Pierre-Antoine Bonnet
University of Montpellier
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Featured researches published by Pierre-Antoine Bonnet.
Toxicological Sciences | 2009
Nadège Ade; Fanny Leon; Marc Pallardy; Jean-Luc Peiffer; Saadia Kerdine-Römer; Marie-Hélène Tissier; Pierre-Antoine Bonnet; Isabelle Fabre; Jean-Claude Ourlin
Electrophilicity is one of the most common features of skin contact sensitizers and is necessary for protein haptenation. The Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 -signaling pathway is dedicated to the detection of electrophilic stress in cells leading to the upregulation of genes involved in protection or neutralization of chemical reactive species. Signals provided by chemical stress could play an important role in dendritic cell activation and the aim of this work was to test whether contact sensitizers were specific activators of the Keap1/Nrf2 pathway. CD34-derived dendritic cells (CD34-DC) and the THP-1 myeloid cell line were treated by a panel of sensitizers (Ni, 1-chloro 2,4-dinitrobenzene, cinnamaldehyde, 7-hydroxycitronellal, 1,4-dihydroquinone, alpha-methyl-trans-cinnamaldehyde, 2-4-tert-(butylbenzyl)propionaldehyde or Lilial, and 1,4-phenylenediamine), irritants (sodium dodecyl sulfate, benzalkonium chloride), and a nonsensitizer molecule (chlorobenzene). Three well-known Nrf2 activators (tert-butylhydroquinone, lipoic acid, sulforaphane) were also tested. Expression of hmox1 and nqo1 was measured using real-time PCR and cellular accumulation of Nrf2 was assessed by Western blot. Our results showed an increased expression at early time points of hmox1 and nqo1 mRNAs in response to sensitizers but not to irritants. Accumulation of the Nrf2 protein was also observed only with chemical sensitizers. A significant inhibition of the expression of hmox1 and nqo1 mRNAs and CD86 expression was found in 1-chloro 2,4-dinitrobenzene-treated THP-1 cells preincubated with N-acetyl cysteine, a glutathione precursor. Altogether, these data suggested that the Keap1/Nrf2-signaling pathway was activated by electrophilic molecules including sensitizers in dendritic cells and in the THP-1 cell line. Monitoring of this pathway may provide new biomarkers (e.g., Nrf2, hmox1) for the detection of the sensitization potential of chemicals.
British Journal of Pharmacology | 1993
F. Laurent; A. Michel; Pierre-Antoine Bonnet; Jean Pierre Chapat; Maurice Boucard
1 Experiments have been performed in order to analyse the mechanism whereby SCA40, a new imidazo[1,2‐α]pyrazine derivative relaxes airway smooth muscle. 2 SCA40 (0.01–10 μm) caused a complete and concentration‐dependent relaxation of guinea‐pig isolated trachea contracted with 20 mm KCl but failed to inhibit completely the spasmogenic effects of 80 mm KCl. 3 Quinine (30 μm) antagonized the relaxant activity of SCA40 in 20 mm KCl‐contracted guinea‐pig isolated trachea. The ATP‐sensitive K+‐channel blocker, glibenclamide (3 μm), did not antagonize the relaxant activity of SCA40 in either 20 mm KCl or 1 μm carbachol‐contracted isolated trachea. 4 SCA40 (0.01–10 μm) and isoprenaline (0.1 nm‐10 μm) caused a complete and concentration‐dependent relaxation of guinea‐pig isolated trachea contracted with carbachol 1 μm. 5 The large‐conductance Ca2+‐activated K+‐channel blocker, charybdotoxin (60–180 nm), non‐competitively antagonized the relaxant activity of isoprenaline on 1 μm carbachol‐contracted trachea. The inhibition was characterized by rightward shifts of the isoprenaline concentration‐relaxation curves with depression of their maxima. 6 The relaxant activity of SCA40 in 1 μm carbachol‐contracted trachea was antagonized by charybdotoxin (60–600 nm) in an apparently competitive manner. The concentration‐relaxation curves to SCA40 were shifted to the right with no significant alteration in the maximum response. 7 It is concluded that SCA40 is a novel potassium channel opener which is a potent relaxant of guinea‐pig airway smooth muscle in vitro. The relaxant activity of SCA40 does not involve ATP‐sensitive K+‐channels but rather large‐conductance Ca2+‐activated K+‐channels or other charybdotoxin‐sensitive K+‐channels.
