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Jan Stolk - One of the best experts 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...

  • characteristics of the inhibition of nadph oxidase activation in neutrophils by Apocynin a methoxy substituted catechol
    American Journal of Respiratory Cell and Molecular Biology, 1994
    Co-Authors: Jan Stolk, T J N Hiltermann, J H Dijkman, A J Verhoeven
    Abstract:

    Phagocytes are able to generate reactive oxygen species by an activatable NADPH oxidase system. We investigated the inhibition of NADPH oxidase activation by a methoxy-substituted catechol, Apocynin. Oxygen uptake by neutrophils incubated with 300 microM Apocynin was completely inhibited at 7 min after addition of serum-treated zymosan (STZ), with a lagtime of inhibition of 2 to 3 min. The lagtime of effect of Apocynin in neutrophils relatively deficient of myeloperoxidase was about 50% longer when compared with normal cells. Inhibition of the STZ-induced respiratory burst by Apocynin was also observed in human eosinophils but not in human alveolar macrophages. Immunoblots of neutrophil membranes, isolated at 2 and 7 min after STZ stimulation of neutrophils, demonstrated translocation of the cytosolic oxidase components p47-phox and p67-phox to the membrane fraction. Translocation at 7 min after STZ stimulation was markedly reduced when the neutrophils had been incubated with 300 microM Apocynin, but tran...

Ralf P Brandes - One of the best experts 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 - One of the best experts 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, Yashpal S Chhonker, Veenu Bala, Yarra Durga Prasad, Telaprolu K Chaitanya, V L Sharma
    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, Yashpal S Chhonker, Veenu Bala, Yarra Durga Prasad, Telaprolu K Chaitanya, V L Sharma, 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.

Stanislava Vrankova - One of the best experts on this subject based on the ideXlab platform.

  • effect of chronic Apocynin treatment on nitric oxide and reactive oxygen species production in borderline and spontaneous hypertension
    Pharmacological Reports, 2009
    Co-Authors: Olga Pechanova, L Jendekova, Stanislava Vrankova
    Abstract:

    Abstract The purpose of this study was to investigate the effect of NAD(P)H oxidase inhibitor – Apocynin (4-hydroxy-3-methoxyacetophenone) on the increase of systolic blood pressure (SBP) in borderline (BHR) and spontaneously hypertensive rats (SHR). Young 6-week-old male BHR (offspring of SHR dams andWistar Kyoto sires) and SHR were treated with Apocynin (30 mg/kg/day) for six weeks. SBP was measured by tail-cuff plethysmography. Nitric oxide synthase (NOS) activity was determined in the left ventricle and aorta. Protein expression of nuclear factor kappa B (NF-κB) and NAD(P)H oxidase subunits p67phox and p22phox as well as concentration of cGMPwere determined for the left ventricle. Apocynin significantly decreased SBP in all groups investigated. Administration of Apocynin had no effect on NOS activity in either tissue studied. However, Apocynin decreased protein expression of NF-κB (p65) and NAD(P)H oxidase subunit p22phox in both hypertensive groups and p67phox subunit in the SHR group. Moreover, Apocynin was able to prevent a decrease in cGMP concentration in the left ventricle of both hypertensive groups. In conclusion, our study demonstrated that Apocynin treatment partially prevented SBP rise in borderline and spontaneously hypertensive rats, yet without increasing activity of NOS in the left ventricle and aorta. However, Apocynin was able to decrease production of reactive oxygen species in hypertensive rats; thus preventing the decrease in cGMP formation.

Bert A. 't Hart - One of the best experts on this subject based on the ideXlab platform.

  • oral treatment with the nadph oxidase antagonist Apocynin mitigates clinical and pathological features of parkinsonism in the mptp marmoset model
    Journal of Neuroimmune Pharmacology, 2013
    Co-Authors: Bert A. 't Hart, Ingrid H C H M Philippens, Jacqueline Wubben, Bente Finsen
    Abstract:

