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1. Chronic Exposure to Both Electronic and Conventional Cigarettes Alters Ileum and Colon Turnover, Immune Function, and Barrier Integrity in Mice

Author

Madjid Djouina, Anaïs Ollivier, Christophe Waxin, Gwenola Kervoaze, Muriel Pichavant, Ségolène Caboche, Djamal Achour, Céline Grare, Delphine Beury, David Hot, Sébastien Anthérieu, Jean-Marc Lo-Guidice, Laurent Dubuquoy, David Launay, Cécile Vignal, Philippe Gosset, and Mathilde Body-Malapel

Subjects
e-cigarette, intestinal, immune response, proliferation, permeability, microbiota, Therapeutics. Pharmacology, RM1-950, Toxicology. Poisons, RA1190-1270
Abstract

Although the effects of cigarette smoke (CS) on the development of several intestinal diseases is well documented, the impact of e-cigarette aerosol (e-cig) on digestive health is largely unknown. To compare the effects of e-cig and CS on mouse ileum and colon, animals were chronically exposed for 6 months by nose-only inhalation to e-cig at 18 or 30 W power, or to 3R4F CS. Results showed that e-cig exposure decreased colon cell proliferation. Several other proliferative defects were observed in response to both e-cig and CS exposure, including up- and down-regulation of cyclin D1 protein levels in the ileum and colon, respectively. E-cig and CS exposure reduced myeloperoxidase activity in the ileum. In the colon, both exposures disrupted gene expression of cytokines and T cell transcription factors. For tight junction genes, ZO-1- and occludin-protein expression levels were reduced in the ileum and colon, respectively, by e-cig and CS exposure. The 16S sequencing of microbiota showed specific mild dysbiosis, according to the type of exposure. Overall, e-cig exposure led to altered proliferation, inflammation, and barrier function in both the ileum and colon, and therefore may be a gut hazard on par with conventional CS.

Published
2024
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2. Recent Progress in Intestinal Toxicity of Microplastics and Nanoplastics: Systematic Review of Preclinical Evidence

Author

Madjid Djouina, Suzie Loison, and Mathilde Body-Malapel

Subjects
microplastic, nanoplastic, intestinal, colon, gut barrier, inflammation, Biology (General), QH301-705.5, Microbiology, QR1-502, Biochemistry, QD415-436
Abstract

The tremendous plastic production and poor post-use management are current and future sources of environmental and human contamination due to their degradation products: microplastics and nanoplastics (MNPLs). Methodological developments have allowed MNPLs to be detected in an increasing variety of human foods, as well as in stool and colonic mucosa. It was suggested early that the direct contact between MNPLs and intestinal tissues could represent a potential risk for human health. In order to assess this, over the last 3 years, numerous studies have evaluated the impact of MNPL ingestion on intestinal homeostasis in rodents. This comprehensive review reports the preclinical studies published between January 2021 and January 2024, and analyzes their contributions as well as their shortcomings. It shows that evidence is accumulating of the intestinal toxicity of spherical MNPLs, which lead to pro-inflammatory, pro-oxidative, barrier-disruptive and dysbiotic effects. However, the available literature has addressed only a minor part of the potential health issues of MNPLs. Many parameters contributing to MNPL toxicity need to be better taken into account in future studies. Particular attention should be paid to improve the representativeness of MNPLs, as well as to better consider the susceptibility factors of MNPL toxicity, generated especially by an underlying pathology or pathological imprinting.

Published
2024
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3. Oral exposure to polyethylene microplastics induces inflammatory and metabolic changes and promotes fibrosis in mouse liver.

Author

Madjid Djouina, Christophe Waxin, Laurent Dubuquoy, David Launay, Cécile Vignal, and Mathilde Body-Malapel

Subjects
Microplastics, Polyethylene, Mice, Liver, Fibrosis, Lipid metabolism, Environmental pollution, TD172-193.5, Environmental sciences, GE1-350
Abstract

Accumulating evidence shows widespread contamination of water sources and food with microplastics. Although the liver is one of the main sites of bioaccumulation within the human body, it is still unclear whether microplastics produce damaging effects. In particular, the hepatic consequences of ingesting polyethylene (PE) microplastics in mammals are unknown. In this study, female mice were fed with food contaminated with 36 and 116 µm diameter PE microbeads at a dosage of 100 µg/g of food for 6 and 9 weeks. Mice were exposed to each type of microbead, or co-exposed to the 2 types of microbeads. Mouse liver showed altered levels of genes involved in uptake, synthesis, and β-oxidation of fatty acids. Ingestion of PE microbeads disturbed the detoxification response, promoted oxidative imbalance, increased inflammatory foci and cytokine expression, and enhanced proliferation in liver. Since relative expression of the hepatic stellate cell marker Pdgfa and collagen deposition were increased following PE exposure, we assessed the effect of PE ingestion in a mouse model of CCl4-induced fibrosis and showed that PE dietary exposure exacerbated liver fibrogenesis. These findings provide the first demonstration of the adverse hepatic effects of PE ingestion in mammals and highlight the need for further health risk assessment in humans.

