Proof of concept of high-rate decentralized pre-composting of kitchen waste : optimizing design and operation of a novel drum reactor

A

Structurally Simple Osmium(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy in the Near Infrared**

Five osmium(II) polypyridyl complexes of the general formula [Os(4,7‐diphenyl‐1,10‐phenanthroline)$_{2}$L]$^{2+}$ were synthesized as photosensitizers for photodynamic therapy by varying the nature of the ligand L. Thanks to the pronounced π‐extended structure of the ligands and the heavy atom effect provided by the osmium center, these complexes exhibit a high absorption in the near‐infrared (NIR) region (up to 740 nm), unlike related ruthenium complexes. This led to a promising phototoxicity in vitro against cancer cells cultured as 2D cell layers but also in multicellular tumor spheroids upon irradiation at 740 nm. The complex [Os(4,7‐diphenyl‐1,10‐phenanthroline)$_{2}$(2,2′‐bipyridine)]$^{2+}$ was found to be the most efficient against various cancer cell lines, with high phototoxicity indexes. Experiments on CT26 tumor‐bearing BALB/c mice also indicate that the Os$^{II}$ complexes could significantly reduce tumor growth following 740 nm laser irradiation. The high phototoxicity in the biological window of this structurally simple complex makes it a promising photosensitizer for cancer treatment

Heterogenic expression of genes encoding secreted proteins at the periphery of Aspergillus niger colonies

P>Colonization of a substrate by fungi starts with the invasion of exploring hyphae. These hyphae secrete enzymes that degrade the organic material into small molecules that can be taken up by the fungus to serve as nutrients. We previously showed that only part of the exploring hyphae of Aspergillus niger highly express the glucoamylase gene glaA. This was an unexpected finding since all exploring hyphae are exposed to the same environmental conditions. Using GFP as a reporter, we here demonstrate that the acid amylase gene aamA, the alpha-glucuronidase gene aguA, and the feruloyl esterase gene faeA of A. niger are also subject to heterogenic expression within the exploring mycelium. Coexpression studies using GFP and dTomato as reporters showed that hyphae that highly express one of these genes also highly express the other genes encoding secreted proteins. Moreover, these hyphae also highly express the amylolytic regulatory gene amyR, and the glyceraldehyde-3-phosphate dehydrogenase gene gpdA. In situ hybridization demonstrated that the high expressers are characterized by a high 18S rRNA content. Taken together, it is concluded that two subpopulations of hyphae can be distinguished within the exploring mycelium of A. niger. The experimental data indicate that these subpopulations differ in their transcriptional and translational activity

BASHY Dyes Are Highly Efficient Lipid Droplet-Targeting Photosensitizers that Induce Ferroptosis through Lipid Peroxidation

Ferroptosis is an iron-dependent lipid-peroxidation-driven mechanism of cell death and a promising therapeutic target to eradicate cancer cells. In this study, we discovered that boronic acid-derived salicylidenehydrazone (BASHY) dyes are highly efficient singlet-oxygen photosensitizers (PSs; Φ up to 0.8) that induce ferroptosis triggered by photodynamic therapy. The best-performing BASHY dye displayed a high phototoxicity against the human glioblastoma multiform U87 cell line, with an IC value in the low nanomolar range (4.40 nM) and a remarkable phototoxicity index (PI > 22,700). Importantly, BASHY dyes were shown to accumulate in lipid droplets (LDs) and this intracellular partition was found to be essential for the enhanced phototoxicity and the induction of ferroptosis through lipid peroxidation. The safety and phototoxicity of this platform were validated using an in vivo zebrafish model (Danio rerio

Formulation nanométrique de la molécule anti-pathogènes intracellulaires Retro-2.1

