Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 Accurate Project).Peer reviewe

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Immunociblage du cerveau par des nanocapsules lipidiques

This thesis concerns the development of a lipidic nanovector recognizing actively the cerebraltissues after its intravenous administration. This system should promote the accumulation into the brain, of therapeutic molecules for the treatment of cerebral diseases such as the malignant gliomas. The first part of our work consisted to attach on the surface of lipid nanocapsules, murine monoclonal antibodies (OX26) or Fab' fragments directed against the rat transferrinreceptor, overexpressed on the cerebral endothelium. Immunonanocapsules bearing between 16 and 183 whole antibodies and between 42 and 173 Fab' fragments were achieved. Their capacity to associate to rat cerebral endothelial cells has then been checked. Moreover, 24after their intravenous administration in rats, the concentration of OX26-immunonanocapsules and Fab'-immunonanocapsules was 2 and 1.5-fold higher than non-targeted nanocapsules.Cette thèse porte sur l'élaboration d'un vecteur particulaire lipidique reconnaissant activementles tissus cérébraux après son administration par voie intraveineuse. Ce système devrait favoriser l'accumulation au sein du cerveau, de molécules thérapeutiques dans le cadre du traitement des maladies cérébrales comme les gliomes malins. La première partie de notre travail consistait à greffer sur la surface de nanocapsules lipidiques (LNC) des anticorpsmonoclonaux d'origine murine (OX26) ou des fragments Fab' dirigés contre le récepteur à la transferrine de rat, surexprimé sur l'endothélium cérébral. Des immunonanocapsules portant entre 16 et 183 anticorps entiers et entre 42 et 173 fragments Fab' ont été obtenues. Leur capacité à s'associer aux cellules endothéliales cérébrales de rat a ensuite été vérifiée. Deplus, 24 h après leur administration chez le rat, la concentration dans le cerveau des OX26-immunonanocapsules et des Fab'-immunonanocapsules était respectivement 2 et 1,5 fois plusélevée que celle des LNC dépourvues de ligands

Influence of nanoparticles on liver tissue and hepatic functions: A review

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Ingestion of titanium dioxide nanoparticles: a definite health risk for consumers and their progeny

International audienceTitanium dioxide (TiO2) is one of the most commonly used nanomaterials in the world. Additive E171, which is used in the food industry, contains a nanometric particle fraction of TiO2. Oral exposure of humans to these nanoparticles (NPs) is intensive, leading to the question of their impact on health. Daily oral intake by rats of amounts of E171 that are relevant to human intake has been associated with an increased risk of chronic intestinal inflammation and carcinogenesis. Due to their food preferences, children are very exposed to this NP. Furthermore, maternal-foetal transfer of TiO2 NPs during pregnancy, as well as exposure of the offspring by breastfeeding, have been recently described. In France, the use of E171 in the production of foodstuffs was suspended in January 2020 as a precautionary measure. To provide some answers to this public health problem and help global regulatory agencies finalize their decisions, we reviewed in vitro and in vivo studies that address the effects of TiO2 NPs through oral exposure, especially their effects on the gastrointestinal tract, one of the most exposed tissues. Our review also highlights the effects of exposure on the offspring during pregnancy and by breastfeeding

Active targeting of brain tumors using nanocarriers.

International audienceThe delivery of drugs to brain tumors is limited by the presence of the blood-brain barrier (BBB) separating the blood from the cerebral parenchyma. An understanding of the specific mechanisms of the brain capillary endothelium has led to the development of various strategies to enhance the penetration of drugs into the brain tissue. Active targeting is a non-invasive approach, which consists in transporting drugs to target organs using site-specific ligands. Drug-loaded nanocarriers capable of recognizing brain capillary endothelial cells and cerebral tumoral cells have shown promising potential in oncology. Endogenous and chimeric ligands binding to carriers or receptors of the BBB have been directly or indirectly conjugated to nanocarriers. This review indexes the main targeted colloidal systems used for drug delivery to the brain. Their pharmacological behavior and their therapeutic effect are discussed

Salting-out effect induced by temperature cycling on a water/nonionic surfactant/oil system.