Published
2023
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4. Murine in utero exposure to simulated complex urban air pollution disturbs offspring gut maturation and microbiota during intestinal suckling-to-weaning transition in a sex-dependent manner

Author

Eva Guilloteau, Patrice Coll, Zhuyi Lu, Madjid Djouina, Mathieu Cazaunau, Christophe Waxin, Antonin Bergé, Ségolène Caboche, Aline Gratien, Elie Al Marj, David Hot, Laurent Dubuquoy, David Launay, Cécile Vignal, Sophie Lanone, and Mathilde Body-Malapel

Subjects
Air pollution, Gestational exposure, Intestinal development, Suckling-to-weaning transition, Microbiota, Maturation, Toxicology. Poisons, RA1190-1270, Industrial hygiene. Industrial welfare, HD7260-7780.8
Abstract

Abstract Background Emerging data indicate that prenatal exposure to air pollution may lead to higher susceptibility to several non-communicable diseases. Limited research has been conducted due to difficulties in modelling realistic air pollution exposure. In this study, pregnant mice were exposed from gestational day 10–17 to an atmosphere representative of a 2017 pollution event in Beijing, China. Intestinal homeostasis and microbiota were assessed in both male and female offspring during the suckling-to-weaning transition. Results Sex-specific differences were observed in progeny of gestationally-exposed mice. In utero exposed males exhibited decreased villus and crypt length, vacuolation abnormalities, and lower levels of tight junction protein ZO-1 in ileum. They showed an upregulation of absorptive cell markers and a downregulation of neonatal markers in colon. Cecum of in utero exposed male mice also presented a deeply unbalanced inflammatory pattern. By contrast, in utero exposed female mice displayed less severe intestinal alterations, but included dysregulated expression of Lgr5 in colon, Tjp1 in cecum, and Epcam, Car2 and Sis in ileum. Moreover, exposed female mice showed dysbiosis characterized by a decreased weighted UniFrac β-diversity index, a higher abundance of Bacteroidales and Coriobacteriales orders, and a reduced Firmicutes/Bacteroidetes ratio. Conclusion Prenatal realistic modelling of an urban air pollution event induced sex-specific precocious alterations of structural and immune intestinal development in mice.

Published
2022
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5. 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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6. Aluminum Ingestion Promotes Colorectal Hypersensitivity in RodentsSummary

Author

Nicolas Esquerre, Lilian Basso, Caroline Dubuquoy, Madjid Djouina, Daniel Chappard, Catherine Blanpied, Pierre Desreumaux, Nathalie Vergnolle, Cécile Vignal, and Mathilde Body-Malapel

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Irritable bowel syndrome (IBS) is a multifactorial disease arising from a complex interplay between genetic predisposition and environmental influences. To date, environmental triggers are not well known. Aluminum is commonly present in food, notably by its use as food additive. We investigated the effects of aluminum ingestion in rodent models of visceral hypersensitivity, and the mechanisms involved. Methods: Visceral hypersensitivity was recorded by colorectal distension in rats administered with oral low doses of aluminum. Inflammation was analyzed in the colon of aluminum-treated rats by quantitative PCR for cytokine expression and by immunohistochemistry for immune cells quantification. Involvement of mast cells in the aluminum-induced hypersensitivity was determined by cromoglycate administration of rats and in mast cell-deficient mice (KitW-sh/W-sh). Proteinase-activated receptor-2 (PAR2) activation in response to aluminum was evaluated and its implication in aluminum-induced hypersensitivity was assessed in PAR2 knockout mice. Results: Orally administered low-dose aluminum induced visceral hypersensitivity in rats and mice. Visceral pain induced by aluminum persisted over time even after cessation of treatment, reappeared and was amplified when treatment resumed. As observed in humans, female animals were more sensitive than males. Major mediators of nociception were up-regulated in the colon by aluminum. Activation of mast cells and PAR2 were required for aluminum-induced hypersensitivity. Conclusions: These findings indicate that oral exposure to aluminum at human dietary level reproduces clinical and molecular features of IBS, highlighting a new pathway of prevention and treatment of visceral pain in some susceptible patients. Keywords: Visceral Hypersensitivity, Risk Factors, Mast Cells, PAR2

Published
2019
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7. Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon

Author

Cécile Vignal, Muriel Pichavant, Laurent Y. Alleman, Madjid Djouina, Florian Dingreville, Esperanza Perdrix, Christophe Waxin, Adil Ouali Alami, Corinne Gower-Rousseau, Pierre Desreumaux, and Mathilde Body-Malapel

Subjects
Particulate matter, Coarse PM, Oxidative stress, Inflammation, Gut-lung axis, N-acetyl-L-cysteine, Toxicology. Poisons, RA1190-1270, Industrial hygiene. Industrial welfare, HD7260-7780.8
Abstract

Abstract Background Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation. Results The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM. Conclusions Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases.

