Silver nanoparticles impair retinoic acid-inducible gene I mediated mitochondrial anti-viral immunity by blocking the autophagic flux in lung epithelial cells

Silver nanoparticles (AgNPs) are microbicidal agents which could be potentially used as alternative to antivirals to treat human infectious diseases, especially Influenza virus infection where antivirals have generally proven unsuccessful. However, concerns about the use of AgNPs on humans arise from their potential toxicity, although mechanisms are not well-understood. We show here, in the context of Influenza virus infection of lung epithelial cells, that AgNPs down-regulated Influenza induced-CCL-5 and -IFN-β release (two cytokines important in anti-viral immunity) through RIG-I inhibition, while enhancing IL-8 production, a cytokine important for mobilizing host antibacterial responses. AgNPs activity was independent of coating and was not observed with gold nanoparticles. Down-stream analysis indicated that AgNPs disorganized the mitochondrial network and prevented the anti-viral IRF-7 transcription factor influx into the nucleus. Importantly, we showed that the modulation of RIG-I-IRF-7 pathway was concomitant with inhibition of either classical or alternative autophagy (ATG-5- and Rab-9 dependent, respectively), depending on the epithelial cell type used. Altogether, this demonstration of a AgNPs-mediated functional dichotomy (down-regulation of IFN-dependent anti-viral responses and up-regulation of IL-8 -dependent antibacterial responses) may have practical implications for their use in the clinic

Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex

<p>Abstract</p> <p>Background</p> <p>Secretory leukoproteinase inhibitor (SLPI) is an important inhibitor of neutrophil elastase (NE), a proteinase implicated in the pathogenesis of lung diseases such as COPD. SLPI also has antimicrobial and anti-inflammatory properties, but the concentration of SLPI in lung secretions in COPD varies inversely with infection and the concentration of NE. A fall in SLPI concentration is also seen in culture supernatants of respiratory cells exposed to NE, for unknown reasons. We investigated the hypothesis that SLPI complexed with NE associates with cell membranes <it>in vitro</it>.</p> <p>Methods</p> <p>Respiratory epithelial cells were cultured in the presence of SLPI, varying doses of proteinases over time, and in different experimental conditions. The likely predicted charge of the complex between SLPI and proteinases was assessed by theoretical molecular modelling.</p> <p>Results</p> <p>We observed a rapid, linear decrease in SLPI concentration in culture supernatants with increasing concentration of NE and cathepsin G, but not with other serine proteinases. The effect of NE was inhibited fully by a synthetic NE inhibitor only when added at the same time as NE. Direct contact between NE and SLPI was required for a fall in SLPI concentration. Passive binding to cell culture plate materials was able to remove a substantial amount of SLPI both with and without NE. Theoretical molecular modelling of the structure of SLPI in complex with various proteinases showed a greater positive charge for the complex with NE and cathepsin G than for other proteinases, such as trypsin and mast cell tryptase, that also bind SLPI but without reducing its concentration.</p> <p>Conclusion</p> <p>These data suggest that NE-mediated decrease in SLPI is a passive, charge-dependent phenomenon <it>in vitro</it>, which may correlate with changes observed <it>in vivo</it>.</p

A star-shaped molecule as hole transporting material in solution-processed thin-film transistors

The semiconductor potentialities of a new star-shaped molecule consisting of a triphenylamine core carrying π-conjugated thiophene and thieno[3,2-b]-thiophene-C9H19 units, VM5C9, has been evaluated by its implementation as active layer in organic thin-film transistors (OTFTs). The photophysical properties of VM5C9 were previously studied by UV–vis absorption and emission spectroscopy in both dilute solutions and thin films. The latter were prepared from solutions in toluene, chloroform (CHCl3), dichloromethane (CH2Cl2) and tetrahydrofuran (THF) by spin-coating on substrates following by an annealing to a controlled temperature ranging from 60 °C to 90 °C. Thin-film morphology and structure were characterized by X-ray diffraction and scanning electron microscopy. Solution processed thin films lead to glassy films. An optimized hole mobility up to 3.8 × 10−4 cm2/V s could be reached by a fine control of the liquid-phase deposition method, the choice of solvent and post-annealing temperature

Systèmes Thienylène-Phénylène sous l'œil du physico-chimiste. Apport du couplage SPE-UV/Quantochimie.

Il existe de nombreuses familles d'oligomères Π-conjugués, telles que celles des oligothiophènes et des oligophénylènes, qui représentent une classe importante de semi-conducteurs. [1] Les propriétés électroniques et optiques sont liées à la fois à la nature des motifs conjugués et également à la longueur de la conjugaison. Plusieurs questions importantes se posent : comment déterminer puis prévoir leurs propriétés, quantifier expérimentalement les interactions inter-cycles, aller plus loin dans la description de ces modèles ? Nous montrerons que l'apport de la physico-chimie s'avère ici intéressant et qu'en particulier la spectroscopie photoélectronique à rayonnement UV, en phase gazeuse, peut être un outil puissant afin de mettre en évidence et quantifier la « magnitude » des interactions Πphényle-Πthiophène. [2] Couplé à la quantochimie, ce « tandem » permet d'aller encore plus loin dans l'étude de ces systèmes, notamment en précisant la nature et l'allure des orbitales intervenant dans la délocalisation mais également en décrivant la nature des interactions favorisant la quasi-planéité de ces systèmes : interactions électrostatique, électronique ... ? Ainsi vous pourrez d'une part comprendre quel rôle jouent les substituants au niveau de la structure géométrique de ces composés et d'autre part « visualiser » expérimentalement leur implication dans la délocalisation. [1] a) S. Hotta, S. A. Lee, Synth. Met. 1999, 101, 551; b) S. Hotta, S. A. Lee, T. Tamaki J. Heterocyclic Chem. 2000, 37, 25; c) S. Hotta, S. A. Lee, H. Kimura J. Heterocyclic Chem. 2000, 37, 25. [2] S. Lois, J.-Ch. Florès, J.-P. Lère-Porte, F. Serein-Spirau, J.E.Moreau, K. Miqueu, J.-M. Sotiropoulos, P. Baylère, M. Tillard, C. Belin Eur. Org. Chem. sous press

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways

Author Correction: Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis (Scientific Reports, (2019), 9, 1, (6516), 10.1038/s41598-019-42751-4)

An amendment to this paper has been published and can be accessed via a link at the top of the paper

WAPing out pathogens and disease in the mucosa: roles for SLPI and Trappin-2

The interface between the external environment and the body’s internal structures is defined by the mucosal tissue and the viscous lining fluid that is responsible for maintaining its integrity and protecting internal structures from damage or infection. Human mucosal fluids include seminal fluid, cervical mucus, bronchial and nasal secretions and tears whose composition is particularly complicated. This review will focus on just two related molecules that are present in the mucosal lining fluid, namely, trappin-2 and secretory leucocyte protease inhibitor (SLPI), that are responsible for many of the homeostatic and host defence functions of these uniquely situated viscous sols. This review will focus on our increasing understanding of these two molecules from a simple role as local antibiotics that respond to pathogen invasion to major orchestrators of cellular interplays, host defence mechanisms and immune homeostasis