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1. Exposure to atmospheric Ag, TiO2, Ti and SiO2 engineered nanoparticles modulates gut inflammatory response and microbiota in mice

Author

Eva Guilloteau, Madjid Djouina, Ségolène Caboche, Christophe Waxin, Karine Deboudt, Delphine Beury, David Hot, Muriel Pichavant, Laurent Dubuquoy, David Launay, Cécile Vignal, Marie Choël, and Mathilde Body-Malapel

Subjects
Engineered nanoparticles, Inhalation, Inflammation, Colitis, Organoid, Mixture, Environmental pollution, TD172-193.5, Environmental sciences, GE1-350
Abstract

The development of nanotechnologies is leading to greater abundance of engineered nanoparticles (EN) in the environment, including in the atmospheric air. To date, it has been shown that the most prevalent EN found in the air are silver (Ag), titanium dioxide (TiO2), titanium (Ti), and silicon dioxide (SiO2). As the intestinal tract is increasingly recognized as a target for adverse effects induced by inhalation of air particles, the aim of this study was to assess the impact of these 4 atmospheric EN on intestinal inflammation and microbiota. We assessed the combined toxicity effects of Ag, Ti, TiO2, and SiO2 following a 28-day inhalation protocol in male and female mice. In distal and proximal colon, and in jejunum, EN mixture inhalation did not induce overt histological damage, but led to a significant modulation of inflammatory cytokine transcript abundance, including downregulation of Tnfα, Ifnγ, Il1β, Il17a, Il22, IL10, and Cxcl1 mRNA levels in male jejunum. A dysbiosis was observed in cecal microbiota of male and female mice exposed to the EN mixture, characterized by sex-dependent modulations of specific bacterial taxa, as well as sex-independent decreased abundance of the Eggerthellaceae family. Under dextran sodium sulfate-induced inflammatory conditions, exposure to the EN mixture increased the development of colitis in both male and female mice. Moreover, the direct dose-response effects of individual and mixed EN on gut organoids was studied and Ag, TiO2, Ti, SiO2, and EN mixture were found to generate specific inflammatory responses in the intestinal epithelium. These results indicate that the 4 most prevalent atmospheric EN could have the ability to disturb intestinal homeostasis through direct modulation of cytokine expression in gut epithelium, and by altering the inflammatory response and microbiota composition following inhalation.

Published
2022
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2. The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases

Author

Audrey Langlois, Madjid Djouina, P. Zerbib, Cécile Vignal, Corinne Gower-Rousseau, Christophe Waxin, Pierre Desreumaux, Ann Marie Schmidt, Eric Boulanger, Mathilde Body-Malapel, Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Inserm, Université de Lille, CHU Lille, Lille Inflammation Research International Center - U 995 [LIRIC], and Université de Lille, LillOA

Subjects
0301 basic medicine, FPS-ZM1, Inhibitor, Colon, Immunology, Receptor for Advanced Glycation End Products, Inflammation, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, RAGE (receptor), Enteritis, Endothelial activation, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Animals, Humans, Molecular Targeted Therapy, Colitis, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Mice, Knockout, business.industry, Dextran Sulfate, Pattern recognition receptor, therapeutic target, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Inflammatory Bowel Diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, RAGE, 3. Good health, Intestines, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Benzamides, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, business, Oxidative stress, 030215 immunology, Signal Transduction
Abstract

International audience; Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage(-/-) mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.

Published
2018
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3. Controlled delivery of a new broad spectrum antibacterial agent against colitis: In vitro and in vivo performance

Author

Christel Neut, Laurent Dubuquoy, Jean-François willart, Luc Dubreuil, Madjid Djouina, Florence Siepmann, M.S. Nieto-Bobadilla, Juergen Siepmann, and N. Tesse

Subjects
Male, Colon, Surface Properties, medicine.drug_class, Drug Compounding, Antibiotics, Administration, Oral, Pharmaceutical Science, Benzoates, Inflammatory bowel disease, Cinnamaldehyde, Microbiology, chemistry.chemical_compound, Drug Delivery Systems, In vivo, medicine, Animals, Colitis, Antibacterial agent, Calorimetry, Differential Scanning, Terpenes, Chemistry, General Medicine, medicine.disease, Controlled release, Anti-Bacterial Agents, Mice, Inbred C57BL, Drug Combinations, Drug Liberation, Diarrhea, Solubility, Cinnamates, medicine.symptom, Tablets, Biotechnology
Abstract

