Repurposing of auranofin and honokiol as antifungals against Scedosporium species and the related fungus Lomentospora prolificans.

peer reviewedThe slowing-down de novo drug-discovery emphasized the importance of repurposing old drugs. This is particularly true when combating infections caused by therapy-refractory microorganisms, such as Scedosporium species and Lomentospora prolificans. Recent studies on Scedosporium responses to oxidative stress underscored the importance of targeting the underlying mechanisms. Auranofin, ebselen, PX-12, honokiol, and to a lesser extent, conoidin A are known to disturb redox-homeostasis systems in many organisms. Their antifungal activity was assessed against 27 isolates belonging to the major Scedosporium species: S. apiospermum, S. aurantiacum, S. boydii, S. dehoogii, S. minutisporum, and Lomentospora prolificans. Auranofin and honokiol were the most active against all Scedosporium species (mean MIC50 values of 2.875 and 6.143 μg/ml, respectively) and against L. prolificans isolates (mean MIC50 values of 4.0 and 3.563μg/ml respectively). Combinations of auranofin with voriconazole or honokiol revealed additive effects against 9/27 and 18/27 isolates, respectively. Synergistic interaction between auranofin and honokiol was only found against one isolate of L. prolificans. The effects of auranofin upon exposure to oxidative stress were also investigated. For all species except S. dehoogii, the maximal growth in the presence of auranofin significantly decreased when adding a sublethal dose of menadione. The analysis of the expression of genes encoding oxidoreductase enzymes upon exposure of S. apiospermum to honokiol unveiled the upregulation of many genes, especially those coding peroxiredoxins, thioredoxin reductases, and glutaredoxins. Altogether, these data suggest that auranofin and honokiol act via dampening the redox balance and support their repurposing as antifungals against Scedosporium species and L. prolificans

Etude de la localisation chromosomique et de la transcription du gene codant pour la proteine Xlr (expression Lymphocytaire Regulee Liee a l'X). Mise en evidence d'un nouveau transcrit testiculaire

SIGLEINIST T 76897 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Oxidative stress response pathways in fungi

International audienc

A new motion-based tool for occupation and monitoring of residents in nursing homes

This research received a financial support from the grant n°ANR- 11-IDFI-0033, obtained from IDEFI by the Réseau des Écoles de Management et d’In- génierie de la Santé (www.idefi-remis.fr), a network of schools in health management and engineering. I am immensely grateful to the specialist in psychomotricity for sharing her wisdom with us during this research. I am also grateful La Retraite, a nursing home in Angers, France, for its collaboration. I thank Paul Richard for his contribution (primary transla- tor).International audiencePopulation ageing bring new challenges in healthcare and has raised issues concerning innovative solutions to optimize the management of elderly. As recommended, new interactive tools must be accessible to users, acceptable, easy to use, motivating and useful for both residents and staff. Virtual Reality is a good candidate to fulfill these specifications. Based on our expertise in Human Computer Interaction and Neuropsychology of ageing, we are developing a platform to offer interactive activities adapted to very-old and dependent people living in nursing homes. It is based on the use of a low-cost markerless RGB-D sensor (AstraTM, Orbbec) to track user body motion. Implemented activities were designed to involve various cognitive abilities, such as sorting game, search game, ball game. In addition, a module records several biomechanical data and generates reports for caregivers. This paper aims to discuss the special needs of research context and to present the designed interaction platform

A Stress Hub in Scedosporium apiospermum: The High Osmolarity Glycerol (HOG) Pathway

International audienceScedosporium species are opportunistic filamentous fungi found in human-impacted areas. Clinically relevant species, such as S. apiospermum, rank as the second most frequent colonizers of the airways of patients with cystic fibrosis (CF), which are characterized by persistent oxidative stress. This raises the question of how Scedosporium species abate conditions imposed in hostile environments. Since the High Osmolarity Glycerol (HOG) pathway plays a central role in fungal adaptation to stress, we aimed to pheno-profile the involvement of the pathway in response to stress in S. apiospermum using Western blot. We show for the first time that a wide range of stress distinctively activates the HOG pathway in S. apiospermum, including oxidants (H2O2, menadione, cumene hydroperoxide, diamide, paraquat, and honokiol), osmotic agents (sorbitol and KCl), cell-wall stress agents (caffeine, calcofluor white, and Congo Red), heavy metals (cadmium and arsenite), fungicides (fludioxonil and iprodione), antifungals (voriconazole and amphotericin B), and acid stress (pH 4). We suggest that the function of the HOG pathway as a general stress regulator is also conserved in S. apiospermum