International audienceThis paper presents original effects induced by temperature cycling on the transitional phase inversion of emulsions, stabilized by a nonionic polyethoxylated C18E6 surfactant model. The phase inversion follow-up is performed by electrical conductivity measurements, which involves focusing the study on the shape and location of the emulsion inversion region. In that way, new observations are brought out as a gradual evolution of the emulsion inversion along the cycling process. Two alternative approaches are considered for tackling these results: (i) first, a molecular approach regarding the particular organization and rearrangement of water clusters surrounding the surfactant polymer polar head, and (ii) second, a thermodynamic approach only considering the whole Gibbs free energy of the system. The volumic approaches are transposed, here, to the water/oil interface, and disclose that the phase inversion zone is included in a metastable region, able to stabilize for a given temperature, either metastable O/W emulsions or stable W/O ones. In that way, this study proposes novel and complementary insights into the phenomena governing the emulsion phase inversion

Small silica nanoparticles transiently modulate the intestinal permeability by actin cytoskeleton disruption in both Caco-2 and Caco-2/HT29-MTX models

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Bioadhesive pellets increase local 5-aminosalicylic acid concentration in experimental colitis

Topical delivery of 5-aminosalicylic acid (5-ASA) to the colonic mucosa is important in order to achieve effective drug concentration in the site of inflammation and to minimize its systemic availability. 5-ASA loaded pellets were prepared by an extrusion/spheronization method. Mucoadhesive biopolymer chitosan was incorporated into the pellets, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® FS. Dissolution profiles of coated pellets revealed no drug release at pH 1.2 within 2h and release as intended in the simulated distal ileum and colon. In vivo, chitosan-core drug loaded pellets (AMCh) showed 2.5-fold higher drug metabolite concentration than after chitosan free pellets (AM) administration in the inflamed colonic tissue. Additionally, AMCh demonstrated decreased in AUC in colitis group (1507 ± 400 ng h/ml) compared with AM (1907 ± 122 ng h/ml). In terms of therapeutic efficiency, administration of pellets markedly decreased the colon/body weight ratio (colitis: 0.0355 ± 0.0028; AM 0.0092 ± 0.0033; AMCh 0.0086 ± 0.0022) and myeloperoxidase activity (colitis: 3212 ± 294 U/g tissue; AM 796 ± 211 U/g; AMCh 552 ± 319 U/g). Bioadhesive chitosan pellets showed additional beneficial properties for colonic 5-ASA delivery in the treatment of inflammatory bowel disease by increasing the drug concentration locally

Crosslinked Fibroin Nanoparticles: Investigations on Biostability, Cytotoxicity, and Cellular Internalization

International audienceRecently, crosslinked fibroin nanoparticles (FNP) using the crosslinker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) or the polymer poly(ethylenimine) (PEI) have been developed and showed potentials as novel drug delivery systems. Thus, this study further investigated the biological properties of these crosslinked FNP by labeling them with fluorescein isothiocyanate (FITC) for in vitro studies. All formulations possessed a mean particle size of approximately 300 nm and a tunable zeta potential (−20 to + 30 mV) dependent on the amount/type of crosslinkers. The FITC-bound FNP showed no significant difference in physical properties compared to the blank FNP. They possessed a binding efficacy of 3.3% w/w, and no FITC was released in sink condition up to 8 h. All formulations were colloidal stable in the sheep whole blood. The degradation rate of these FNP in blood could be controlled depending on their crosslink degree. Moreover, no potential toxicity in erythrocytes, Caco-2, HepG2, and 9L cells was noted for all formulations at particle concentrations of < 1 mg/mL. Finally, all FNP were internalized into the Caco-2 cells after 3 h incubation. The uptake rate of the positively charged particles was significantly higher than the negatively charged ones. In summary, the crosslinked FNP were safe and showed high potentials as versatile systems for biomedical applications