Initially identified during a high-throughput screening campaign aiming at finding an antidote to ricin, a vegetal toxin implicated in bioterrorism, the molecule Retro-2.1 provides a potential broad-spectrum therapeutic approach by inhibiting the retrograde transport of intracellular pathogens such as toxins, viruses, parasites and intracellular bacteria. Due to its original mode of action, Retro-2.1 shows a very low toxicity in vitro and in vivo. Moreover, it doesn’t target directly the pathogens, limiting the resistance appearance risk. However, its physicochemical properties, and particularly its low aqueous solubility, limit its clinical interest. Throughout this work, several Retro-2.1 formulations were developed in order to increase its apparent aqueous solubility and to improve its pharmacological profile, including its pharmacokinetic properties and its metabolic stability. These formulations are based on polymeric or cross-linkable surfactants, vegetable oils or thermosensitive hydrogels. These formulations were optimized and their influence on the molecule’s pharmacokinetic properties were studied in a mouse model. Furthermore, an in vitro study of Retro-2.1 metabolism was performed and the results were confirmed in vivo in mice. This study allowed to identify Retro-2.1’s main metabolite which provided a better understanding of the molecule’s behavior once administered in vivo. The results of this study led to the rational development of an administration protocol allowing a prolonged exposure of the animal to the drug in vivo. This administration protocol will allow to evaluate the molecule’s efficiency in several pathology models in vivo. Furthermore, a pegylated water-soluble Retro-2.1 prodrug was synthesized. Preliminary results in vitro show the ability of the prodrug to release the drug in biological media. This new molecule offers new application perspectives.Initialement identifiée comme antidote contre la ricine, une toxine végétale impliquée dans le bioterrorisme, Retro-2.1 offre aujourd'hui une potentielle approche thérapeutique à large spectre en inhibant le transport rétrograde de pathogènes intracellulaires tels que des toxines, des virus, des parasites et des bactéries intracellulaires. En raison de son mode d'action original, cette molécule présente une très faible toxicité in vitro et in vivo et offre l'avantage de ne pas cibler directement le pathogène, limitant le risque d'apparition de résistances chez les agents pathogènes visés. Cependant, ses propriétés physicochimiques, et notamment sa faible solubilité aqueuse, limitent son intérêt clinique. Au cours de ces travaux de thèse, différentes formulations de Retro-2.1 basées sur des surfactants réticulables ou polymériques, des huiles végétales ou des hydrogels thermosensibles ont été optimisées et leur influence sur les paramètres pharmacocinétiques de la molécule a été étudiée chez la souris. L'étude du métabolisme du principe actif in vitro et in vivo chez la souris a permis d'identifier son métabolite majoritaire et a mené à une meilleure compréhension du comportement de cette molécule dans l'organisme. Ces résultats ont guidé le développement d'un protocole d'administration permettant la libération prolongée de Retro-2.1 qui permettra d'évaluer l'efficacité de la molécule in vivo dans différents modèles de pathologie. En outre, une prodrogue soluble d'un analogue de Retro-2.1 capable de libérer la molécule active in vivo après administration a été synthétisée. Cette nouvelle molécule offre de nouvelles perspectives d'applications pour cette famille de composés

