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Abstract: Epilepsy affects more than 40 million people worldwide, constituting one of the most debilitating disorders of the Central Nervous System (CNS). It results from an imbalance in the electrical activity of neurons, which is primarily mediated by calcium ions. In many cases, treatment with Antiepileptic Drugs (AEDs) that regulate calcium channel activity results in successful seizure control. However, AEDs frequently cause adverse effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure. Moreover, 30% of epileptic patients show drug-resistant epilepsy and do not respond to any form of medical treatment. In this context, nanotechnology has emerged as an excellent tool to overcome AEDs limitations. Numerous nano-strategies have been proposed as therapeutics and diagnostics for epilepsy through inhibition of different calcium channel types in the brain. In addition, limited brain access of classical AEDs in patients showing refractory epilepsy could be improved through the design of targeted drug delivery nanosystems. This report presents a review of the nanocarriers developed so far that could facilitate the interaction with calcium channels in the brain and the transport of AEDs through the blood-brain-barrier, mapping out a potential future direction in the research of epilepsy treatment.

Carrying out exposure studies on children who are not toilet trained is challenging because of the difficulty of urine sampling. In this study, we optimized a protocol for urine collection from disposable diapers for the analysis of phthalate metabolites. The exposure of Swiss children (n = 113) between 6 months and 3 years of life to seven phthalates was assessed by gas chromatography–mass spectrometry measurements. The study showed limited exposures to phthalates, with only 22% of the samples containing some of the metabolites investigated. The three most frequently detected metabolites were monoethyl phthalate, mono-cyclohexyl phthalate, and mono-benzyl phthalate. We also detected mono-n-octyl phthalate and mono(3,5,5-trimethylhexyl) phthalate, which have rarely been observed in urine from infants and toddlers, therefore, di-n-octyl phthalate and bis(3,5,5-trimethylhexyl) phthalate can be considered as potentially new emerging phthalates. This study presents an initial snapshot of the Swiss children’s exposure to phthalates and provides a promising approach for further phthalate biomonitoring studies on young children using disposable diapers as urine sampling technique.

We introduce a nonlinear all-optical theranostics protocol based on the excitation wavelength decoupling between imaging and photoinduced damage of human cancer cells labeled by bismuth ferrite (BFO) harmonic nanoparticles (HNPs). To characterize the damage process, we rely on a scheme for in situ temperature monitoring based on upconversion nanoparticles: by spectrally resolving the emission of silica coated NaGdF4:Yb3+/Er3+ nanoparticles in close vicinity of a BFO HNP, we show that the photointeraction upon NIR-I excitation at high irradiance is associated with a temperature increase >100 °C. The observed laser–cell interaction implies a permanent change of the BFO nonlinear optical properties, which can be used as a proxy to read out the outcome of a theranostics procedure combining imaging at 980 nm and selective cell damage at 830 nm. The approach has potential applications to monitor and treat lesions within NIR light penetration depth in tissues.

The first total synthesis of the alkaloid natural product jerantinine E is based on a selective cyclization of an aminocyclopropane. Preliminary investigations show that it inhibits the polymerization of tubulin, displaying significant cytotoxicity and antimigratory activity against both breast and lung cancer cell lines.

Bone substitute materials allowing trans-scaffold migration and in-scaffold survival of human bone-derived cells are mandatory for development of cell-engineered permanent implants to repair bone defects. In this study, we evaluated the influence on human bone-derived cells of the material composition and microstructure of foam scaffolds of calcium aluminate. The scaffolds were prepared using a direct foaming method allowing wide-range tailoring of the microstructure for pore size and pore openings. Human fetal osteoblasts (osteo-progenitors) attached to the scaffolds, migrated across the entire bioceramic depending on the scaffold pore size, colonized, and survived in the porous material for at least 6 weeks. The long-term biocompatibility of the scaffold material for human bone-derived cells was evidenced by in-scaffold determination of cell metabolic activity using a modified MTT assay, a repeated WST-1 assay, and scanning electron microscopy. Finally, we demonstrated that the osteo-progenitors can be covalently bound to the scaffolds using biocompatible click chemistry, thus enhancing the rapid adhesion of the cells to the scaffolds. Therefore, the different microstructures of the foams influenced the migratory potential of the cells, but not cell viability. Scaffolds allow covalent biocompatible chemical binding of the cells to the materials, either localized or widespread integration of the scaffolds for cell-engineered implants.