Coated pellets and mini-tablets were prepared containing a new broad spectrum antibacterial agent: CIN-102, a well-defined, synergistic blend of trans-cinnamaldehyde, trans-2-methoxycinnamaldehyde, cinnamyl acetate, linalool, β-caryophyllene, cineol and benzyl benzoate. The aim was to provide a new treatment method for colitis, especially for Inflammatory Bowel Disease (IBD) patients. Since the simple oral gavage of CIN-102 was not able to reduce the pathogenic bacteria involved in colitis (rat model), the drug was incorporated into multiparticulates. The idea was to minimize undesired drug release in the upper gastrointestinal tract and to control CIN-102 release in the colon, in order to optimize the resulting antibiotic concentration at the site of action. A particular challenge was the fact that CIN-102 is a volatile hydrophobic liquid. Pellet cores were prepared by extrusion-spheronization and coated with polymer blends, which are sensitive to colonic bacterial enzymes. Mini-tablets were prepared by direct compression. The release of the main compound of CIN-102 (cinnamaldehyde, 86.7% w/w) was monitored in vitro. Optimized coated pellets and mini-tablets were also tested in vivo: in seven-week-old, male mice suffering from dextran sodium sulfate induced colitis. Importantly, both types of multiparticulates were able: (i) to significantly reduce the number of luminal and mucosal enterobacteria in the mice (the levels of which are increased in the disease state), and (ii) to improve the clinical course of the intestinal inflammation (decrease in the percentages of mice with bloody stools and diarrhea). Thus, the proposed coated pellets and matrix mini-tablets allowing for controlled CIN-102 release show a promising potential for new treatment methods of colitis.

Published
2015
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4. Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis

Author

Nicolas Renault, Pierre Desreumaux, Jamal El Bakali, Frederique Klupsch, Alina Ghinet, Philippe Chavatte, Didier M. Lambert, Giulio G. Muccioli, Madjid Djouina, Régis Millet, Amélie Barczyk, Mathilde Body-Malapel, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), We are grateful for financial support from the Conseil régional du Nord-Pas de Calais and University of Lille 2., Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Inserm, Université de Lille, CHU Lille, Lille Neurosciences & Cognition (LilNCog) - U 1172, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Lille Inflammation Research International Center - U 995 [LIRIC], and Lille Inflammation Research International Center (LIRIC) - U995

Subjects
Agonist, Cannabinoid receptor, inflammatory bowel disease, quinolone, conformational restriction, colitis, endocannabinoid, medicine.drug_class, Chemistry, [SDV]Life Sciences [q-bio], Organic Chemistry, Pharmacology, medicine.disease, Biochemistry, Endocannabinoid system, Inflammatory bowel disease, 3. Good health, Oral administration, Drug Discovery, medicine, Cannabinoid receptor type 2, [CHIM]Chemical Sciences, Colitis, Receptor
Abstract

International audience; The CB2 cannabinoid receptor has been implicated in the regulation of intestinal inflammation. Following on from the promising activity of a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide, we developed constrained analogues based on a 2H-pyrazolo[4,3-c]quinolin-3(5H)-one scaffold, with improved affinity for the hCB2 receptor and had very high selectivity over the hCB1 receptor. Importantly, the lead of this series (26, hCB2: K i = 0.39 nM, hCB1: K i > 3000 nM) was found to protect mice against experimental colitis after oral administration.

Published
2014
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5. Switching cannabinoid response from CB(2) agonists to FAAH inhibitors

Author

Mathilde Body-Malapel, Benoît Rigo, Philippe Chavatte, Pierre Desreumaux, Madjid Djouina, Aurélien Tourteau, Régis Millet, Natascha Leleu-Chavain, Amélie Barczyk, Virginie Andrzejak, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université catholique de Lille (UCL), This work was financially supported by the ‘Conseil Régional Nord Pas De Calais’ (CPER PRIM)., and The authors thank Ms. Perrine Six and Frederique Klupsch for the LC–MS analyses, NMR and CUMA department of the Faculty of Pharmacy of the University of Lille 2 for the biophysics analyses, and the binding platform of ICPAL for the biological evaluations.

