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Servin A.L.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | Servin A.L.,University Paris - Sud
Clinical Microbiology Reviews | Year: 2014

The pathogenicity and clinical pertinence of diffusely adhering Escherichia coli expressing the Afa/Dr adhesins (Afa/Dr DAEC) in urinary tract infections (UTIs) and pregnancy complications are well established. In contrast, the implication of intestinal Afa/Dr DAEC in diarrhea is still under debate. These strains are age de-pendently involved in diarrhea in children, are apparently not involved in diarrhea in adults, and can also be asymptomatic intestinal microbiota strainsin children and adult. This comprehensive review analyzes the epidemiology and diagnosis and highlights recent progress which has improved the understanding of Afa/Dr DAEC pathogenesis. Here,Isummarize the roles of Afa/Dr DAEC virulence factors, including Afa/Dr adhesins, flagella, Sat toxin, and pks island products, in the development of specific mechanisms of pathogenicity. In intestinal epithelial polarized cells, the Afa/Dr adhesins trigger cell membrane receptor clustering and activation of the linked cell signaling pathways, promote structural and functional cell lesions and injuries in intestinal barrier, induce proinflammatory responses, create angiogenesis, instigate epithelial-mesenchymal transition-like events, and lead to pks-dependent DNA damage. UTI-associated Afa/Dr DAEC strains, following adhesin-membrane receptor cell interactions and activation of associated lipid raft-dependent cell signaling pathways, internalize in a microtubule-dependent manner within urinary tract epithelial cells, develop a particular intracellular lifestyle, and trigger a toxin-dependent cell detachment. In response to Afa/Dr DAEC infection, the host epithelial cells generate antibacterial defense responses. Finally, I discuss a hypothetical role of intestinal Afa/Dr DAEC strains that can act as “silent pathogens” with the capacity to emerge as “pathobionts” for the development of inflammatory bowel disease and intestinal carcinogenesis. © 2014, American Society for Microbiology. All Rights Reserved.


Moal V.L.-L.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | Moal V.L.-L.,Laboratory of Excellence in Research on Medication and Innovative Therapeutics | Moal V.L.-L.,University Paris - Sud | Servina A.L.,Laboratory of Excellence in Research on Medication and Innovative Therapeutics | Servina A.L.,University Paris - Sud
Microbiology and Molecular Biology Reviews | Year: 2013

Hosts are protected from attack by potentially harmful enteric microorganisms, viruses, and parasites by the polarized fully differentiated epithelial cells that make up the epithelium, providing a physical and functional barrier. Enterovirulent bacteria interact with the epithelial polarized cells lining the intestinal barrier, and some invade the cells. A better understanding of the cross talk between enterovirulent bacteria and the polarized intestinal cells has resulted in the identification of essential enterovirulent bacterial structures and virulence gene products playing pivotal roles in pathogenesis. Cultured animal cell lines and cultured human nonintestinal, undifferentiated epithelial cells have been extensively used for understanding the mechanisms by which some human enterovirulent bacteria induce intestinal disorders. Human colon carcinoma cell lines which are able to express in culture the functional and structural characteristics of mature enterocytes and goblet cells have been established, mimicking structurally and functionally an intestinal epithelial barrier. Moreover, Caco-2- derived M-like cells have been established, mimicking the bacterial capture property of M cells of Peyer's patches. This review intends to analyze the cellular and molecular mechanisms of pathogenesis of human enterovirulent bacteria observed in infected cultured human colon carcinoma enterocyte-like HT-29 subpopulations, enterocyte-like Caco-2 and clone cells, the colonic T84 cell line, HT-29 mucus-secreting cell subpopulations, and Caco-2-derived M-like cells, including cell association, cell entry, intracellular lifestyle, structural lesions at the brush border, functional lesions in enterocytes and goblet cells, functional and structural lesions at the junctional domain, and host cellular defense responses. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Pous J.,CNRS Natural Product Chemistry Institute | Courant T.,CNRS Natural Product Chemistry Institute | Bernadat G.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | Iorga B.I.,CNRS Natural Product Chemistry Institute | And 2 more authors.
Journal of the American Chemical Society | Year: 2015

Chiral phosphoric acid-catalyzed asymmetric nitroso-Diels-Alder reaction of nitrosoarenes with carbamate-dienes afforded cis-3,6-disubstituted dihydro-1,2-oxazines in high yields with excellent regio-, diastereo-, and enantioselectivities. Interestingly, we observed that the catalyst is able not only to control the enantioselectivity but also to reverse the regioselectivity of the noncatalyzed nitroso-Diels-Alder reaction. The regiochemistry reversal and asynchronous concerted mechanism were confirmed by DFT calculations. © 2015 American Chemical Society.


Nicolas V.,IFR 141 IPSIT | Nicolas V.,University Paris - Sud | Moal V.L.-L.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | Moal V.L.-L.,LabEx LERMIT Laboratory of Excellence in Research on Medication | Moal V.L.-L.,University Paris - Sud
Infection and Immunity | Year: 2015

Both the endogenous antisecretory factor (AF) protein and peptide AF-16, which has a sequence that matches that of the active N-terminal region of AF, inhibit the increase in the epithelial transport of fluid and electrolytes induced by bacterial toxins in animal and ex vivo models. We conducted a study to investigate the inhibitory effect of peptide AF-16 against the increase of transcellular passage and paracellular permeability promoted by the secreted autotransporter toxin (Sat) in a cultured cellular model of the human intestinal epithelial barrier. Peptide AF-16 produced a concentration-dependent inhibition of the Sat-induced increase in the formation of fluid domes, in the mucosal-to-serosal passage of D-[1-14C]mannitol, and in the rearrangements in the distribution and protein expression of the tight junction (TJ)-associated proteins ZO-1 and occludin in cultured human enterocyte-like Caco-2/TC7 cell monolayers. In addition, we show that peptide AF-16 also inhibits the cholera toxin-induced increase of transcellular passage and the Clostridium difficile toxin-induced effects on paracellular permeability and TJ protein organization in Caco-2/TC7 cell monolayers. Treatment of cell monolayers by the lipid raft disorganizer methyl-β-cyclodextrin abolished the inhibitory activity of peptide AF-16 at the transcellular passage level and did not modify the effect of the peptide at the paracellular level. © 2015, American Society for Microbiology.


Gravel E.,CEA Saclay Nuclear Research Center | Harfouche A.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | Salame R.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | Leblanc K.,CNRS Biomolecules: Conception, Isolation, and Synthesis Laboratory | And 2 more authors.
Chemistry - A European Journal | Year: 2013

Mixtures of tryptamine and reactive C5 units, presumably derived from lysine in nature, were studied to ascertain the spontaneous formation of the complex polycyclic alkaloid nitrarine. Several indolic compounds tracing the unified metabolism within the Nitraria genus were also characterized. Des mélanges de tryptamine et d'unités en C5 potentiellement dérivées de la lysine ont été étudiés et ont révélé la formation spontanée de la nitrarine, un alcaloïde polycyclique complexe, mais aussi de squelettes signant l'homogénéité surprenante du métabolisme secondaire dans le genre Nitraria. Just mix! The simple mixing of tryptamine and C5 units (presumably derived from L-lysine in nature) allowed the spontaneous formation of several indolic skeletons, including the unique structure of nitrarine (see scheme). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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