Published
2017
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8. Oral exposure to polyethylene microplastics alters gut morphology, immune response, and microbiota composition in mice

Author

Madjid Djouina, Cécile Vignal, Alexandre Dehaut, Ségolène Caboche, Nell Hirt, Christophe Waxin, Charlotte Himber, Delphine Beury, David Hot, Laurent Dubuquoy, David Launay, Guillaume Duflos, Mathilde Body-Malapel, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de sécurité des aliments de Maisons-Alfort (LSAl), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), 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)-Centre National de la Recherche Scientifique (CNRS), and Laboratoire de Boulogne sur mer

Subjects
Inflammation, [SDV]Life Sciences [q-bio], Microbiota, Microplastics, Immunity, Biochemistry, Mice, Intestinal, Polyethylene, MESH: Microbiota, Animals, MESH: Microplastics, Plastics, ComputingMilieux_MISCELLANEOUS, Biomarkers, Water Pollutants, Chemical, General Environmental Science
Abstract

The ubiquitous and growing presence of microplastics (MPs) in all compartments of the environment raises concerns about their possible harmful effects on human health. Human exposure to MPs occurs largely through ingestion. Polyethylene (PE) is widely employed for reusable bags and food packaging and found to be present in drinking water and food. It is also one of the major polymers detected in human stool. The aim of this study was to characterize the effects of intestinal exposure to PE MPs on gut homeostasis. Mice were orally exposed for 6 weeks to PE microbeads of 2 different sizes, 36 and 116 μm, that correspond to those found in human stool. They were administrated either individually or as a mixture at a dose of 100 μg/g of food. Both PE microbead sizes were detected in mouse stool. Different parameters related to major intestinal functions were compared between control mice, mice exposed to each type of microbead, or co-exposed to the 2 types of microbeads. Intestinal disturbances were observed after individual exposure to each size of PE microbead, and the most marked deleterious effects were found in co-exposed mice. At the histomorphological level, crypt depth was increased throughout the intestinal tissues. Significant variations of gene expression related to epithelial, permeability, and inflammatory biomarkers were quantified. Defective recruitment of some intestinal immune cells was observed from the proximal portion of the small intestine to the colon. Several bacterial taxa at the order level were found to be affected by exposure to the MPs by metagenomic analysis of cecal microbiota. These results show that ingestion of PE microbeads induces significant alterations of crucial intestinal markers in mice and underscores the need to further study the health impact of MP exposure in humans.

Published
2022
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9. Thymidylate Synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer

Author

Julie Kerr-Conte, Julien Thevenet, Adeline Page, Vanessa Dehennaut, Céline Schulz, Gérard Vergoten, Ninon Very, Tony Lefebvre, Ikram El Yazidi-Belkoura, Amélie Decourcelle, Madjid Djouina, Stéphan Hardivillé, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), 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)-Centre National de la Recherche Scientifique (CNRS), Recherche translationnelle sur le diabète - U 1190 (RTD), 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), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), SFR Biosciences, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), EL YAZIDI-BELKOURA, IKRAM, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Recherche translationnelle sur le diabète (RTD) - U1190, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Lille Inflammation Research International Center - U 995 (LIRIC), and Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP)

Subjects
Cancer Research, Gene knockdown, Colorectal cancer, [SDV]Life Sciences [q-bio], Thymidylate Synthase, Biology, medicine.disease, medicine.disease_cause, Thymidylate synthase, In vitro, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, In vivo, Tumor progression, Genetics, medicine, biology.protein, Cancer research, Carcinogenesis, Molecular Biology, Sensitization
Abstract

International audience; Alteration of O-GlcNAcylation, a dynamic post-translational modification, is associated with tumorigenesis and tumor progression. Its role in chemotherapy response is poorly investigated. Standard treatment for colorectal cancer (CRC), 5-fluorouracil (5-FU), mainly targets Thymidylate Synthase (TS). TS O-GlcNAcylation was reported but not investigated yet. We hypothesize that O-GlcNAcylation interferes with 5-FU CRC sensitivity by regulating TS. In vivo, we observed that combined 5-FU with Thiamet-G (O-GlcNAcase (OGA) inhibitor) treatment had a synergistic inhibitory effect on grade and tumor progression. 5-FU decreased O-GlcNAcylation and, reciprocally, elevation of O-GlcNAcylation was associated with TS increase. In vitro in non-cancerous and cancerous colon cells, we showed that 5-FU impacts O-GlcNAcylation by decreasing O-GlcNAc Transferase (OGT) expression both at mRNA and protein levels. Reciprocally, OGT knockdown decreased 5-FU-induced cancer cell apoptosis by reducing TS protein level and activity. Mass spectrometry, mutagenesis and structural studies mapped O-GlcNAcylated sites on T251 and T306 residues and deciphered their role in TS proteasomal degradation. We reveal a crosstalk between O-GlcNAcylation and 5-FU metabolism in vitro and in vivo that converges to 5-FU CRC sensitization by stabilizing TS. Overall, our data propose that combining 5-FU-based chemotherapy with Thiamet-G could be a new way to enhance CRC response to 5-FU.