Nanometric formulation of the anti-intracellular pathogen inhibitor Retro-2.1

Initialement identifiée comme antidote contre la ricine, une toxine végétale impliquée dans le bioterrorisme, Retro-2.1 offre aujourd'hui une potentielle approche thérapeutique à large spectre en inhibant le transport rétrograde de pathogènes intracellulaires tels que des toxines, des virus, des parasites et des bactéries intracellulaires. En raison de son mode d'action original, cette molécule présente une très faible toxicité in vitro et in vivo et offre l'avantage de ne pas cibler directement le pathogène, limitant le risque d'apparition de résistances chez les agents pathogènes visés. Cependant, ses propriétés physicochimiques, et notamment sa faible solubilité aqueuse, limitent son intérêt clinique. Au cours de ces travaux de thèse, différentes formulations de Retro-2.1 basées sur des surfactants réticulables ou polymériques, des huiles végétales ou des hydrogels thermosensibles ont été optimisées et leur influence sur les paramètres pharmacocinétiques de la molécule a été étudiée chez la souris. L'étude du métabolisme du principe actif in vitro et in vivo chez la souris a permis d'identifier son métabolite majoritaire et a mené à une meilleure compréhension du comportement de cette molécule dans l'organisme. Ces résultats ont guidé le développement d'un protocole d'administration permettant la libération prolongée de Retro-2.1 qui permettra d'évaluer l'efficacité de la molécule in vivo dans différents modèles de pathologie. En outre, une prodrogue soluble d'un analogue de Retro-2.1 capable de libérer la molécule active in vivo après administration a été synthétisée. Cette nouvelle molécule offre de nouvelles perspectives d'applications pour cette famille de composés.Initially identified during a high-throughput screening campaign aiming at finding an antidote to ricin, a vegetal toxin implicated in bioterrorism, the molecule Retro-2.1 provides a potential broad-spectrum therapeutic approach by inhibiting the retrograde transport of intracellular pathogens such as toxins, viruses, parasites and intracellular bacteria. Due to its original mode of action, Retro-2.1 shows a very low toxicity in vitro and in vivo. Moreover, it doesn’t target directly the pathogens, limiting the resistance appearance risk. However, its physicochemical properties, and particularly its low aqueous solubility, limit its clinical interest. Throughout this work, several Retro-2.1 formulations were developed in order to increase its apparent aqueous solubility and to improve its pharmacological profile, including its pharmacokinetic properties and its metabolic stability. These formulations are based on polymeric or cross-linkable surfactants, vegetable oils or thermosensitive hydrogels. These formulations were optimized and their influence on the molecule’s pharmacokinetic properties were studied in a mouse model. Furthermore, an in vitro study of Retro-2.1 metabolism was performed and the results were confirmed in vivo in mice. This study allowed to identify Retro-2.1’s main metabolite which provided a better understanding of the molecule’s behavior once administered in vivo. The results of this study led to the rational development of an administration protocol allowing a prolonged exposure of the animal to the drug in vivo. This administration protocol will allow to evaluate the molecule’s efficiency in several pathology models in vivo. Furthermore, a pegylated water-soluble Retro-2.1 prodrug was synthesized. Preliminary results in vitro show the ability of the prodrug to release the drug in biological media. This new molecule offers new application perspectives

Formulation nanométrique de la molécule anti-pathogènes intracellulaires Retro-2.1

Initially identified during a high-throughput screening campaign aiming at finding an antidote to ricin, a vegetal toxin implicated in bioterrorism, the molecule Retro-2.1 provides a potential broad-spectrum therapeutic approach by inhibiting the retrograde transport of intracellular pathogens such as toxins, viruses, parasites and intracellular bacteria. Due to its original mode of action, Retro-2.1 shows a very low toxicity in vitro and in vivo. Moreover, it doesn’t target directly the pathogens, limiting the resistance appearance risk. However, its physicochemical properties, and particularly its low aqueous solubility, limit its clinical interest. Throughout this work, several Retro-2.1 formulations were developed in order to increase its apparent aqueous solubility and to improve its pharmacological profile, including its pharmacokinetic properties and its metabolic stability. These formulations are based on polymeric or cross-linkable surfactants, vegetable oils or thermosensitive hydrogels. These formulations were optimized and their influence on the molecule’s pharmacokinetic properties were studied in a mouse model. Furthermore, an in vitro study of Retro-2.1 metabolism was performed and the results were confirmed in vivo in mice. This study allowed to identify Retro-2.1’s main metabolite which provided a better understanding of the molecule’s behavior once administered in vivo. The results of this study led to the rational development of an administration protocol allowing a prolonged exposure of the animal to the drug in vivo. This administration protocol will allow to evaluate the molecule’s efficiency in several pathology models in vivo. Furthermore, a pegylated water-soluble Retro-2.1 prodrug was synthesized. Preliminary results in vitro show the ability of the prodrug to release the drug in biological media. This new molecule offers new application perspectives.Initialement identifiée comme antidote contre la ricine, une toxine végétale impliquée dans le bioterrorisme, Retro-2.1 offre aujourd'hui une potentielle approche thérapeutique à large spectre en inhibant le transport rétrograde de pathogènes intracellulaires tels que des toxines, des virus, des parasites et des bactéries intracellulaires. En raison de son mode d'action original, cette molécule présente une très faible toxicité in vitro et in vivo et offre l'avantage de ne pas cibler directement le pathogène, limitant le risque d'apparition de résistances chez les agents pathogènes visés. Cependant, ses propriétés physicochimiques, et notamment sa faible solubilité aqueuse, limitent son intérêt clinique. Au cours de ces travaux de thèse, différentes formulations de Retro-2.1 basées sur des surfactants réticulables ou polymériques, des huiles végétales ou des hydrogels thermosensibles ont été optimisées et leur influence sur les paramètres pharmacocinétiques de la molécule a été étudiée chez la souris. L'étude du métabolisme du principe actif in vitro et in vivo chez la souris a permis d'identifier son métabolite majoritaire et a mené à une meilleure compréhension du comportement de cette molécule dans l'organisme. Ces résultats ont guidé le développement d'un protocole d'administration permettant la libération prolongée de Retro-2.1 qui permettra d'évaluer l'efficacité de la molécule in vivo dans différents modèles de pathologie. En outre, une prodrogue soluble d'un analogue de Retro-2.1 capable de libérer la molécule active in vivo après administration a été synthétisée. Cette nouvelle molécule offre de nouvelles perspectives d'applications pour cette famille de composés