Bismuth Ferrite (BFO) nanoparticles (BFO-NP) display interesting optical (nonlinear response) and magnetic properties which make them amenable for bio-oriented applications as intra- and extra membrane contrast agents. Due to the relatively recent availability of this material in well dispersed nanometric form, its biocompatibility was not known to date. In this study, we present a thorough assessment of the effects of in vitro exposure of human adenocarcinoma (A549), lung squamous carcinoma (NCI-H520), and acute monocytic leukemia (THP-1) cell lines to uncoated and poly(ethylene glycol)-coated BFO-NP in the form of cytotoxicity, haemolytic response and biocompatibility. Our results support the attractiveness of the functional-BFO towards biomedical applications focused on advanced diagnostic imaging., Word Count: 109 Complete Word Count (body text and figure legends) : 4886 Number of Figures: 6 Number of Tables: 0 Number of reference: 45

A novel bio-photonics approach based on the nonlinear optical process of second harmonic generation by non-centrosymmetric nanoparticles is presented and demonstrated on malignant human cell lines. The proposed method allows to directly interact with DNA in absence of photosensitizing molecules, to enable independent imaging and therapeutic modalities switching between the two modes of operation by simply tuning the excitation laser wavelength, and to avoid any risk of spontaneous activation by any natural or artificial light source.

Surface functionalization of hydroxyapatite (HA) and ?-tricalcium phosphate (TCP) bioceramics with chemical ligands containing a pyrrogallol moiety was developed to improve the adhesion of bone cell precursors to the biomaterials. Fast and biocompatible copper-free click reaction with azido-modified human fetal osteoblasts resulted in improved cell binding to both HA and TCP bioceramics, opening the way for using this methodology in the preparation of cell-engineered bone implants.

Ten oxidosqualene c-yclase inhibitors with high efficacy as cholesterol-lowering agents and of different chemical structure classes were evaluated as potential anticancer agents against human cancer cells from various tissue origins and nontumoral human-brain-derived endothelial cells. Inhibition of cancer cell growth was demonstrated at micromolar concentrations, comparable to the concentrations of statins necessary for antitumor effect. Human glioblastoma cells were among the most sensitive cells. These compounds were also able to decrease the proliferation of angiogenic brain-derived endothelial cells, as a model of tumor-induced neovasculation. Additive effects in human glioblastoma cells were also demonstrated for oxidosqualene cyclase inhibitors in combination with atorvastatin while maintaining selectivity against endothelial cells. Thus, not only statins targeting the 3-hydroxy-3-methylglutaryl coenzyme A reductase but also inhibitors of oxidosqualene cyclase decrease tumor growth, suggesting new therapeutic opportunities of combined anti-cholesterol agents for dual treatment of glioblastoma.

International audience; Nonlinear optical nanocrystals have been recently introduced as a promising alternative to fluorescent probes for multiphoton microscopy. We present for the first time a complete survey of the properties of five nanomaterials (KNbO3, LiNbO3, BaTiO3, KTP, and ZnO), describing their preparation and stabilization and providing quantitative estimations of their nonlinear optical response. In the light of their prospective use as biological and clinical markers, we assess their biocompatibility on human healthy and cancerous cell lines. Finally, we demonstrate the great potential for cell imaging of these inherently nonlinear probes in terms of optical contrast, wavelength flexibility, and signal photostability.