Published
2021
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10. Exposure to atmospheric Ag, TiO

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
Male, Titanium, Mice, Microbiota, Animals, Cytokines, Nanoparticles, Female, Silicon Dioxide, Gastrointestinal Microbiome
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 (TiO

Published
2021

11. Gene/environment interaction in the susceptibility of Crohn's disease patients to aluminum

Author

Madjid Djouina, Christophe Waxin, Frédéric Leprêtre, Meryem Tardivel, Olivier Tillement, Francis Vasseur, Martin Figeac, Antonino Bongiovanni, Shéhérazade Sebda, Pierre Desreumaux, David Launay, Laurent Dubuquoy, Mathilde Body-Malapel, Cécile Vignal, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), 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)-Centre National de la Recherche Scientifique (CNRS), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Inflammation, Environmental Engineering, [SDV]Life Sciences [q-bio], Inflammatory Bowel Diseases, Pollution, Xenobiotics, Crohn Disease, Cytokines, Humans, Environmental Chemistry, Gene-Environment Interaction, Caco-2 Cells, Waste Management and Disposal, Aluminum
Abstract

The key role of environmental factors in the pathogenesis of Inflammatory Bowel Diseases (IBD) is recognized. Aluminum is suspected to be a risk factor for IBD. However, mechanisms linking aluminum exposure to disease development are unknown. We examined the role of aluminum transport and subcellular localisation on human colon susceptibility to aluminum-induced inflammation.Human colon biopsies isolated from Crohn's disease (CD) or control patients and Caco-2 cells were incubated with aluminum. The effects of aluminum were evaluated on cytokine secretion and transporter expression. The role of aluminum kinetics parameters was studied in Caco-2 using transport inhibitors and in human colon biopsies by assessing genetic polymorphisms of transporters.Aluminum exposure was shown to induce cytokine secretion in colon of CD but not healthy patients. In Caco-2 cells, aluminum internalisation was correlated with inflammatory status. In human colon, analysis of genetic polymorphisms and expression of ABCB1 and SLC26A3 transporters showed that their decreased activity was involved in aluminum-induced inflammation.We hypothesize that alteration in detoxifying response would lead to a deregulation of intestinal homeostasis and to the expression of IBD. Our study emphasizes the complexity of gene/environment interaction for aluminum adverse health effect, highlighting at risk populations or subtypes of patients. A better understanding of correlations between gene expression or SNP and xenobiotic kinetics parameters would shift the medical paradigm to more personalized disease management and treatment.

Published
2022
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12. Benzo[d]thiazol-2(3H)-ones as new potent selective CB2 agonists with anti-inflammatory properties

Author

Amélie Barczyk, Madjid Djouina, Nicolas Renault, Davy Baudelet, Valéria Moas Heloire, Pascal Carato, Régis Millet, Diana Escalante Rocha, Natascha Leleu-Chavain, Mathilde Body-Malapel, 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), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier

Subjects
Cannabinoid receptor, medicine.drug_class, Colon, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Anti-Inflammatory Agents, Inflammation, Pharmacology, 01 natural sciences, Anti-inflammatory, 03 medical and health sciences, Structure-Activity Relationship, Drug Discovery, medicine, Cannabinoid receptor type 2, Humans, Benzothiazoles, Receptor, Cytotoxicity, Cannabinoid, 030304 developmental biology, Cannabinoid Receptor Agonists, 0303 health sciences, Colon inflammatory, 010405 organic chemistry, Chemistry, Organic Chemistry, CB(2) agonist, General Medicine, CB2, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], lipids (amino acids, peptides, and proteins), medicine.symptom
Abstract

International audience; The high distribution of CB receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: selective CB agonists are able to modulate inflammation without triggering psychotropic effects. In this work, we report a new series of selective CB agonists based on a benzo[d]thiazol-2(3H)-one scaffold. This drug design project led to the discovery of compound 9, as a very potent CB agonist (K = 13.5 nM) with a good selectivity versus CB. This compound showed no cytotoxicity, acceptable ADME-Tox parameters and demonstrates the ability to counteract colon inflammatory process in vivo.