Subjects
Drug, Male, medicine.medical_treatment, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Clinical Biochemistry, IBD, Anti-Inflammatory Agents, Pharmaceutical Science, Adamantane, Pharmacology, CB(2), Biochemistry, Amidohydrolases, Receptor, Cannabinoid, CB2, 03 medical and health sciences, Mice, Structure-Activity Relationship, 0302 clinical medicine, Drug Discovery, medicine, [CHIM]Chemical Sciences, Animals, FAAH, Colitis, Enzyme Inhibitors, Molecular Biology, Cannabinoid, Acute colitis, 030304 developmental biology, media_common, 0303 health sciences, Chemistry, Cannabinoids, Organic Chemistry, Body Weight, Isoxazoles, medicine.disease, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, 030220 oncology & carcinogenesis, Molecular Medicine, lipids (amino acids, peptides, and proteins), Protein Binding
Abstract

International audience; A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.

Published
2013
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6. 3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis

Author

Virginie Andrzejak, Nicolas Renault, Lucas Lemaire, Philippe Chavatte, Madjid Djouina, Pierre Desreumaux, Didier M. Lambert, Natascha Leleu-Chavain, Giulio G. Muccioli, Amélie Lemoine, Jamal El Bakali, Régis Millet, Mathilde Body-Malapel, Benoît Rigo, Aurélien Tourteau, Roxane Mansouri, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut de médecine predictive et de recherche thérapeutique (IMPRT), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bioanalysis and pharmacology of bioactive lipids laboratory, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), Unité de Pharmacologie Cellulaire et Moléculaire [Brussels], Louvain Drug Research Institute [Bruxelles, Belgique] (LDRI), Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), This work was financially supported by the ‘Conseil Régional Nord Pas De Calais’., The authors thank Ms. Perrine Six and Frederique Klupsch for the LC–MS analyses, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), UCL - SSS/LDRI - Louvain Drug Research Institute, CHU Lille, Inserm, Université de Lille, Institut de Chimie Pharmaceutique Albert Lespagnol [ICPAL], and Lille Inflammation Research International Center - U 995 [LIRIC]

Subjects
Male, Cannabinoid receptor, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Interleukin-1beta, Anti-Inflammatory Agents, Pharmaceutical Science, Pharmacology, Biochemistry, Inflammatory bowel disease, Receptor, Cannabinoid, CB2, chemistry.chemical_compound, Mice, 0302 clinical medicine, Receptor, Cannabinoid, CB1, Drug Discovery, Cannabinoid receptor type 2, Receptor, 0303 health sciences, Chemistry, Dextran Sulfate, Anandamide, Colitis, 3. Good health, 030220 oncology & carcinogenesis, Molecular Medicine, lipids (amino acids, peptides, and proteins), HT29 Cells, Protein Binding, IBD, CB(2), 03 medical and health sciences, Structure-Activity Relationship, medicine, [CHIM]Chemical Sciences, Animals, Humans, Molecular Biology, Cannabinoid, Acute colitis, 030304 developmental biology, Cell Proliferation, Tumor Necrosis Factor-alpha, Organic Chemistry, CB2, Isoxazoles, medicine.disease, Mice, Inbred C57BL
Abstract

International audience; Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.

Published
2013
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7. Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice

Author

T-D Kanneganti, Cécile Vignal, Isabelle Frey-Wagner, Pierre Desreumaux, Frédéric Altare, Kirstin Atrott, Nicolas Esquerre, F Deknuydt, J-F Colombel, Madjid Djouina, Gerhard Rogler, G. Pineton de Chambrun, Antoine Cortot, Marie-Claire Arrieta, Christel Neut, Mathilde Body-Malapel, Division of Gastroenterology and Hepatology [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH)-University hospital of Zurich [Zurich], Hôpital Claude Huriez [Lille], CHU Lille, Ecologie comportementale (EC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), University of Zurich, Vignal, C, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Rennes (UR)-Université Claude Bernard Lyon 1 (UCBL), University of Zürich [Zürich] (UZH)-University hospital of Zurich [Zurich], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and École normale supérieure - Paris (ENS Paris)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Rennes 1 (UR1)

Subjects
Male, Lipopolysaccharide, [SDV]Life Sciences [q-bio], chemistry.chemical_compound, Mice, Intestinal mucosa, Immunology and Allergy, Intestinal Mucosa, Aluminum Compounds, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Granuloma, Interleukin, Colitis, 3. Good health, Interleukin-10, Interleukin 10, 10219 Clinic for Gastroenterology and Hepatology, 2723 Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, medicine.symptom, Inflammation Mediators, Immunology, 610 Medicine & health, Inflammation, complex mixtures, Article, Proinflammatory cytokine, Cell Line, Phosphates, medicine, Animals, Humans, 2403 Immunology, Wound Healing, business.industry, medicine.disease, Inflammatory Bowel Diseases, Disease Models, Animal, chemistry, Gene Expression Regulation, Trinitrobenzenesulfonic Acid, 13. Climate action, Chronic Disease, business, Wound healing, Aluminum
Abstract

