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Azzi S.,French Institute of Health and Medical Research | Azzi S.,University Paris - Sud | Gallerne C.,French Institute of Health and Medical Research | Gallerne C.,University Paris - Sud | And 17 more authors.
Neoplasia (United States) | Year: 2015

Intrarenal interleukin-15 (IL-15) participates to renal pathophysiology, but the role of its different membrane-bound isoforms remains to be elucidated. In this study, we reassess the biology of membrane-bound IL-15 (mb-IL-15) isoforms by comparing primary cultures of human renal proximal tubular epithelial cells (RPTEC) to peritumoral (ptumTEC), tumoral (RCC), and cancer stem cells (CSC/CD105+). RPTEC express a 14 to 16 kDa mb-IL-15, whose existence has been assumed but never formally demonstrated and likely represents the isoform anchored at the cell membrane through the IL-15 receptor a (IL-15Rα) chain, because it is sensitive to acidic treatment and is not competent to deliver a reverse signal. By contrast, ptumTEC, RCC, and CSC express a novel N-hyperglycosylated, short-lived transmembrane mb-IL-15 (tmb-IL-15) isoform around 27 kDa, resistant to acidic shock, delivering a reverse signal in response to its soluble receptor (sIL-15Rα). This reverse signal triggers the down-regulation of the tumor suppressor gene E-cadherin in ptumTEC and RCC but not in CSC/CD105+, where it promotes survival. Indeed, through the AKT pathway, tmb-IL-15 protects CSC/CD105+ fromnon-programmed cell death induced by serumstarvation. Finally, both mb-IL-15 and tmb-IL-15 are sensitive to metalloproteases, and the cleaved tmb-IL-15 (25 kDa) displays a powerful antiapoptotic effect on human hematopoietic cells. Overall, our data indicate that both mb-IL-15 and tmb-IL-15 isoforms play a complex role in renal pathophysiology downregulating E-cadherin and favoring cell survival. Moreover, "apparently normal" ptumTEC cells, sharing different properties with RCC, could contribute to organize an enlarged peritumoral "preneoplastic" environment committed to favor tumor progression. © 2015 The Authors.


Nuti E.,University of Pisa | Cuffaro D.,University of Pisa | D'Andrea F.,University of Pisa | Rosalia L.,University of Pisa | And 12 more authors.
ChemMedChem | Year: 2016

Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP-12 inhibitor with improved water solubility, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


Le Visage C.,University Paris Diderot | Gournay O.,French Institute of Health and Medical Research | Benguirat N.,French Institute of Health and Medical Research | Hamidi S.,University Paris Diderot | And 10 more authors.
Tissue Engineering - Part A | Year: 2012

The use of mesenchymal stem cells (MSCs) for tissue regeneration is often hampered by modest engraftment in host tissue. This study was designed to quantitatively compare MSCs engraftment rates after delivery using a polysaccharide-based porous scaffold or endocardial (EC) injection in a rat myocardial infarction model. Cellular engraftment was measured by quantitative reverse transcription-polymerase chain reaction using MSCs previously transduced with a lentiviral vector that expresses green fluorescent protein (GFP). The use of a scaffold promoted local cellular engraftment and survival. The number of residual GFP+ cells was greater with the scaffold than after EC injection (9.7% vs. 5.1% at 1 month and 16.3% vs. 6.1% at 2 months, respectively [n=5]). This concurred with a significant increase in mRNA vascular endothelial growth factor level in the scaffold group (p<0.05). Clusters of GFP + cells were detected in the peri-infarct area, mainly phenotypically consistent with immature MSCs. Functional assessment by echocardiography at 2 months postinfarct also showed a trend toward a lower left ventricular dilatation and a reduced fibrosis in the scaffold group in comparison to direct injection group (n=10). These findings demonstrate that using a porous biodegradable scaffold is a promising method to improve cell delivery and engraftment into damaged myocardium. © 2012 Mary Ann Liebert, Inc.

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