2, and ultimately induces HO‐1 expression.

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Section: Involvement Of Nadph Oxidase and Ros Generation In Lta-inducsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells

Lee¹,

Wang²,

Lee³

et al. 2008

The Journal of Immunology

132

153

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“…7 Apocynin prevents the translocation of p47phox to Nox2 in leukocytes, monocytes, and endothelial cells. [7][8][9] The inhibitory action of the compound, however, occurs after a lag time only, as also observed in the present study. It was, therefore, assumed that apocynin has to covalently modify components of the NADPH oxidase and/or undergoes activation.…”

supporting

confidence: 89%

Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant

et al. 2008

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Abstract-A large body of literature suggest that vascular reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species. Many studies, however, relied on data obtained with the inhibitor apocynin (4Ј-hydroxy-3Јmethoxyacetophenone). Because the mode of action of apocynin, however, is elusive, we determined its mechanism of inhibition on vascular NADPH oxidases. In HEK293 cells overexpressing NADPH oxidase isoforms (Nox1, Nox2, or Nox4), apocynin failed to inhibit superoxide anion generation detected by lucigenin chemiluminescence. In contrast, apocynin interfered with the detection of reactive oxygen species in assay systems selective for hydrogen peroxide or hydroxyl radicals. Importantly, apocynin interfered directly with the detection of peroxides but not superoxide, if generated by xanthine/xanthine oxidase or nonenzymatic systems. In leukocytes, apocynin is a prodrug that is activated by myeloperoxidase, a process that results in the formation of apocynin dimers. Endothelial cells and smooth muscle cells failed to form these dimers and, therefore, are not able to activate apocynin. Dimer formation was, however, observed in Nox-overexpressing HEK293 cells when myeloperoxidase was supplemented. As a consequence, apocynin should only inhibit NADPH oxidase in leukocytes, whereas in vascular cells, the compound could act as an antioxidant. Indeed, in vascular smooth muscle cells, the activation of the redox-sensitive kinases p38-mitogen-activate protein kinase, Akt, and extracellular signal-regulated kinase 1/2 by hydrogen peroxide and by the intracellular radical generator menadione was prevented in the presence of apocynin. These observations indicate that apocynin predominantly acts as an antioxidant in endothelial cells and vascular smooth muscle cells and should not be used as an NADPH oxidase inhibitor in vascular systems. Key Words: apocynin Ⅲ NADPH oxidase Ⅲ Nox1 Ⅲ Nox4 Ⅲ leukocytes Ⅲ reactive oxygen species R eactive oxygen species (ROS) have a strong impact on vascular homeostasis. 1 ROS originate from several sources, including xanthine oxidase, cytochrome P450 monooxygenases, mitochondria, and uncoupled NO synthase, as well as from the proteins of the Nox family, the NADPH oxidases. The identification of the individual contribution of these generator systems to oxidative burden has been a focus of an impressive amount of publications. The motivation of these studies is that a site-directed ROS lowering therapy to inhibit individual generator systems should be superior to the presently unsuccessful approaches with antioxidants in preventing ROS-dependent cardiovascular diseases. 2 Although it is generally appreciated that molecular techniques involving antisense oligonucleotides, small-interfering RNA, or transgenic animals are to be preferred to pharmacological inhibitors to characterize the contribution of individual ROS generator systems, the latter studies still represent the majority of scientific contributions in the field.Different from N...

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“…The use of apocynin as an inhibitor of the activation of the NADPH oxidase complex is based on the inhibition of the assembly process, as the migration of the p47phox component to the membrane is impeded in its presence [40]. It is also known that the oxidation of apocynin plays an important role in its inhibitory effect.…”

Section: Discussionmentioning

confidence: 99%

Apocynin decreases hydrogen peroxide and nirtate concentrations in exhaled breath in healthy subjects

Stefańska

Sokołowska

Sarniak

et al. 2010

Pulmonary Pharmacology & Therapeutics

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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. M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS AbstractThe imbalance between reactive oxygen species (ROS) synthesis and antioxidants might be involved in the pathogenesis of many inflammatory diseases. NADPH oxidase, an enzyme responsible for ROS production, may represent an attractive therapeutic target to inhibit for the treatment of these diseases.Apocynin is an inhibitor of activation of NADPH oxidase complex present in the inflammatory cells.In double blind, placebo controlled, cross-over study, we investigated the effect of nebulized apocynin on ROS synthesis in 10 nonsmoking healthy volunteers. Apocynin (6 ml of 0.5 mg/ml) was administered by nebulization and its effects on H 2 O 2 , NO 2 -and NO 3 -generation were assessed after 30, 60 and 120 minutes by collecting exhaled breath condensate (EBC) samples using an EcoScreen analyzer. Additionally, respiratory parameters have been evaluated, utilizing spirometry and DLCO. We also analyzed peripheral blood differential counts and NO 2 -serum level, cough scale control and blood pressure as safety parameters. Thus, as apocynin significantly influence ROS concentration, it might have also antiinflammatory properties. As it is safe, it may have a potential to become a drug in airway inflammatory diseases treatment.

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Apocynin prevents cyclooxygenase 2 expression in human monocytes through NADPH oxidase and glutathione redox-dependent mechanisms

Cited by 147 publications

References 47 publications

Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells

Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells

Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant

Apocynin decreases hydrogen peroxide and nirtate concentrations in exhaled breath in healthy subjects

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