The mechanisms of action of SepA, a serine protease, remain unknown although studies have suggested that proteases via their activation of protease activated receptor are involved in the pathogenesis of GI inflammation, in part by increasing paracellular permeability. Interestingly, an increase in paracellular permeability is observed in human mouse xenograft model prior to any mucosal damage but the involvement of SepA in these effects remain unknown. Probably due to the hypoxia of the explants, as previously reported. The decrease of IL-8 secretion induced by S. flexneri could also be due to the death of IL-8 secreting cells such as IEC, immune cells or even neurons. Finally we showed that S. flexneri has the potential to induce degenerative processes both in enteric neurons and glial cells. Until Itacitinib recently, only mucosal components of the gut such as epithelial cells, immune cells were sought to be the target of S. flexneri.Non-expressed promoters have nucleosomes that are less organized and lack an NDR at early stages, suggesting that NDR formation correlates with gene expression. However, blocking hox gene transcription by disruption of the RA signaling pathway results in no change in nucleosome positioning or NDR formation, indicating that transcription does not drive nucleosome organization at hox promoters. This latter suggest that excitotoxic effects of glutamate could be involved in neurodegenerative processes induced following infection with S. flexneri. A previous study has shown that glutamate, via the activation of NMDA receptors, can induce cell death in enteric neurons in vivo or ex vivo. The origin of the glutamate responsible for these effects is currently unknown but could be produced by S. flexneri itself, cells of the mucosal environment or even neurons. The increase in the proportion of VIP-IR neurons observed in this study is probably more to be associated with neurodegenerative processes than to changes in neuronal phenotype. Indeed, the total VIP level in the submucosal plexus was not altered following incubation with S. flexneri, as compared to controls. Therefore, the increase in the proportion of VIP-IR enteric neurons is probably due to reduced axonal transport of VIP and its subsequent accumulation in the neuronal cell body. Indeed, axonal transport is Pixantrone Maleate significantly affected and reduced during early neurodegenerative processes. In conclusion, using an ex vivo model, we have shown that infection by S. flexneri induces rapid mucosal and neuronal alterations in the human colon. In particular, we have shown the major role of SepA in the induction of mucosal desquamation while NMDA dependent pathways could account for S. flexneri – induced degenerative processes in the ENS. Finally, this human model should allow us to gain better insight into the early pathogenic events following S. flexneri infection and the mechanisms involved. The molecular mechanisms underlying the reduced endothelial progenitor cell number and function by high glucose are not yet clearly defined. Recently, Marchetti et al. demonstrated that high glucose levels increased apoptosis of endothelial progenitor cells in vitro and impaired the PI3-kinase/Akt pathway.