The increasing incidence of inflammatory bowel diseases (IBDs) in developing countries has highlighted the critical role of environmental pollutants as causative factors in their pathophysiology. Despite its ubiquity and immune toxicity, the impact of aluminum in the gut is not known. This study aimed to evaluate the effects of environmentally relevant intoxication with aluminum in murine models of colitis and to explore the underlying mechanisms. Oral administration of aluminum worsened intestinal inflammation in mice with 2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis and chronic colitis in interleukin 10-negative (IL10(-/-)) mice. Aluminum increased the intensity and duration of macroscopic and histologic inflammation, colonic myeloperoxidase activity, inflammatory cytokines expression, and decreased the epithelial cell renewal compared with control animals. Under basal conditions, aluminum impaired intestinal barrier function. In vitro, aluminum induced granuloma formation and synergized with lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial cells. Deleterious effects of aluminum on intestinal inflammation and mucosal repair strongly suggest that aluminum might be an environmental IBD risk factor.

Published
2013
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8. 4-Oxo-1,4-dihydropyridines as Selective CB 2 Cannabinoid Receptor Ligands Part 2: Discovery of New Agonists Endowed with Protective Effect Against Experimental Colitis

Author

Virginie Andrzejak, Jamal El Bakali, Amélie Barczyk, Giulio G. Muccioli, Pauline Gilleron, Pierre Desreumaux, Didier M. Lambert, Madjid Djouina, Mathilde Body-Malapel, Frédérique Klupsch, Roxane Mansouri, Christophe Furman, Emmanuelle Lipka, Philippe Chavatte, Régis Millet, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université Catholique de Louvain = Catholic University of Louvain (UCL), Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), We are grateful for the financial support from ANR emergence (ANR-09-EBIO-007: CAB-MICI) and PRIM (Pole de Recherche Interdisciplinaire pour le Medicament)., ANR-09-EBIO-0007,CAB-MICI,Développement de nouveaux agonistes CB2 et leurs utilisations dans le traitement et la prévention des Maladies Inflammatoires Chroniques de l'Intestin (MICI)(2009), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Cannabinoid receptor, Adamantane, [SDV]Life Sciences [q-bio], Pharmacology, 01 natural sciences, Intestinal absorption, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Cannabinoid receptor type 2, medicine, Structure–activity relationship, [CHIM]Chemical Sciences, Colitis, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Chinese hamster ovary cell, biology.organism_classification, medicine.disease, 0104 chemical sciences, 3. Good health, Molecular Medicine, Cricetulus
Abstract

International audience; Further on to our earlier work on the 4-oxo-1,4-dihydropyridine, we describe herein our strategy to get access to potent selective CB₂ receptor agonists. Thus, we designed and synthesized 29 compounds, evaluated on both hCB₁ and hCB₂ cannabinoid receptors, and assessed 11 of them in the TNBS-induced colitis model in mice. Compound 48 was found to be the most efficient of our series, exhibiting an exquisite protection against experimental colitis, superior to the one observed after treatment with Pentasa.

Published
2012
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9. AIEC colonization and pathogenicity: influence of previous antibiotic treatment and preexisting inflammation

Author

Cécile Vignal, Pierre Desreumaux, Antoine Cortot, Luc Dubreuil, Maryline Drouet, Madjid Djouina, Christel Neut, and Elisabeth Singer

Subjects
Male, medicine.drug_class, Antibiotics, Blotting, Western, Nod2 Signaling Adaptor Protein, Inflammation, Ileum, Biology, Real-Time Polymerase Chain Reaction, Bacterial Adhesion, Microbiology, Mice, NOD2, medicine, Escherichia coli, Immunology and Allergy, Animals, Humans, Colonization, RNA, Messenger, Colitis, Escherichia coli Infections, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Dextran Sulfate, Gastroenterology, medicine.disease, digestive system diseases, Anti-Bacterial Agents, Intestines, Mice, Inbred C57BL, medicine.anatomical_structure, Bacterial Translocation, Knockout mouse, Immunology, Female, medicine.symptom, Dysbiosis
Abstract

