Osteogenic effects of simvastatin-loaded mesoporous titania thin films

The use of statins in the field of bone regeneration is under current investigation due to the existing demand for non-toxic anabolic agents capable of enhancing bone formation in cases of substantial loss. Simvastatin, a coenzyme currently prescribed in clinics to inhibit cholesterol biosynthesis, has been proven to promote osteogenic differentiation by stimulating bone formation and inhibiting osteoclasts activity. We present the loading of simvastatin in mesoporous TiO2 thin films toward combining the pro-osteogenic properties of this molecule with the demonstrated bioactivity of titania. TiO2 thin films processing and characterization were carried out, as well as evaluation of MC3T3-E1 pre-osteoblasts viability when directly incubated with different concentrations of simvastatin, followed by the analysis of osteogenic activity promoted by simvastatin upon loading in the thin films. The accessible porosity of 36% quantified on the 95 ± 5 nm thick mesoporous thin films, together with pore diameters of 5.5 nm, necks between pores of 2.8 nm and interpore distances of 12 ± 2 nm allow the loading of the simvastatin molecule, as confirmed by FTIR spectroscopy. Simvastatin was found to promote MC3T3-E1 pre-osteoblasts viability at concentrations ≤0.01 g l−1, with a cytotoxicity threshold of 0.05 g l−1. We additionally found that film loadings with 0.001 g l−1 simvastatin promotes statistically higher MC3T3-E1 pre-osteoblast proliferation whereas a higher concentration of 0.01 g l−1 leads to statistically higher osteogenic activity (ALP synthesis), after 21 days of incubation, as compared to unloaded films. These results demonstrate the potential of simvastatin local administration based on bioactive mesoporous thin films to promote pro-osteogenic properties. By focusing this strategy on the coating of metallic prostheses, the supply of simvastatin to the target tissue can be favored and risks of systemic side effects will be reduced while enhancing the osteointegration of the implants.Fil: Lopez Alvarez, Miriam. Universidad de Vigo; EspañaFil: López Puente, Vanesa. Universidad de Vigo; EspañaFil: Rodriguez Valencia, Cosme. Universidad de Vigo; EspañaFil: Angelome, Paula Cecilia. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Liz Marzan, Luis M. Ikerbasque; EspañaFil: Serra, Julia. Universidad de Vigo; EspañaFil: Pastoriza Santos, Isabel. Universidad de Vigo; EspañaFil: Gonzalez, Pio. Universidad de Vigo; Españ

Tucumanin, a β-hydroxy-γ-lactone bistetrahydrofuranic acetogenin from Annona cherimolia, is a potent inhibitor of mitochondrial complex I

A new β-hydroxy-γ-methyl-γ-lactone bistetrahydrofuranic acetogenin, tucumanin, with the infrequent symmetrical threo/trans/threo/trans/ threo relative configuration at the tetrahydrofuran rings was isolated from Annona cherimolia (Annonaceae) seeds. The inhibitory potency on the mitochondrial complex I of acetogenins with this relative configuration (tucumanin and asimicin) was compared with that shown by the corresponding pairs with an asymmetrical threo/trans/threo/trans/erythro relative configuration (laherradurin/rolliniastatin-2, and itrabin/molvizarin). All these compounds act as selective inhibitors of mitochondrial complex 1 in the 0.18 - 1.55 nM range.Fil: Barrachina, Isabel. Universidad de Valencia; EspañaFil: Neske, Adriana. Universidad Nacional de Tucumán; ArgentinaFil: Granell, Susana. Universidad de Valencia; EspañaFil: Bermejo, Almudena. Universidad de Valencia; EspañaFil: Chahboune, Nadia. Universidad de Valencia; EspañaFil: El Aouad, Noureddine. Universidad de Valencia; EspañaFil: Alvarez, Olga. Universidad Nacional de Tucumán; ArgentinaFil: Bardon, Alicia del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina. Universidad Nacional de Tucumán; ArgentinaFil: Zafra Polo, M. Carmen. Universidad de Valencia; Españ

Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs

[EN] Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.Financial support from University Sapienza Progetti di Ricerca: grant RP116154C2EF9AC8 and grant RM11715C1743EE89 are acknowledged. Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez and Marival Bermejo acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).Di Meo, C.; Martínez Martínez, M.; Coviello, T.; Bermejo, M.; Merino Sanjuán, V.; Gonzalez-Alvarez, I.; Gonzalez-Alvarez, M.... (2018). Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs. Pharmaceutics. 10(4):1-15. https://doi.org/10.3390/pharmaceutics10040213S115104Allison, D. D., & Grande-Allen, K. J. (2006). Review. Hyaluronan: A Powerful Tissue Engineering Tool. Tissue Engineering, 12(8), 2131-2140. doi:10.1089/ten.2006.12.2131Prestwich, G. D. (2008). Engineering a clinically-useful matrix for cell therapy. Organogenesis, 4(1), 42-47. doi:10.4161/org.6152Ossipov, D. A. (2010). Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opinion on Drug Delivery, 7(6), 681-703. doi:10.1517/17425241003730399Rao, N. V., Yoon, H. Y., Han, H. S., Ko, H., Son, S., Lee, M., … Park, J. H. (2015). Recent developments in hyaluronic acid-based nanomedicine for targeted cancer treatment. Expert Opinion on Drug Delivery, 13(2), 239-252. doi:10.1517/17425247.2016.1112374Dosio, F., Arpicco, S., Stella, B., & Fattal, E. (2016). Hyaluronic acid for anticancer drug and nucleic acid delivery. Advanced Drug Delivery Reviews, 97, 204-236. doi:10.1016/j.addr.2015.11.011Montanari, E., D’Arrigo, G., Di Meo, C., Virga, A., Coviello, T., Passariello, C., & Matricardi, P. (2014). Chasing bacteria within the cells using levofloxacin-loaded hyaluronic acid nanohydrogels. European Journal of Pharmaceutics and Biopharmaceutics, 87(3), 518-523. doi:10.1016/j.ejpb.2014.03.003Svanovsky, E., Velebny, V., Laznickova, A., & Laznicek, M. (2008). The effect of molecular weight on the biodistribution of hyaluronic acid radiolabeled with111In after intravenous administration to rats. European Journal of Drug Metabolism and Pharmacokinetics, 33(3), 149-157. doi:10.1007/bf03191112Harris, E. N., Kyosseva, S. V., Weigel, J. A., & Weigel, P. H. (2006). Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE). Journal of Biological Chemistry, 282(5), 2785-2797. doi:10.1074/jbc.m607787200Choi, K. Y., Min, K. H., Na, J. H., Choi, K., Kim, K., Park, J. H., … Jeong, S. Y. (2009). Self-assembled hyaluronic acid nanoparticles as a potential drug carrier for cancer therapy: synthesis, characterization, and in vivo biodistribution. Journal of Materials Chemistry, 19(24), 4102. doi:10.1039/b900456dPedrosa, S. S., Pereira, P., Correia, A., & Gama, F. M. (2017). Targetability of hyaluronic acid nanogel to cancer cells : In vitro and in vivo studies. European Journal of Pharmaceutical Sciences, 104, 102-113. doi:10.1016/j.ejps.2017.03.045Yang, C., Li, C., Zhang, P., Wu, W., & Jiang, X. (2017). Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors. Theranostics, 7(6), 1719-1734. doi:10.7150/thno.18340Rosso, F., Quagliariello, V., Tortora, C., Di Lazzaro, A., Barbarisi, A., & Iaffaioli, R. V. (2013). Cross-linked hyaluronic acid sub-micron particles: in vitro and in vivo biodistribution study in cancer xenograft model. Journal of Materials Science: Materials in Medicine, 24(6), 1473-1481. doi:10.1007/s10856-013-4895-4Nakai, T., Hirakura, T., Sakurai, Y., Shimoboji, T., Ishigai, M., & Akiyoshi, K. (2012). Injectable Hydrogel for Sustained Protein Release by Salt-Induced Association of Hyaluronic Acid Nanogel. Macromolecular Bioscience, 12(4), 475-483. doi:10.1002/mabi.201100352Montanari, E., Capece, S., Di Meo, C., Meringolo, M., Coviello, T., Agostinelli, E., & Matricardi, P. (2013). Hyaluronic Acid Nanohydrogels as a Useful Tool for BSAO Immobilization in the Treatment of Melanoma Cancer Cells. Macromolecular Bioscience, 13(9), 1185-1194. doi:10.1002/mabi.201300114Montanari, E., Di Meo, C., Sennato, S., Francioso, A., Marinelli, A. L., Ranzo, F., … Matricardi, P. (2017). Hyaluronan-cholesterol nanohydrogels: Characterisation and effectiveness in carrying alginate lyase. New Biotechnology, 37, 80-89. doi:10.1016/j.nbt.2016.08.004Montanari, E., De Rugeriis, M. C., Di Meo, C., Censi, R., Coviello, T., Alhaique, F., & Matricardi, P. (2015). One-step formation and sterilization of gellan and hyaluronan nanohydrogels using autoclave. Journal of Materials Science: Materials in Medicine, 26(1). doi:10.1007/s10856-014-5362-6Di Meo, C., Montanari, E., Manzi, L., Villani, C., Coviello, T., & Matricardi, P. (2015). Highly versatile nanohydrogel platform based on riboflavin-polysaccharide derivatives useful in the development of intrinsically fluorescent and cytocompatible drug carriers. Carbohydrate Polymers, 115, 502-509. doi:10.1016/j.carbpol.2014.08.107Manzi, G., Zoratto, N., Matano, S., Sabia, R., Villani, C., Coviello, T., … Di Meo, C. (2017). «Click» hyaluronan based nanohydrogels as multifunctionalizable carriers for hydrophobic drugs. Carbohydrate Polymers, 174, 706-715. doi:10.1016/j.carbpol.2017.07.003Lozoya-Agullo, I., Araújo, F., González-Álvarez, I., Merino-Sanjuán, M., González-Álvarez, M., Bermejo, M., & Sarmento, B. (2018). PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen. European Journal of Pharmaceutical Sciences, 115, 119-125. doi:10.1016/j.ejps.2017.12.009Samiei, N., Mangas-Sanjuan, V., González-Álvarez, I., Foroutan, M., Shafaati, A., Zarghi, A., & Bermejo, M. (2013). Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments. European Journal of Pharmaceutical Sciences, 49(4), 499-504. doi:10.1016/j.ejps.2013.04.025Wei, X., Senanayake, T. H., Bohling, A., & Vinogradov, S. V. (2014). Targeted Nanogel Conjugate for Improved Stability and Cellular Permeability of Curcumin: Synthesis, Pharmacokinetics, and Tumor Growth Inhibition. Molecular Pharmaceutics, 11(9), 3112-3122. doi:10.1021/mp500290

Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue

[EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects.The authors acknowledge the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, SAF2016-78756 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project GVA/2014/13).Gonzalez-Alvarez, M.; Coll Merino, MC.; Gonzalez-Alvarez, I.; Giménez Morales, C.; Aznar, E.; Martínez-Bisbal, M.; Lozoya Agulló, I.... (2017). Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue. Molecular Pharmaceutics. 14(12):4442-4453. https://doi.org/10.1021/acs.molpharmaceut.7b00565S44424453141

La autoeficacia física percibida y el rendimiento deportivo en taekwondo

En el contexto físico-­‐deportivo una de las variables de mayor interés tanto para entrenadores, deportistas como para el público en general es el rendimiento deportivo. Actualmente se tiende a identificar características o habilidades psicológicas que pueden estar interviniendo en dicho rendimiento. Una de las variables psicológicas más estudiadas, en los últimos años, en relación con el rendimiento deportivo es la auto-­‐confianza en las propias capacidades físicas

Performance of upstream interaction region detectors for the FIRST experiment at GSI

The FIRST (Fragmentation of Ions Relevant for Space and Therapy) experiment at GSI has been designed to study carbon fragmentation, measuring 12C double differential cross sections (∂2σ/ ∂θ∂E) for different beam energies between 100 and 1000 MeV/u. The experimental setup integrates newly designed detectors in the, so called, Interaction Region around the graphite target. The Interaction Region upstream detectors are a 250 μm thick scintillator and a drift chamber optimized for a precise measurement of the ions interaction time and position on the target. In this article we review the design of the upstream detectors along with the preliminary results of the data taking performed on August 2011 with 400 MeV/u fully stripped carbon ion beam at GSI. Detectors performances will be reviewed and compared to those obtained during preliminary tests, performed with 500 MeV electrons (at the BTF facility in the INFN Frascati Laboratories) and 80 MeV/u protons and carbon ions (at the INFN LNS Laboratories in Catania)