Published
2019
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13. Benzo[d]thiazol-2(3H)-ones as new potent selective CB

Author

Natascha, Leleu-Chavain, Davy, Baudelet, Valéria Moas, Heloire, Diana Escalante, Rocha, Nicolas, Renault, Amélie, Barczyk, Madjid, Djouina, Mathilde, Body-Malapel, Pascal, Carato, and Régis, Millet

Subjects
Cannabinoid Receptor Agonists, Inflammation, Receptor, Cannabinoid, CB2, Structure-Activity Relationship, Colon, Anti-Inflammatory Agents, Humans, Benzothiazoles
Abstract

The high distribution of CB

Published
2018

14. Alteration of lung defense mechanisms after acute and chronic exposure to urban coarse PM

Author

Philippe Gosset, Cécile Vignal, Gwenola Kervoaze, Esperenza Perdrix, Muriel Pichavant, Christophe Waxin, Laurent Y. Alleman, Corinne Gower-Rousseau, Madjid Djouina, Mathilde Body-Malapel, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille 2-Faculté des Sciences du Sport et de l'Education Physique, Ecole nationale supérieure Mines-Télécom Lille Douai (IMT Lille Douai), and Institut Mines-Télécom [Paris] (IMT)

Subjects
Lung, Inhalation, medicine.diagnostic_test, business.industry, Inflammation, Flow cytometry, medicine.anatomical_structure, Immune system, Immunology, medicine, [INFO]Computer Science [cs], Respiratory system, medicine.symptom, business, Homeostasis, ComputingMilieux_MISCELLANEOUS, SLPI
Abstract

Background: Ambient particulate matter (PM) exposure has been shown to increase the risks of respiratory diseases and to contribute to the substantial worldwide burden of respiratory infections. However, the immune response to inhaled PM remains largely unexplored. Aim: We studied the effects of urban coarse PM on the pulmonary immunologic homeostasis. Methods: Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 3 and 15 days at a concentration relevant to episodic elevation peak of air pollution. Then the characteristics of PM-induced inflammation were assessed by flow cytometry and real-time PCR. Results: Acute and chronic exposures to urban coarse PM led to different immune patterns in the lung compartment. The acute phase was associated to the recruitment of neutrophils and activated alveolar macrophages. The chronic phase was characterized by the influx of activated conventional T cells whereas invariant natural killer T (iNKT) cells were recruited during both phases. Moreover, genes involved in anti-microbial responses, such as Reg3g, Lcn-2, Lyz and Slpi were downregulated in the lungs after acute PM exposure, whereas they were going back to baseline or slightly increased after chronic exposure. Independently of the time course, exposure to PM, leads to a decrease in IL-1b expression. Conclusion: This study provided a characterization of immunologic profiles in lungs following acute and chronic exposure to a realistic dose of PM. It suggested new mechanistic insights which should be further explored, especially the involvement of iNKT cells in pulmonary response to PM inhalation and the effects of PM exposure on the susceptibility to pulmonary infections.

Published
2018

15. Chronic ingestion of deoxynivalenol at human dietary levels impairs intestinal homeostasis and gut microbiota in mice

Author

Madjid Djouina, David Hot, Mathilde Body-Malapel, Muriel Pichavant, Corinne Gower-Rousseau, Christophe Waxin, Cécile Vignal, Ségolène Caboche, Delphine Beury, 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), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, This work was supported by grants from the FHU Imminent and Digestscience (European Research Foundation on Intestinal Diseases and Nutrition)., We thank the animal facility of Lille University Hospital for the animal care., 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), 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)-Centre National de la Recherche Scientifique (CNRS), Inserm, Université de Lille, CHU Lille, CNRS, Lille Inflammation Research International Center - U 995 [LIRIC], and Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]

Subjects
0301 basic medicine, Male, Colon, Health, Toxicology and Mutagenesis, Regulatory B cells, Trichothecene, Inflammation, Ileum, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, Biology, Gut flora, Toxicology, Jejunum, Dietary Exposure, 03 medical and health sciences, Mice, 0302 clinical medicine, RNA, Ribosomal, 16S, medicine, Mesenteric lymph nodes, Animals, Homeostasis, Humans, Intestinal Mucosa, Cell Proliferation, Intestine, Microbiota, Deoxynivalenol, Mycotoxin, General Medicine, biology.organism_classification, medicine.disease, 3. Good health, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, 13. Climate action, 030220 oncology & carcinogenesis, Immunology, medicine.symptom, Edible Grain, Trichothecenes, Dysbiosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; The mycotoxin deoxynivalenol (DON) is a frequent contaminant of cereals and their by-products in areas with a moderate climate. Produced by Fusarium species, it is one of the most prevalent mycotoxins in cereal crops worldwide, and the most frequently occurring type B trichothecene in Europe. Due to its toxic properties, high stability and prevalence, the presence of DON in the food chain could represent a major public health risk. However, despite its well-known acute toxicological effects, information on the adverse effects of realistic exposure remains limited. We orally exposed mice during 9 months to DON at doses relevant for currently estimated human intake and explored the impact on various gut health parameters. DON exposure induced recruitment of regulatory B cells, and activation of regulatory T cells and dendritic cells in mesenteric lymph nodes. Several inflammatory parameters were increased in colon of DON-exposed mice, whereas inversely inflammatory markers were decreased in ileum. Histomorphological impairments were observed from the duodenum to the colon. Both colon and jejunum presented a hyperproliferation of epithelial cells and an increased expression of mature absorptive cells markers. Finally, DON exposure reshaped gut microbial structure and drastically disturbed the abundance of several bacterial phyla, families, and genera, leading to dysbiosis. Chronic oral exposure to human relevant doses of DON induces several disturbances of gut homeostasis with likely pathological implications for susceptible individuals.

