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Apocynin

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Jan Stolk – 1st expert on this subject based on the ideXlab platform

  • effect of Apocynin on ozone induced airway hyperresponsiveness to methacholine in asthmatics
    Free Radical Biology and Medicine, 2001
    Co-Authors: Elisabeth A Peters, Jeroen T N Hiltermann, Jan Stolk

    Abstract:

    Abstract Apocynin is an inhibitor of NADPH oxidase present in inflammatory cells such as eosinophils and neutrophils. We investigated the effect of inhaled Apocynin on ozone-induced bronchial hyperresponsiveness in vivo. Seven mild atopic asthmatics participated in a placebo-controlled, cross-over study with two exposures to O 3 at 2-week intervals. Apocynin (3 ml of 0.5 mg/ml) was inhaled 2 times before and 6 times after O 3 exposure at hourly intervals. At 36 h before and 16 h after O 3 exposure, methacholine inhalation challenge tests (Mch) were performed, and PC 20 and maximal % fall from baseline (MFEV 1 ) were calculated from dose-response curves. O 3 -induced change in PC 20 (ΔPC 20 ) after placebo treatment was −1.94 ± 0.39 DD (mean ± SEM doubling dose Mch) ( p = .001) and Apocynin was −0.6 ± 0.33 DD ( p = .17). The difference between Apocynin and placebo treatment was 1.3 DD ± 0.42 ( p = .02). O 3 -induced ΔMFEV 1 was 11.9 ± 1.5% ( p = .008) during placebo inhalation and 3.85 ± 1.8% during Apocynin ( p = .47). Apocynin reduced the ΔMFEV 1 by 8.05% compared to placebo ( p = .025). We conclude that Apocynin markedly reduced O 3 -induced hyperreactivity for Mch as well as maximal airway narrowing. The results suggest that Apocynin may have a role in preventing ozone-induced exacerbations of asthma.

  • Apocynin increases glutathione synthesis and activates ap 1 in alveolar epithelial cells
    FEBS Letters, 1999
    Co-Authors: Therese S Lapperre, Jan Stolk, Luis A Jimenez, Frank Antonicelli, Ellen M Drost, Pieter S Hiemstra, William Macnee, Irfan Rahman

    Abstract:

    Apocynin (4-hydroxy-3-methoxy-acetophenone) is a potent intracellular inhibitor of superoxide anion production in neutrophils. In this study, we studied the effect of Apocynin on the regulation of the antioxidant glutathione (GSH) and activation of the transcription factor AP-1 in human alveolar epithelial cells (A549). Apocynin enhanced intracellular GSH by increasing γ-glutamylcysteine synthetase activity in A549 cells. Apocynin also increased the expression of γ-GCS heavy subunit mRNA. This was associated with increased AP-1 DNA binding as measured by the electrophoretic mobility shift assay. These data indicate that Apocynin displays antioxidant properties, in part, by increasing glutathione synthesis through activation of AP-1.

  • Apocynin improves the efficacy of secretory leukocyte protease inhibitor in experimental emphysema.
    American Journal of Respiratory and Critical Care Medicine, 1994
    Co-Authors: Jan Stolk, William Rossie, Joop H. Dijkman

    Abstract:

    Secretory leukocyte protease inhibitor (SLPI) is a potent proteinase inhibitor produced in the lung. Stimulated neutrophils at sites of inflammation can inactivate SLPI by myeloperoxidase-mediated oxidation of the methionine residue in the active site of SLPI. Apocynin is a selective inhibitor of NADPH oxidase and may therefore protect SLPI against neutrophil-mediated oxidative inactivation. The aim of the present study was to determine the effect of Apocynin on the efficacy of SLPI in preventing experimental emphysema. To investigate the effect of Apocynin on emphysema without SLPI treatment, three groups of eight hamsters each received drinking water containing Apocynin at concentrations of 2, 20, and 200 micrograms/ml, respectively. Emphysema was induced in these hamsters by intratracheal instillations of 500 micrograms of lipopolysaccharide (LPS) twice a week for 4 wk. In hamsters that received 200 micrograms/ml Apocynin, the development of emphysema was reduced by 26.2% (p = 0.01). Other Apocynin con…

Ralf P Brandes – 2nd expert on this subject based on the ideXlab platform

  • Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant. Commentary
    Hypertension, 2020
    Co-Authors: Rhian M Touyz, Sabine Heumuller, Sven Wind, Harald H H W Schmidt, Rudi Busse, Katrin Schroder, Eduardo Barbosa-sicard, Ralf P Brandes

    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 (4′-hydroxy-3’methoxyacetophenone). 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 (Noxl, 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.