Bioorganic & Medicinal Chemistry | 1999
Olivier Vitse; Florence Laurent; T. M. Pocock; Veronique Benezech; Lahcen Zanik; Keith R.F. Elliott; Guy Subra; Karine Portet; Jacques Bompart; Jean Pierre Chapat; R.C. Small; Alain Michel; Pierre-Antoine Bonnet
New imidazo[1,2-a]pyrazine derivatives have been synthesized either by direct cyclization from pyrazines or by electrophilic substitutions. The presence of electron donating groups on position 8 greatly enhances the reactivity of the heterocycle towards such reactions on position 3 of the heterocycle. The activities of these derivatives in trachealis muscle relaxation and in inhibiting cyclic nucleotide phosphodiesterase (PDE) isoenzyme types III and IV have been assessed. All compounds demonstrated significantly higher relaxant potency than theophylline. All the derivatives were moderately potent in inhibiting the type IV isoenzyme of PDE but only those with a cyano group on position 2 were potent in inhibiting the type III isoenzyme.
Bioorganic & Medicinal Chemistry | 2008
Georges Moarbess; Carine Deleuze-Masquefa; Vanessa Bonnard; Stéphanie Gayraud-Paniagua; Jean-Rémi Vidal; Françoise Bressolle; Frédéric Pinguet; Pierre-Antoine Bonnet
Imidazoquinoxaline and pyrazoloquinoxaline derivatives, analogues of imiquimod, were synthesized, and their in vitro cytotoxic and pharmacodynamic activities were evaluated. In vitro cytotoxicity studies were assessed against melanoma (A375, M4Be, RPMI-7591), colon (LS174T), breast (MCF7), and lymphoma (Raji) human cancer cell lines. In vivo studies were carried out in M4Be xenografted athymic mice. EAPB0103, EAPB0201, EAPB0202, and EAPB0203 showed significant in vitro activities against A375 compared to fotemustine and imiquimod used as references. These compounds were 6-110 and 2-45 times more active than fotemustine and imiquimod, respectively. EAPB0203 bearing phenethyl as substituent at position 1 and methylamine at position 4 showed the highest activity. EAPB0203 has also a more potent cytotoxic activity than imiquimod and fotemustine in M4Be and RPMI-7591 and interesting cytotoxic activity in other tumor cell lines tested. In vivo, EAPB0203 treatment schedules caused a significant decrease in tumor size compared to vehicle control and fotemustine treatments.
Journal of Chromatography B | 2014
Pascal Gimeno; Sébastien Thomas; Claudine Bousquet; Annie-Françoise Maggio; Corinne Civade; Charlotte Brenier; Pierre-Antoine Bonnet
A GC/MS method was developed for the identification and quantification of 14 phthalates: 8 phthalates classified H360 (DBP, DEHP, BBP, DMEP, DnPP, DiPP, DPP and DiBP), 3 phthalates proposed to be forbidden in medical devices (DnOP, DiNP and DiDP) and 3 other phthalates none regulated (DMP, DCHP and DEP) which may interfere with hormone function. In order to identify and quantify other plasticizers that are commonly used in PVC medical devices such as DEHP substitute, 5 non-phthalate plasticizers (ATBC, DEHA, DEHT, TOTM, and DINCH) were included in this study. Analyses are carried out on a GC/MS system with electron impact ionization mode (EI). The separation of plasticizers is obtained on a cross-linked 5%-phenyl/95%-dimethylpolysiloxane capillary column 30m×0.25mm (i.d.)×0.25μm film thickness using a gradient temperature. Compounds quantification is performed by external calibration using an internal standard. Validation elements on standard solutions were determined using the ISO 12787 standard approach. Plasticizers are extracted from PVC medical devices using THF for dissolving the PVC part of the sample followed by precipitation of the PVC by addition of ethanol. The supernatant is injected into a GC/MS system after dilution in ethanol. Different validation elements, including extraction recoveries for all compounds or for DEHP a cross-validation of the extraction process using the European pharmacopoeia monograph 3.1.14 as reference method, are discussed. Results obtained on 61 medical devices in PVC and 12 raw materials used as plasticizers are given.