Published
2018
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16. 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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17. 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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18. Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon

Author

Laurent Y. Alleman, Adil Ouali Alami, Corinne Gower-Rousseau, Madjid Djouina, Pierre Desreumaux, Mathilde Body-Malapel, Esperanza Perdrix, Cécile Vignal, Muriel Pichavant, Florian Dingreville, Christophe Waxin, Body-Malapel, Mathilde, 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), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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)-Centre National de la Recherche Scientifique (CNRS), Département Sciences de l'Atmosphère et Génie de l'Environnement, École des Mines de Douai (Mines Douai EMD), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de Gastroenterologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This work was supported by the Hauts-de-France Region and the Ministère de l’Enseignement Supérieur et de la Recherche (CPER Climibio), the European Fund for Regional Economic Development, and Digestscience (European Research Foundation on Intestinal Diseases and Nutrition)., The authors thank Bruno Mallet., 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), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Inserm, Université de Lille, CHU Lille, Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 8204, Lille Inflammation Research International Center - U 995 [LIRIC], and Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]

Subjects
0301 basic medicine, Male, Coarse PM, MESH: Air Pollutants, Health, Toxicology and Mutagenesis, medicine.medical_treatment, MESH: Solvents, 010501 environmental sciences, Toxicology, medicine.disease_cause, 01 natural sciences, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Antioxidants, 11. Sustainability, Gut-lung axis, N-acetyl-L-cysteine, MESH: Animals, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Lung, Air Pollutants, Inhalation Exposure, MESH: Cytokines, MESH: Oxidative Stress, Inhalation, Mesh:Air Pollutants/toxicity, Mesh:Solubility, Mesh:Inflammation Mediators/immunology, Mesh:Mice, Mesh:Inbred C57BL, Mesh:Colon/immunology, Mesh:Colon/metabolism, Mesh:Acetylcysteine/pharmacology, Mesh:Animals, Mesh:Cytokines/metabolism, Mesh:Oxidative Stress/drug effects, Mesh:Colon/drug effects, Mesh:Water/chemistry, Mesh:Lung/drug effects, Mesh:Lung/metabolism, Mesh:Cytokines/immunology, Mesh:Air Pollutants/chemistry, Mesh:Antioxidants/pharmacology, Mesh:Male, Mesh:Inflammation Mediators/metabolism, Mesh:Particulate Matter/chemistry, Mesh:Inhalation Exposure/adverse effects, Mesh:Lung/immunology, Mesh:Particulate Matter/toxicity, Mesh:Particle Size, Mesh:Solvents/chemistry, Inflammation, Particulate matter, Oxidative stress, General Medicine, 3. Good health, medicine.anatomical_structure, Cytokine, MESH: Particulate Matter, Bronchitis, Cytokines, MESH: Inhalation Exposure, medicine.symptom, Inflammation Mediators, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Colon, MESH: Inflammation Mediators, lcsh:Industrial hygiene. Industrial welfare, 03 medical and health sciences, Immune system, MESH: Acetylcysteine, lcsh:RA1190-1270, MESH: Mice, Inbred C57BL, medicine, MESH: Water, Animals, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, MESH: Lung, MESH: Particle Size, Particle Size, MESH: Colon, 0105 earth and related environmental sciences, Asthma, lcsh:Toxicology. Poisons, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Research, MESH: Antioxidants, Water, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, Acetylcysteine, Mice, Inbred C57BL, MESH: Solubility, 030104 developmental biology, Solubility, 13. Climate action, Immunology, Solvents, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, lcsh:HD7260-7780.8
Abstract

Background Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation. Results The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM. Conclusions Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases. Electronic supplementary material The online version of this article (10.1186/s12989-017-0227-z) contains supplementary material, which is available to authorized users.