  • Apocynin is not an inhibitor of vascular nadph oxidases but an antioxidant
    Hypertension, 2008
    Co-Authors: Sabine Heumuller, Sven Wind, Eduardo Barbosasicard, Harald H H W Schmidt, Rudi Busse, Katrin Schroder, Ralf P Brandes

    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 (4′-hydroxy-3′methoxyacetophenone). 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.

V L Sharma – 3rd expert on this subject based on the ideXlab platform

  • pharmacokinetic bioavailability metabolism and plasma protein binding evaluation of nadph oxidase inhibitor Apocynin using lc ms ms
    Journal of Chromatography B, 2015
    Co-Authors: Hardik Chandasana, V L Sharma, Yashpal S Chhonker, Veenu Bala, Yarra Durga Prasad, Telaprolu K Chaitanya

    Abstract:

    Abstract Apocynin is a major active constituent of Picrorhiza kurroa that exhibits potent anti-inflammatory activity by inhibiting superoxide-generating NADPH oxidase enzyme. To elucidate detailed pharmacokinetic profile of Apocynin, high-performance liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) method was developed in rat and human plasma. To the best of our knowledge, this is the first method for complete validation of Apocynin in biological matrix using LC–MS/MS. Apocynin was rapidly absorbed after oral administration at 50 mg/kg in rats and peak plasma level achieved within 5 min. Moreover, plasma levels were observed up to 48 h. The bioavailibity of Apocynin was found to be 8.3%. In vitro plasma protein binding was found to be 83.41–86.07% and 71.39–73.34% in rat and human plasma, respectively. Apocynin was found stable in gastric (pH 1.2), intestinal (pH 6.8) and physiological (pH 7.4) fluids including microsomal (rat and human) stability studies. Further, Apocynin did not convert to its dimeric form diApocynin in any of these studies. The data presented here provide crucial information about Apocynin to support its pharmacological efficacy and further development as a potential anti-inflammatory drug candidate.

  • Pharmacokinetic, bioavailability, metabolism and plasma protein binding evaluation of NADPH-oxidase inhibitor Apocynin using LC-MS/MS.
    Journal of Chromatography B, 2015
    Co-Authors: Hardik Chandasana, V L Sharma, Yashpal S Chhonker, Veenu Bala, Yarra Durga Prasad, Telaprolu K Chaitanya, Rabi S. Bhatta

    Abstract:

    Abstract Apocynin is a major active constituent of Picrorhiza kurroa that exhibits potent anti-inflammatory activity by inhibiting superoxide-generating NADPH oxidase enzyme. To elucidate detailed pharmacokinetic profile of Apocynin, high-performance liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) method was developed in rat and human plasma. To the best of our knowledge, this is the first method for complete validation of Apocynin in biological matrix using LC–MS/MS. Apocynin was rapidly absorbed after oral administration at 50 mg/kg in rats and peak plasma level achieved within 5 min. Moreover, plasma levels were observed up to 48 h. The bioavailibity of Apocynin was found to be 8.3%. In vitro plasma protein binding was found to be 83.41–86.07% and 71.39–73.34% in rat and human plasma, respectively. Apocynin was found stable in gastric (pH 1.2), intestinal (pH 6.8) and physiological (pH 7.4) fluids including microsomal (rat and human) stability studies. Further, Apocynin did not convert to its dimeric form diApocynin in any of these studies. The data presented here provide crucial information about Apocynin to support its pharmacological efficacy and further development as a potential anti-inflammatory drug candidate.