Background: Inflammatory bowel diseases (IBD) patients are abnormally colonized by adherent-invasive Escherichia coli (AIEC). NOD2 gene mutations impair intracellular bacterial clearance. We evaluated the impact of antibiotic treatment on AIEC colonization in wildtype (WT) and NOD2 knockout mice (NOD2KO) and the consequences on intestinal inflammation. Methods: After 3 days of antibiotic treatment, mice were infected for 2 days with 109 CFU AIEC and sacrificed 1, 5, and 60 days later. In parallel, mice were challenged with AIEC subsequent to a dextran sodium sulfate (DSS) treatment and sacrificed 9 days later. Ileum, colon, and mesenteric tissues were sampled for AIEC quantification and evaluation of inflammation. Results: Without antibiotic treatment, AIEC was not able to colonize WT and NOD2KO mice. Compared with nontreated animals, antibiotic treatment led to a significant increase in ileal and colonic colonization of AIEC in WT and/or NOD2KO mice. Persistent AIEC colonization was observed until day 5 only in NOD2KO mice, disappearing at day 60. Mesenteric translocation of AIEC was observed only in NOD2KO mice. No inflammation was observed in WT and NOD2KO mice treated with antibiotics and infected with AIEC. During DSS-induced colitis, colonization and persistence of AIEC was observed in the colon. Moreover, a dramatic increase in clinical, histological, and molecular parameters of colitis was observed in mice infected with AIEC but not with a commensal E. coli strain. Conclusions: Antibiotic treatment was necessary for AIEC colonization of the gut and mesenteric tissues and persistence of AIEC was dependent on NOD2. AIEC exacerbated a preexisting DSS-induced colitis in WT mice. (Inflamm Bowel Dis 2012)

Published
2011

10. New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis

Author

Pierre Desreumaux, Madjid Djouina, Régis Millet, Nicolas Renault, Virginie Andrzejak, Jamal El Bakali, Giulio G. Muccioli, Mathilde Body-Malapel, Didier M. Lambert, Philippe Chavatte, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was financially supported by the ‘Conseil Régional Nord Pas de Calais’., The authors thank Ms. Perrine Six for the NMR and LC–MS analysis, as well as Dr. Geoffray Labar for the preparation of the human recombinant enzymes., Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Models, Molecular, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Pharmacology, Inhibitory postsynaptic potential, 01 natural sciences, Biochemistry, Amidohydrolases, 03 medical and health sciences, chemistry.chemical_compound, Inhibitory Concentration 50, Mice, Intestinal inflammation, Drug Discovery, medicine, Animals, Humans, [CHIM]Chemical Sciences, Isoxazole, Colitis, Enzyme Inhibitors, Molecular Biology, 030304 developmental biology, 0303 health sciences, Molecular Structure, 010405 organic chemistry, Chemistry, Aryl, Organic Chemistry, Experimental colitis, Anandamide, Isoxazoles, medicine.disease, Endocannabinoid system, 0104 chemical sciences, 3. Good health, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, nervous system, Molecular Medicine, lipids (amino acids, peptides, and proteins), psychological phenomena and processes
Abstract

International audience; Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment of inflammatory bowel diseases. In this paper, we report the first series of carboxamides derivatives possessing FAAH inhibitory activities. Among them, compound 39 displayed significant inhibitory FAAH activity (IC(50)=0.088 μM) and reduced colitis induced by intrarectal administration of TNBS.

Published
2011
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11. S02 Aluminum enhances inflammation and decreases healing in experimental models of colitis

Author

Antoine Cortot, Pierre Desreumaux, Frédéric Altare, Marie-Claire Arrieta, Madjid Djouina, Christel Neut, Cécile Vignal, Mathilde Body-Malapel, J.-F. Colombel, and G. Pineton de Chambrun

Subjects
medicine.medical_specialty, business.industry, Internal medicine, medicine, Inflammation, Disease, medicine.symptom, Colitis, medicine.disease, business, Gastroenterology
Published
2010
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12. Aluminum Enhances Inflammation and Decreases Healing in Experimental Models of Colitis

Author

Marie-Claire Arrieta, Christel Neut, Jean-Frederic Colombel, Mathilde Body-Malapel, Madjid Djouina, Pierre Desreumaux, Guillaume Pineton de Chambrun, Frédéric Altare, Cécile Vignal, and Antoine Cortot

Subjects
medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Gastroenterology, medicine, Inflammation, Colitis, medicine.symptom, business, medicine.disease

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