The pro-inflammatory cytokine TNF-α and the female hormone estrogen have been implicated in the pathophysiology of two common gynecological diseases, endometriosis and endometrial adenocarcinoma. Here we describe a novel capacity of TNF-α to activate ER signaling in endometrial epithelial cells. TNF-α induced luciferase expression in the absence and presence of estradiol and also augmented expression of the estrogen-regulated genes c-fos, GREB1, and progesterone receptor. Furthermore, TNF-α mediated ER transcriptional activity is dependent on the Extracellular Regulated Kinase (ERK) 1/2 pathway. Co-treatment with a pure ER antagonist resulted in an inhibition of this TNF-α-induced ERE luciferase activity and gene expression, demonstrating that this cytokine signals through ERs. Additional investigations confirmed that TNF-α acts specifically via ERα. Taken together, these data provide a rationale for the potential use of inhibitors of TNF-α and estrogen production/activity in combination for the treatment of endometrial pathologies.

To control the selective adhesion of human endothelial cells and human serum proteins to bioceramics of different compositions, a multifunctional ligand containing a cyclic arginine-glycine-aspartate (RGD) peptide, a tetraethylene glycol spacer, and a gallate moiety was designed, synthesized, and characterized. The binding of this ligand to alumina-based, hydroxyapatite-based, and calcium phosphate-based bioceramics was demonstrated. The conjugation of this ligand to the bioceramics induced a decrease in the nonselective and integrin-selective binding of human serum proteins, whereas the binding and adhesion of human endothelial cells was enhanced, dependent on the particular bioceramics.

The chemical functionalization of cell-surface proteins of human primary fetal bone cells with hydrophilic bioorthogonal intermediates was investigated. Toward this goal, chemical pathways were developed for click reaction-mediated coupling of alkyne derivatives with cellular azido-expressing proteins. The incorporation via a tetraethylene glycol linker of a dipeptide and a reporter biotin allowed the proof of concept for the introduction of cell-specific peptide ligands and allowed us to follow the reaction in living cells. Tuning the conditions of the click reaction resulted in chemical functionalization of living human fetal osteoblasts with excellent cell survival.

Catherine A Schütz,1,* Davide Staedler,2,* Kieran Crosbie-Staunton,3 Dania Movia,4 Catherine Chapuis Bernasconi,1 Blanka Halamoda Kenzaoui,1 Adriele Prina-Mello,3,4 Lucienne Juillerat-Jeanneret11Centre Hospitalier Universitaire Vaudois (CHUV), UNIL, 2Institute of Chemical Sciences and Engineering, EPFL, CH-1015, Lausanne, Switzerland; 3School of Medicine, 4CRANN, Trinity College Dublin, Dublin, Ireland*These authors contributed equally to this workAbstract: Therapeutic engineered nanoparticles (NPs), including ultrasmall superparamagnetic iron oxide (USPIO) NPs, may accumulate in the lower digestive tract following ingestion or injection. In order to evaluate the reaction of human colon cells to USPIO NPs, the effects of non-stabilized USPIO NPs (NS-USPIO NPs), oleic-acid-stabilized USPIO NPs (OA-USPIO NPs), and free oleic acid (OA) were compared in human HT29and CaCo2colon epithelial cancer cells. First the biophysical characteristics of NS-USPIO NPs and OA-USPIO NPs in water, in cell culture medium supplemented with fetal calf serum, and in cell culture medium preconditioned by HT29and CaCo2cells were determined. Then, stress responses of the cells were evaluated following exposure to NS-USPIO NPs, OA-USPIO NPs, and free OA. No modification of the cytoskeletal actin network was observed. Cell response to stress, including markers of apoptosis and DNA repair, oxidative stress and degradative/autophagic stress, induction of heat shock protein, or lipid metabolism was determined in cells exposed to the two NPs. Induction of an autophagic response was observed in the two cell lines for both NPs but not free OA, while the other stress responses were cell- and NP-specific. The formation of lipid vacuoles/droplets was demonstrated in HT29and CaCo2cells exposed to OA-USPIO NPs but not to NS-USPIO NPs, and to a much lower level in cells exposed to equimolar concentrations of free OA. Therefore, the induction of lipid vacuoles in colon cells exposed to OA utilized as a stabilizer for USPIO NPs is higly amplified compared to free OA, and is not observed in the absence of this lipid in NS-USPIO NPs.Keywords: oleic acid, ultrasmall iron oxide nanoparticles, human colon cells, lipid vacuoles, stress reaction, heat shock proteins