The two Janus faces of CpRu-based deallylation catalysts and their application for in cellulo prodrug uncaging.

In the past 16 years, metal-catalyzed deallylation has proven a useful tool for studying biological processes in cellulo and in the early development of innovative therapeutic catalytic strategies. This reaction is catalyzed by Ru-piano stool complexes and has been reported to be compatible with air, water, and thiol-containing compounds such as glutathione. However, little is known about the true influence of biological components on the outcome of this reaction. The results presented herein reveal that the co-solvent used in this reaction affects the complex’s stability and activity in air, while the presence of glutathione contributes to minimizing the formation of N-allylated by-products. In addition, we studied the effect of air on the Ru-catalyzed deallylation. Importantly, we found that, in the presence of air, the complex is deactivated and oxidizes glutathione into its disulfide

Physical, Spectroscopic, and Biological Properties of Ruthenium and Osmium Photosensitizers Bearing Diversely Substituted 4,4'-di(styryl)-2,2'-bipyridine Ligands

International audienceCapitalising on the previous identification of a distyryl coordinated Ru(II) polypyridine complex as a promising photosensitizer for photodynamic therapy, eight new complexes were synthesized by modifications of the ligands or by changing the metal coordinated. We report in this work the effects of these modifications on the physical, spectroscopic, and biological properties of the synthesized complexes. Subtle structural modifications of the distyryl ligand only had a moderate effect on the corresponding complexes visible light absorption and singlet oxygen quantum yield. These modifications however had a significant effect on the lipophilicity, the cellular uptake and the phototoxicity of the complexes. Although the lipophilicity of the complexes had a somewhat expected effect on their cellular uptake, this last parameter could not be directly correlated to their phototoxicity, revealing other underlying phenomena. Overall, this work allowed to identify two promising ruthenium complexes as photosensitisers for photodynamic therapy and provides some guidance on how to design better photosensitizers

Iodine(III)-Mediated para-Selective Direct Imidation of Anilides

International audienceThe direct, nucleophilic imidation of acetanilide derivatives has been performed under mild, iodine(III)-mediated or -catalyzed conditions, employing lithium triflimide as the nitrogen source. The reaction exhibits exclusive regioselectivity for the para position and shows a good tolerance for varied functional groups at both the ortho or meta positions. Preliminary mechanistic data suggest that the LiNTf2 reagent plays a key role in the reactivity