Analytica Chimica Acta | 2010
I. Storme-Paris; Hervé Rebiere; M. Matoga; Corinne Civade; Pierre-Antoine Bonnet; Marie-Hélène Tissier; P. Chaminade
This study was initiated by the laboratories and control department of the French Health Products Safety Agency (AFSSAPS) as part of the fight against the public health problem of rising counterfeit and imitation medicines. To test the discriminating ability of Near InfraRed Spectroscopy (NIRS), worse cases scenarios were first considered for the discrimination of various pharmaceutical final products containing the same Active Pharmaceutical Ingredient (API) with different excipients, such as generics of proprietary medicinal products (PMP). Two generic databases were explored: low active strength hard capsules of Fluoxetine and high strength tablets of Ciprofloxacin. Then 4 other cases involving suspicious samples, counterfeits and imitations products were treated. In all these cases, spectral differences between samples were studied, giving access to API or excipient contents information, and eventually allowing manufacturing site identification. A chemometric background is developed to explain the optimisation methodology, consisting in the choices of appropriate pretreatments, algorithms for data exploratory analyses (unsupervised Principal Component Analysis), and data classification (supervised cluster analysis, and Soft Independent Modelling of Class Analogy). Results demonstrate the high performance of NIRS, highlighting slight differences in formulations, such as 2.5% (w/w) in API strength, 1.0% (w/w) in excipient and even coating variations (<1%, w/w) with identical contents, approaching the theoretical limits of NIRS sensitivity. All the different generic formulations were correctly discriminated and foreign PMP, constituted of formulations slightly different from the calibration ones, were also all discriminated. This publication addresses the ability of NIRS to detect counterfeits and imitations and presents the NIRS as an ideal tool to master the global threat of counterfeit drugs.
British Journal of Pharmacology | 1996
Julio Cortijo; Victoria Villagrasa; C. Navarrete; C.M. Sanz; Luisa Berto; Alain Michel; Pierre-Antoine Bonnet; Esteban J. Morcillo
1 SCA40 (0.1 nM‐0.1 mM) produced concentration‐dependent suppression of the spontaneous tone of human isolated bronchus (‐log EC50 = 6.85 ± 0.09; n = 10) and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (‐log EC50 values) of SCA40 compared to other relaxants was rolipram (7.44 ± 0.12; n = 9) > SCA40 ≥ levcromakalim (6.49 ± 0.04; n = 6) > SKF94120 (5.87 ± 0.10; n = 9). 2 When tested against the activity of the isoenzymes of cyclic nucleotide phosphodiesterase (PDE) isolated from human bronchus, SCA40 proved highly potent against PDE III (‐log IC50 = 6.47 ± 0.16; n = 4). It was markedly less potent against PDE IV (4.82 ± 0.18; n = 4) and PDE V (4.32 ± 0.11; n = 4). 3 Human polymorphonuclear leukocytes (PMNs) stimulated with N‐formylmethionyl‐leucyl‐phenylalanine (FMLP) produced a concentration‐dependent superoxide anion generation and elastase release. SCA40 (1 nM‐10 μm) produced a concentration‐related inhibition of FMLP (30 nM ∼ EC50)‐induced superoxide production (‐log IC50 = 5.48 ± 0.10; n = 6) and elastase release (‐log IC50 = 5.50 ± 0.26; n = 6). Rolipram was an effective inhibitor of superoxide generation and elastase release (‐log IC50 values ∼8) while SKF94120 and levcromakalim were scarcely effective. 4 FMLP (30 nM) and thimerosal (20 μm) induced leukotriene B4 production and elevation of intracellular calcium concentration in human PMNs. The production of leukotriene B4 was inhibited by SCA40 in a concentration‐related manner (‐log IC50 = 5.94 α 0.22; n = 6) but SCA40 was less effective against the elevation of intracellular calcium. Rolipram was an effective inhibitor of leukotriene B4 synthesis (‐log IC50 ∼7) and intracellular calcium elevation (‐log IC50 ∼6) while SKF94120 and levcromakalim were scarcely effective. 5 It is concluded that SCA40 is an effective inhibitor of the inherent tone of human isolated bronchus. The bronchodilatation produced by SCA40 appears mainly related to PDE inhibition since the potency of SCA40 as a relaxant of human isolated bronchus was found to be close to its potency as inhibitor of PDE III activity isolated from human bronchus. In addition, SCA40 exhibited inhibitory effects on human PMN function stimulated by FMLP. These effects may be related to the ability of SCA40 to inhibit PDE IV from human PMNs while the contribution of PDE V inhibition is uncertain. We found no evidence of a role for levcromakalim‐sensitive plasmalemmal K+‐channels in human PMNs.