Stratégie antibiofilm pour une ultramicroélectrode à paracétamol durable

National audienc

Repurposing of auranofin and honokiol as antifungals against Scedosporium

peer reviewedThe slowing-down de novo drug-discovery emphasized the importance of repurposing old drugs. This is particularly true when combating infections caused by therapy-refractory microorganisms, such as Scedosporium species and Lomentospora prolificans. Recent studies on Scedosporium responses to oxidative stress underscored the importance of targeting the underlying mechanisms. Auranofin, ebselen, PX-12, honokiol, and to a lesser extent, conoidin A are known to disturb redox-homeostasis systems in many organisms. Their antifungal activity was assessed against 27 isolates belonging to the major Scedosporium species: S. apiospermum, S. aurantiacum, S. boydii, S. dehoogii, S. minutisporum, and Lomentospora prolificans. Auranofin and honokiol were the most active against all Scedosporium species (mean MIC50 values of 2.875 and 6.143 μg/ml, respectively) and against L. prolificans isolates (mean MIC50 values of 4.0 and 3.563μg/ml respectively). Combinations of auranofin with voriconazole or honokiol revealed additive effects against 9/27 and 18/27 isolates, respectively. Synergistic interaction between auranofin and honokiol was only found against one isolate of L. prolificans. The effects of auranofin upon exposure to oxidative stress were also investigated. For all species except S. dehoogii, the maximal growth in the presence of auranofin significantly decreased when adding a sublethal dose of menadione. The analysis of the expression of genes encoding oxidoreductase enzymes upon exposure of S. apiospermum to honokiol unveiled the upregulation of many genes, especially those coding peroxiredoxins, thioredoxin reductases, and glutaredoxins. Altogether, these data suggest that auranofin and honokiol act via dampening the redox balance and support their repurposing as antifungals against Scedosporium species and L. prolificans

Fc-receptor-mediated intracellular delivery of Cu/Zn-superoxyde dismutase (SOD1) protects against redox-induced apoptosis though a nitric oxide dependant mecanism.

International audienceBackground: Using specific antibodies against bovine Cu/Zn-superoxide dismutase (EC 1.15.1.1, SOD1) we demonstrated that anti-SOD antibodies (IgG1) are able to promote the intracellular translocation of the antioxidant enzyme. The transduction signalling mediated by IgG1 immune complexes are known to promote a concomitant production of superoxide and nitric oxide leading to the production of peroxynitrites and cell death by apoptosis. The Fcmediated intracellular delivery of SOD1 thus limited the endogenous production of superoxide. It was thus of interest to confirm that in the absence of superoxide anion, the production of nitric oxide protected cells against apoptosis. Study in greater detail clearly stated that under superoxide anion-free conditions, nitric oxide promoted the cell antioxidant armature and thus protected cells against redox-induced apoptosis. Materials and Methods: The murine macrophage cell-lines J774 A1 were preactivated or not with interferon- and were then stimulated by IgG1 immune complexes (IC), free SOD1 or SOD1 IC and superoxide anion, nitric oxide, peroxynitrite, and tumor necrosis factor- (TNF- ) production was evaluated. The redox consequences of these activation processes were also evaluated on mitochondrial respiration and apoptosis as well as on the controlled expression of the cellular antioxidant armature. Results: We demonstrated that SOD1 IC induced a Fc receptor (Fc R)-dependent intracellular delivery of the antioxidant enzyme in IFN- activated murine macrophages (the J774 A1 cell line). The concomitant stimulation of the Fc R and the translocation of the SOD1 in the cytoplasm of IFN- -activated macrophages not only reduced the production of superoxide anion but also induced the expression of the inducible form of nitric oxide synthase (iNOS) and the related NO production. This inducing effect in the absence of superoxide anion production reduced mitochondrial damages and cell death by apoptosis and promoted the intracellular antioxidant armature. Conclusions: To define the pharmacologic mechanism of action of bovine SOD1, we attempted to identify the second messengers that are induced by SOD1 IC. In this work, we propose that Fcmediated intracellular delivery of the SOD1 that reduced the production of superoxide anion and of peroxynitrite, promoted a NO-induced protective effect in inducing the antioxidant armature of the cells. Taken together, these data suggested that specific immune responses against antigenic SOD1 could promote the pharmacological properties of the antioxidant enzyme likely via a NO-dependent mechanism

Scedosporium boydii CatA1 and SODC recombinant proteins, new tools for serodiagnosis of Scedosporium infection of patients with cystic fibrosis

International audienc

The high osmolarity glycerol (HOG) pathway in fungi

International audienc