    This study evaluates the therapeutic efficacy of the NADPH oxidase inhibitor Apocynin, isolated as principal bioactive component from the medicinal plant Picrorhiza kurroa, in a marmoset MPTP model of Parkinson’s disease (PD). The methoxy-substituted catechol Apocynin has a similar structure as homovanillic acid (HVA), a metabolite of dopamine (DA). Apocynin acquires its selective inhibitory capacity of the reactive oxygen species generating NADPH oxidase via metabolic activation by myeloperoxidase (MPO). As MPO is upregulated in activated brain microglia cells of PD patients and in MPTP animal models, the conditions for metabolic activation of Apocynin and inhibition of microglia NADPH oxidase are in place. Marmoset monkeys received oral Apocynin (100 mg/kg; p.o.) (n = 5) or Gum Arabica (controls; n = 5) three times daily until the end of the study, starting 1 week before PD induction with MPTP (1 mg/kg s.c. for 8 days). Parkinsonian symptoms, motor function, home-cage activity and body weight were monitored to assess the disease development and severity. Post-mortem numbers of the tyrosine hydroxylase expressing DA neurons in the substantia nigra were counted. During the MPTP injections, Apocynin limited the body weight loss and relieved parkinsonian symptoms compared to controls (Linear regression, P < 0.05) indicating a reduction of disease progression. During the last test week, Apocynin also improved the hand-eye coordination performance compared with vehicle treatment (resp. 39.3 ± 4.5 % and 17.7 ± 6.7 %; P = 0.048) and improved the home cage activity with 32 % (P = 0.029), indicating anti-Parkinson efficacy. Apocynin also increased the number of surviving DA neurons in MPTP-treated marmosets with 8.5 % (P = 0.059), indicating a tendency towards a neuroprotective efficacy. In conclusion, compensation for the loss of DA and its metabolite HVA by Apocynin mitigates the PD progression and limits the parkinsonian signs and motor-function deterioration.

  • Effect of Apocynin on the induction of ulcerative lesions in rat skin injected with tubercle bacteria.
    International Journal of Immunopharmacology, 1992
    Co-Authors: Bert A. 't Hart, Jan G.r. Elferink, Peter H. Nibbering
    Abstract:

    Abstract Apocynin is an effective and selective inhibitor of the neutrophil oxidative burst in vitro . Other neutrophil functions, tested in vitro , such as chemotaxis, exocytosis, phagocytosis and intracellular killing of bacteria are unaffected by Apocynin. These properties make Apocynin a potential anti-inflammatory agent in vivo . This was tested in WAG/Rij rats, injected intracutaneously with tubercle bacteria in oil (complete Freund's adjuvant). We show here that continuous administration of Apocynin via the drinking water prevents the formation of ulcerative lesions in the inflamed skin. No effects on humoral and cellular immunity were observed after treatment with Apocynin (between 1 and 100 μg/ml drinking water) measuring serum antibodies and delayed-type hypersensitivity, respectively.

  • effects of Apocynin a drug isolated from the roots of picrorhiza kurroa on arachidonic acid metabolism
    FEBS Letters, 1992
    Co-Authors: Ferdi Engels, Bert A. 't Hart, Bastien F Renirie, R P Labadie, Frans P Nijkamp
    Abstract:

    Apocynin is a constituent of root extracts of the medicinal herb Picrorhiza kurroa and has been shown to possess anti-inflammatory properties. We investigated the effects of Apocynin on the production of arachidonic acid-derived inflammatory mediators by guinea pig pulmonary macrophages. Apocynin concentration-dependently inhibited the formation of thromboxane A2, whereas the release of prostaglandins E2 and F2α was stimulated. Apocynin potently inhibited arachidonic acid-induced aggregation of bovine platelets, possibly through inhibition of thromboxane formation. The present results suggest that Apocynin might, beside its therapeutic effects in inflammatory conditions when given in a root extract of P. kurroa, also be a valuable tool in the development of new anti-inflammatory or anti-thrombic drugs.

  • antiarthritic activity of the newly developed neutrophil oxidative burst antagonist Apocynin
    Free Radical Biology and Medicine, 1990
    Co-Authors: Bert A. 't Hart, J M Simons, Knaanshanzer Shoshan, N.p.m. Bakker, Rudi P. Labadie
    Abstract:

    Abstract The plant-phenol 4-hydroxy-3-methoxyacetophenone (trivial name Apocynin) is a strong inhibitor of neutrophil superoxide anion (O2−) release in vitro. In vitro the inhibitory effect of Apocynin is restricted to cells with the capacity to release peroxidase and reactive oxygen species (ROS). Peroxidase deficient cells are insensitive to Apocynin. In the present study the antinflammatory activity of Apocynin in the drinking water starting at the onset of joint-swelling and terminating 14 days later, at the time when joint swelling in the control group was maximal. Apocynin-treated animals had a normal plasma level of collagen-specific antibodies, but showed a significant reduction of the joint swelling. Also the plasma IL-6 level in Apocynin-treated animals was substantially lower than in control animals. No flare-up of joint swelling after termination of the treatment was observed in the Apocynin-treated groups.