Food Additives and Contaminants Part A-chemistry Analysis Control Exposure & Risk Assessment | 2012
Hervé Rebiere; Pauline Guinot; Corinne Civade; Pierre-Antoine Bonnet; Alain Nicolas
The presence on the market of illegal products for slimming purposes or the treatment of overweight is a public health issue. These products may contain illicit chemicals in order to improve their effectiveness. Some of these weight-loss compounds are responsible for adverse events, including fatal outcomes. A general strategy for the analysis of any suspect formulation begins with a large screening for the general search of a wide range of compounds. A methodology for the qualitative and quantitative determination of 34 compounds in slimming preparations (such as dietary supplements or medicinal products) was used for the control of slimming formulations from the market, including over the Internet. The fast liquid chromatography system (ultra-high-pressure liquid chromatography) used a gradient of solvent (phosphate buffer and acetonitrile), a C18 endcapped column and a diode array detector. This system allows dual identification based on retention time and UV spectra. The analytical method is simple, fast and selective since 34 weight-loss compounds can be detected in a 15-min run time. Thus, 32 commercial slimming formulations were analysed using this method, allowing the detection and quantification of hazardous active substances: caffeine, clenbuterol, nicotinamide, phenolphthalein, rimonabant, sibutramine, didesmethylsibutramine, synephrine and yohimbine.
European Journal of Medicinal Chemistry | 2009
Carine Deleuze-Masquefa; Georges Moarbess; Sonia Khier; Nadège David; Stéphanie Gayraud-Paniagua; Françoise Bressolle; Frédéric Pinguet; Pierre-Antoine Bonnet
New imidazo[1,2-a]quinoxaline analogues have been synthesized in good yields via a bimolecular condensation of 2-imidazole carboxylic acid, followed by a coupling with ortho-fluoroaniline and subsequent substitution on the imidazole ring by Suzuki Cross-coupling reaction using microwave assistance. Antitumor activities of these derivatives were evaluated by growth inhibition of A375 cells in vitro. All compounds exhibited high activities compared to imiquimod and fotemustine used as references.
Blood | 2008
Georges Moarbess; Hiba El-Hajj; Youmna Kfoury; Marwan El-Sabban; Yves Lepelletier; Olivier Hermine; Carine Deleuze-Masquefa; Pierre-Antoine Bonnet; Ali Bazarbachi
Imiquimod is an immune response modifier currently used as a topical treatment of genital warts, basal cell carcinoma, cutaneous metastasis of malignant melanoma, and vascular tumors. We developed more efficient killers from the same family of compounds that can induce apoptosis without the prominent pro-inflammatory response associated with imiquimod. Among these new products, tk;4EAPB0203, a member of the imidazo[1,2-a]quinoxalines, exhibits an important cytotoxic activity in vitro. HTLV-I-associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using potentially achievable concentrations of EAPB0203, we demonstrate inhibition of cell proliferation, G2/M cell- cycle arrest, and induction of apoptosis in HTLV-I-transformed and HTLV-I-negative malignant T cells and fresh ATL cells, whereas normal resting or activated T lymphocytes were resistant. EAPB0203 treatment significantly down-regulated the antiapoptotic proteins c-IAP-1 and Bcl-XL and resulted in a significant loss of mitochondrial membrane potential, cytoplasmic release of cytochrome c, and caspase-dependent apoptosis. Moreover, in HTLV-I-transformed cells only, EAPB0203 treatment stabilized p21 and p53 proteins but had no effect on NF-kappaB activation. These results support a potential therapeutic role for EAPB0203 in ATL and HTLV-I-negative T-cell lymphomas, either as a systemic or topical therapy for skin lesions.
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Agence française de sécurité sanitaire des produits de santé
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View shared research outputsAgence française de sécurité sanitaire des produits de santé
View shared research outputsAgence française de sécurité sanitaire des produits de santé
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