Analyses structurales et fonctionnelles de l'hémoglobine extracellulaire de l'annélide polychète Arenicola marina dans les cadre de la mise au point d'un substitut sanguin

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Nigratine as first-in-class dual inhibitor of necroptosis and ferroptosis regulated cell death

Nigratine (also known as 6E11), a natural flavanone derivative, was characterized as highly specific non-ATP competitive inhibitor of RIPK1 kinase, one of the key component of necroptotic cell death signaling. We show here that nigratine inhibited both necroptosis (induced by Tumor Necrosis Factor-α) and ferroptosis (induced by glutamate, erastin or RSL3 small chemical compounds) with EC50 in the µM range. Altogether, the data obtained showed that nigratine is the first-in-class dual inhibitor of necroptosis and ferroptosis cell death routes and opened new therapeutic avenues for treating complex necrosis-related diseases

Dose-Ranging Study of the Performance of the Natural Oxygen Transporter HEMO 2 Life in Organ Preservation

International audienceThe intensity of ischemia-reperfusion injury of the donor organ during the preservation phase and after anastomosis is acknowledged as being a key factor for long-term graft outcome. We previously showed that the addition of 5 g/L of the natural oxygen carrier HEMO(2)Life was beneficial for the cold static preservation of kidney grafts in both University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate solutions. Herein, we refined these findings by evaluating HEMO(2)Life at various dose levels in UW, both in vitro with endothelial cells and in vivo in a pig kidney autotransplantation preclinical model. We showed in vitro that cells were significantly better preserved with HEMO(2)Life in a dose-dependent manner, with benefits in terms of survival, metabolic activity, and cellular integrity. In vivo, serum creatinine measurements at reperfusion confirmed the important benefits of HEMO(2)Life treatment on function recovery at the dose levels of 1, 2, and 5 g/L. Likewise, histological analysis of kidney parenchyma biopsies from day 7 confirmed the superiority of HEMO(2)Life-supplemented UW over UW alone, and there was no difference between the doses. Three months' follow-up confirmed the trend of the first 2 weeks, with creatinine and fibrosis levels similar to those in pretransplant kidneys

A Transversal Approach Combining In Silico, In Vitro and In Vivo Models to Describe the Metabolism of the Receptor Interacting Protein 1 Kinase Inhibitor Sibiriline

International audienceSibiriline is a novel drug inhibiting receptor-interacting protein 1 kinase (RIPK1) and necroptosis, a regulated form of cell death involved in several disease models. In this study, we aimed to investigate the metabolic fate of sibiriline in a cross-sectional manner using an in silico prediction, coupled with in vitro and in vivo experiments. In silico predictions were performed using GLORYx and Biotransformer 3.0 freeware; in vitro incubation was performed on differentiated human HepaRG cells, and in vivo experiments including a pharmacokinetic study were performed on mice treated with sibiriline. HepaRG culture supernatants and mice plasma samples were analyzed with ultra-high-performance liquid chromatography, coupled with tandem mass spectrometry (LC-HRMS/MS). The molecular networking bioinformatics tool applied to LC-HRMS/MS data allowed us to visualize the sibiriline metabolism kinetics. Overall, 14 metabolites, mostly produced by Phase II transformations (glucuronidation and sulfation) were identified. These data provide initial reassurance regarding the toxicology of this new RIPK1 inhibitor, although further studies are required

In vivo biodistribution and oxygenation potential of a new generation of oxygen carrier.

International audienceNatural giant extracellular hemoglobins (Hbs) from polychaete annelids are currently actively investigated as promising oxygen carriers. Their powerful oxygenating ability and their safety have been demonstrated in preclinical studies, motivating their development for therapeutic and industrial applications. HEMARINA-M101 (M101) is derived from the marine invertebrate Arenicola marina. It is formulated as a manufactured product designated HEMOXYCarrier(®) (HEMARINA SA, France). The aim of the present study was to unveil the fate of M101 after a single intravenous (i.v.) injection in mice. For this purpose, M101 was tagged with a far-red fluorescent dye. Repeated non-invasive fluorescent imaging revealed a rapid diffusion of M101 in the whole body of animals, reaching all the examined organs such as brain, liver, lungs and ovaries. Functional M101 was circulating in bloodstream for several hours, without inducing any obvious side-effects. Last, a single i.v. injection of M101 in mice bearing human-derived subcutaneous tumors demonstrated the ability of this Hb to reduce hypoxia in poorly vascularized tissues, thus supporting the biological relevance of M101 oxygen release to vertebrate tissues. Altogether, these results further encourage the development of M101 as an oxygen carrying therapeutic