Published
2017
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19. Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis

Author

Johan Auwerx, Dine Koriche, Pierre Desreumaux, Guillaume Bouguen, Jean-Frederic Colombel, Alice Mongy, Madjid Djouina, Laurent Dubuquoy, Julien Branche, Audrey Langlois, Benjamin Bertin, and Edmone Dewaeles

Subjects
Male, Genetically modified mouse, medicine.medical_specialty, Colon, Receptors, Cytoplasmic and Nuclear, Peroxisome proliferator-activated receptor, Mice, Transgenic, BASIC SCIENCES, Biology, INTESTINAL EPITHELIUM, Immune tolerance, Small hairpin RNA, Mice, Internal medicine, Gene expression, Immune Tolerance, medicine, Animals, Humans, RNA, Messenger, Intestinal Mucosa, Receptor, Glucocorticoids, chemistry.chemical_classification, Gene knockdown, MOLECULAR BIOLOGY, Gastroenterology, Epithelial Cells, Intestinal epithelium, PPAR gamma, Endocrinology, chemistry, SIGNALING, Gene Knockdown Techniques, ULCERATIVE COLITIS, Colitis, Ulcerative, Caco-2 Cells
Abstract

Background and aims Immune tolerance breakdown during UC involves the peroxisome proliferator-activated receptor-γ (PPARγ), a key factor in mucosal homoeostasis and the therapeutic target of 5-aminosalycilates, which expression is impaired during UC. Here we assess the impact of glucocorticoids (GCs) on PPARγ expression, focusing especially on extra-adrenal cortisol production by colonic epithelial cells (CECs). Methods Activation of PPARγ in the colon was evaluated using transgenic mice for the luciferase gene under PPAR control (peroxisome proliferator response element-luciferase mice). Protein and mRNA expression of PPARγ were evaluated with colon fragments and purified CEC from mice. Cortisol production and steroidogenic factor expression were quantified in human CEC of patients with UC and those of controls. Gene expression knockdown by short hairpin RNA in Caco-2 cells was used for functional studies. Results GCs were able to raise luciferase activity in peroxisome proliferator response element-luciferase mice. In the mice colons and Caco-2 cells, PPARγ expression was increased either with GCs or with an inducer of steroidogenesis and then decreased after treatment with a steroidogenesis inhibitor. Cortisol production and steroidogenic factor expression, such as liver receptor homologue-1 (LRH-1), were decreased in CEC isolated from patients with UC, directly correlating with PPARγ impairment. Experiments on Caco-2 cells lacking LRH-1 expression confirmed that LRH-1 controls PPARγ expression by regulating GC synthesis in CEC. Conclusions These results demonstrate cortisol control of PPARγ expression in CEC, highlighting cortisol production deficiency in colonocytes as a key molecular event in the pathophysiology of UC.

Published
2014
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20. P049 HLA B27 transgenic rat: a new animal model of ileitis post-surgery reproducing inflammatory bowel disease

Author

Caroline Dubuquoy, Charbel Chater, Christel Neut, Lucil Schneider, Madjid Djouina, Benjamin Pariente, François-René Pruvot, A. Chau, Pierre Desreumaux, Dine Koriche, Silvia Speca, Philippe Zerbib, and Laurent Dubuquoy

Subjects
HLA-B27, Animal model, business.industry, Transgene, Immunology, Gastroenterology, medicine, Ileitis, General Medicine, Post surgery, medicine.disease, business, Inflammatory bowel disease
Published
2018
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21. Toxicological consequences of experimental exposure to aluminum in human intestinal epithelial cells

Author

Cécile Vignal, Pierre Desreumaux, Madjid Djouina, Nicolas Esquerre, Mathilde Body-Malapel, Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ecologie comportementale (EC), 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), 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), 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), 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), Inserm, Université de Lille, CHU Lille, Lille Inflammation Research International Center - U 995 [LIRIC], Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, 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
0301 basic medicine, inorganic chemicals, Mesh:HT29 Cells, Mesh:Humans, Mesh:Intestinal Mucosa/drug effects, Mesh:Transcriptome, Mesh:Membrane Potentials/drug effects, Mesh:Aluminum/toxicity, HT-29 cells, Cytotoxicity, Transcriptomics, Aluminum, [SDV]Life Sciences [q-bio], Biology, Toxicology, complex mixtures, Membrane Potentials, Flow cytometry, 03 medical and health sciences, HT29 Cells, 0302 clinical medicine, Intestinal mucosa, medicine, Humans, MTT assay, Viability assay, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, General Medicine, Intestinal epithelium, Cell biology, 030104 developmental biology, Apoptosis, 030220 oncology & carcinogenesis, Immunology, Transcriptome, Food Science
Abstract

International audience; Aluminum (Al), a non-essential element, is ubiquitous in industrialized societies. Whereas adult intake is estimated between 3 and 12 mg/day according to dietary aluminum studies conducted in many countries, it is not known if aluminum may have a toxic effect on intestinal epithelium. The aim of this work was to evaluate the cytotoxicity and RNA expression patterns induced in HT-29 cells by aluminum. Both classical toxicological methods and a global transcriptomic approach were used. Cytotoxicity determined by MTT assay showed a time and dose dependent decrease of cell viability in aluminum treated cells compared to control cells. Cell cycle analysis by flow cytometry revealed that aluminum induced accumulation of cells in phase G0/G1, associated with a decrease in the proportion of cells in S and G2/M phases. Aluminum led to apoptosis as evidenced by nuclear morphology changes and mitochondrial membrane perturbations, and induced reactive oxygen species generation. Transcriptomic pattern argued in favor of pro-tumorigenic and pro-inflammatory effects of aluminum in intestinal epithelial cells. These results highlight several pathways by which aluminum has a disturbing impact on intestinal epithelial cells, supporting that the effects of aluminum on intestine warrants further investigation.

Published
2016
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22. 1053 - Hla B27 Transgenic Rat: A New Animal Model of Ileitis Post Surgery Reproducing Inflammatory Disease

Author

Pierre Desreumaux, Laurent Dubuquoy, Dine Koriche, Caroline Dubuquoy, Lucil Schneider, Amélie Chau, Benjamin Pariente, François-René Pruvot, Christel Neut, Madjid Djouina, Charbel Chater, Silvia Speca, and Philippe Zerbib

Subjects
HLA-B27, Animal model, Hepatology, business.industry, Transgene, Immunology, Gastroenterology, medicine, Ileitis, Disease, Post surgery, medicine.disease, business
Published
2018
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23. 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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24. 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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25. 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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26. 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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27. Tu1881 HLA B27 Transgenic Rat: A New Animal Model of Postsurgical Ileitis in Inflammatory Bowel Disease

Author

Charbel Chater, Benjamin Pariente, François-René Pruvot, Dine Koriche, Silvia Speca, Christel Neut, Philippe Zerbib, Amélie Chau, Laurent Dubuquoy, Madjid Djouina, Pierre Desreumaux, and Caroline Dubuquoy

Subjects
Pathology, medicine.medical_specialty, HLA-B27, Hepatology, business.industry, Transgene, Gastroenterology, medicine.disease, Inflammatory bowel disease, Animal model, Immunology, Medicine, Ileitis, business
Published
2016
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28. Su1868 Dissecting the Role of RAGE in Intestinal Fibrosis

Author

Chantal Fradin, Mathilde Body-Malapel, Silvia Speca, Madjid Djouina, Eric Boulanger, Pierre Desreumaux, Ann Marie Schmidt, and Cécile Vignal

Subjects
Pathology, medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, Medicine, Intestinal fibrosis, business, Rage (emotion)
Published
2016
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29. 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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30. 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

31. 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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32. 4-Oxo-1,4-dihydropyridines as Selective CB 2 Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series

Author

Giulio G. Muccioli, Virginie Andrzejak, Nicolas Renault, Delphine Pradal, Jamal El Bakali, Laurie Hamtiaux, Philippe Chavatte, Didier M. Lambert, Mathilde Body-Malapel, Madjid Djouina, Pierre Desreumaux, Régis Millet, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Université Catholique de Louvain = Catholic University of Louvain (UCL), Université Lille Nord de France (COMUE), Physiopathologie des Maladies Inflammatoires de l'Intestin, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé

Subjects
Models, Molecular, Dihydropyridines, Cannabinoid receptor, Drug Inverse Agonism, Stereochemistry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Substituent, CHO Cells, Ligands, 01 natural sciences, Receptor, Cannabinoid, CB2, Radioligand Assay, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, Cricetinae, Drug Discovery, medicine, Animals, Humans, Inverse agonist, Structure–activity relationship, [CHIM]Chemical Sciences, Amino Acid Sequence, Receptor, 030304 developmental biology, G protein-coupled receptor, 0303 health sciences, 010405 organic chemistry, Stereoisomerism, Combinatorial chemistry, 3. Good health, 0104 chemical sciences, chemistry, Molecular Medicine, lipids (amino acids, peptides, and proteins), Cannabinoid, Sequence Alignment
Abstract

International audience; Growing evidence shows that CB2 receptor is an attractive therapeutic target. Starting from a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective CB2 agonists, we describe here the medicinal chemistry approach leading to the development of CB2 receptor inverse agonists with a 4-oxo-1,4-dihydropyridine scaffold. The compounds reported here show high affinity and potency at the CB2 receptor while showing only modest affinity for the centrally expressed CB1 cannabinoid receptor. Further, we found that the functionality of this series is controlled by its C-6 substituent because agonists bear a methyl or a tert-butyl group and inverse agonists, a phenyl or 4-chlorophenyl group, respectively. Finally, in silico studies suggest that the C-6 substituent could modulate the conformation of W6.48 known to be critical in GPCR activation.

Published
2010
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33. 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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34. 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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