Nigratine as dual inhibitor of necroptosis and ferroptosis regulated cell death

International audienceNigratine (also known as 6E11), a flavanone derivative of a plant natural product, was characterized as highly specific non-ATP competitive inhibitor of RIPK1 kinase, one of the key components of necroptotic cell death signaling. We show here that nigratine inhibited both necroptosis (induced by Tumor Necrosis Factor-α) and ferroptosis (induced by the small molecules glutamate, erastin, RSL3 or cumene hydroperoxide) with EC 50 in the µM range. Taken together, our data showed that nigratine is a dual inhibitor of necroptosis and ferroptosis cell death pathways. These findings open potential new therapeutic avenues for treating complex necrosis-related diseases

Spatially-consistent Feature Matching and Learning for Heritage Image Analysis

International audienceProgress in the digitization of cultural assets leads to online databases that become too large for a human to analyze. Moreover, some analyses might be challenging, even for experts. In this paper, we explore two applications of computer vision to analyze historical data: watermark recognition and one-shot repeated pattern detection in artwork collections. Both problems present computer vision challenges which we believe to be representative of the ones encountered in cultural heritage applications: limited supervision is available, the tasks are fine-grained recognition, and the data comes in several different modalities. Both applications are also highly practical, as recognizing watermarks makes it possible to date and locate documents, while detecting repeated patterns allows exploring visual links between artworks. We demonstrate on both tasks the benefits of relying on deep mid-level features. More precisely, we define an image similarity score based on geometric verification of mid-level features and show how spatial consistency can be used to fine-tune out-of-the-box features for the target dataset with weak or no supervision. This paper relates and extends our previous works. Our code and data are available at \url{http://imagine.enpc.fr/~shenx/HisImgAnalysis/}

L’accès à l’eau en Afrique

En 2019, près de 60 % de la population de l’Afrique subsaharienne n’a pas un accès minimal à l’eau, soit près de 800 millions de personnes. Même dans les pays les plus riches, comme l’a montré la crise de l’eau dans la ville du Cap en 2018, la situation est précaire et marquée par de fortes inégalités. Naturalisation — le manque d’eau serait dû à la sécheresse — et fatalisme — la pénurie serait structurelle en Afrique — dominent les discours. Il y a plus de 25 ans, la conférence internationale sur l’eau et l’environnement de Dublin de 1992, avait proposé un « modèle » mondial de gestion de l’eau, fondé sur la gestion intégrée des ressources en eau, les partenariats public-privé et la marchandisation de la ressource en eau. Mais ces politiques ont prouvé leurs limites en Afrique lorsqu’elles ont été appliquées dans des territoires où les configurations hydro-sociales étaient très différentes de celles des pays du Nord où elles avaient été pensées. Les douze chapitres de ce livre, regroupés autour de trois thèmes (compétitions, conflits et coopérations autour de l’accès et des usages de l’eau ; échelles et modalités de la gestion de l’eau ; justices et injustices) montrent, au contraire, l’émergence de nouvelles conditions diversifiées d’accès à la ressource, qui reposent sur des formes de solidarités anciennes ou émergentes, et qui intègrent les configurations hydro-sociales locales. L’objectif de cet ouvrage est d’explorer, à partir de situations concrètes fondées sur des données empiriques récentes, ces formes nouvelles d’organisation, et de voir dans quelle mesure elles pourraient apporter des solutions alternatives aux nombreux problèmes actuels liées à l’accès inégal à l’eau en Afrique

Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor

International audienceThe purpose of this work is to investigate the protein kinase inhibitory activity of constituents from stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia