Complejos metalosupramoleculares de Cu(I), Ag(I), Au(I), Pd(II) y Pt(II): síntesis, caracterización estructural y propiedades biológicas

En esta tesis se han desarrollado compuestos metalosupramoleculares de Cu(I), Ag(I), Au(I), Pd(II) y Pt(II) a partir de ligandos funcionalizados con fosfinas (bases de Schiff, tiosemicarbazonas y semicarbazona), que han permitido obtener información valiosa para la comprensión de los procesos de autoensamblaje en sistemas de esta naturaleza. Particularmente, se ha estudiado en detalle el proceso de desulfurización de un helicato clúster doble derivado de Ag(I) y tiosemicarbazona. La gran relevancia de algunos de estos iones metálicos a nivel biológico ha permitido evaluar de forma preliminar la aplicación de alguno de los complejos como posibles metalofármacos

Prothymosin α is phosphorylated by casein kinase-2

AbstractProthymosin α (ProTα) is a 12.5 kDa acidic polypeptide that is considered to have a nuclear function related to cell proliferation. Inspection of its amino acid sequence revealed the presence of sequences that may serve as targets for phosphorylation by casein kinase-2 (CK-2). ProTα isolated from calf thymocytes was phosphorylated in vitro by CK-2. The phosphorylation sites are Ser and Thr residues located among the first 14 amino acid residues in the ProTα sequence. Another site that is theoretically suitable for phosphorylation by CK-2, at the C-terminus of the polypeptide, is not, in fact, phosphorylated. Thymosin α1 (Tα1), a peptide whose sequence corresponds to the first 28 amino acids of ProTα, is also phosphorylated by CK-2 at the same phosphorylation sites as ProTα. In cultured splenic lymphocytes ProTα was phosphorylated at Thr residues located at positions 7, 12 and/or 13. Based on these observations we conclude that CK-2, or another cellular kinase with similar sequence specifity, is responsible for phosphorylation of ProTα in vivo

Design, development, and characterization of an idebenone-loaded poly-ε-caprolactone intravitreal implant as a new therapeutic approach for LHON treatment

Leber's Hereditary Optic Neuropathy (LHON) is a hereditary mitochondrial neurodegenerative disease of unclear etiology and lack of available therapeutic alternatives. The main goal of the current pilot study was based on the evaluation of the feasibility and characteristics of prolonged and controlled idebenone release from a PCL intravitreal implant. The design, development, and characterization of idebenone-loaded PCL implants prepared by an homogenization/extrusion/solvent evaporation method allowed the obtention of high PY, EE and LC values. In vitro characterization was completed by the assessment of mechanical and instrumental properties. The in vitro release of idebenone from the PCL implants was assessed and the implant erosion was monitored by the mass loss and surface morphology changes. DSC was used to estimate stability and interaction among implant’s components. The present work demonstrated the controlled and prolonged idebenone delivery from the PCL implants in an in vitro model. A consistent preclinical base was established, supporting the idea of idebenone-loaded PCL implants as a new strategy of long-term sustained intraocular delivery for the LHON treatmentRVF acknowledges the financial support of the FIDIS (Health Research Institute of Santiago de Compostela Foundation). This work was supported by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100)S

Oxidative stress-induced angiogenesis is mediated by miR-205-5p

miR-205-5p is known to be involved in VEGF-related angiogenesis and seems to reg-ulate associated cell signalling pathways, such as cell migration, proliferation and ap-optosis. Therefore, several studies have focused on the potential role of miR-205-5p as an anti-angiogenic factor. Vascular proliferation is observed in diabetic retinopathy and the ‘wet’ form of age-related macular degeneration. Today, the most common treatments against these eye-related diseases are anti-VEGF therapies. In addition, both AMD and DR are typically associated with oxidative stress; hence, the use of antioxidant agents is accepted as a co-adjuvant therapy for these patients. According to previous data, ARPE-19 cells release pro-angiogenic factors when exposed to oxi-dative insult, leading to angiogenesis. Matching these data, results reported here, indicate that miR-205-5p is modulated by oxidative stress and regulates VEGFA-angiogenesis. Hence, miR-205-5p is proposed as a candidate against eye-related pro-liferative diseasesUniversidad Católica de Valencia San Vicente Mártir research Fund and Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, Grant/Award Number: 2018-128-001, 2019-128-001; Escuela de Doctorado Universidad Católica de Valencia San Vicente Mártir, Grant/Award Number: EDUCV-PRE-2015-006 and EDUCV-PRE-2016-005Medicin

Enhancement in corneal permeability of riboflavin using cyclodextrin derivates complexes as a previous step to transepithelial cross-linking

Corneal cross-linking has been described as an effective treatment to slow the progression of keratoconus. The standard protocol entails corneal epithelial removal to allow the diffusion of riboflavin into the stroma. Although, de-epithelization can generate risks or complications that transepithelial cross-linking tries to solve or avoid. Different formulations were developed after verifying that hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobuthylether-β-cyclodextrin (SBEβCD) in a 20% concentration, increased the solubility of practically insoluble in water drugs such as riboflavin from 0.12 mg/mL to 0.35 mg/mL and 0.29 mg/mL respectively. These values were higher when chitosan and arginine were added to the formulation, showing solubility of 0.78 mg/mL when HPβCD concentration was not modified. Ex vivo corneal permeability was measured after having kept in contact bovine corneas with intact epithelium for 5 h with the 0.1 mg/mL riboflavin solution, the formulations developed and a reproduced nanoemulsion from another work. Riboflavin’s permeability was increased when cyclodextrins, chitosan, and arginine were part of the formulations, compared to the control drug solution. The best permeability coefficient was reached when riboflavin was combined with 40% (w/v) HPβCD, 0.5% (w/w) arginine, and 0.5% (w/w) chitosan. After having carried out toxicity studies as bovine corneal opacity and permeability (BCOP) and Heńs Egg Test - Chorioallantoic Membrane Test (HET-CAM) it was verified that both, the active ingredients and the excipients of the different formulations were not harmful without generating irritation, loss of transparency or corneal permeability alterations. The results show the great potential of the ocular developed solution for their use in transepithelial cross-linking for keratoconus treatmentS

La realidad aumentada en la docencia de ciencias de la salud. Nuevos caminos para la comprensión

[SPA] La evolución de las nuevas tecnologías y formatos electrónicos ha influido en las nuevas formas de enseñanza. La Realidad Aumentada (AR) es una variante de la realidad virtual en el que la imagen virtual se superpone con el mundo real. Creamos un libro con realidad aumentada (AR BOOK) una herramienta para los estudiantes y los instructores como parte del material docente. En esta primera parte, se centró en la anatomía de la extremidad inferior, el AR BOOK fue utilizado por los estudiantes de 1º de grado de podología de varias universidades españolas. 211 estudiantes fueron divididos en dos grupos: un grupo estudió con el AR BOOK y el otro con metodologías estándar. El conocimiento adquirido fue estadísticamente significativo (1,13 puntos en comparación con el grupo de la enseñanza tradicional, p <0,0001). Algunos datos coinciden con los resultados encontrados en otros estudios, lo que sugiere que el uso de las nuevas tecnologías debe ser considerado como una herramienta interesante para el proceso de enseñanza-aprendizaje con una serie de ventajas en términos de beneficios, el costo y/o la portabilidad.[ENG] The evolution of new technologies and electronic formats has also influenced on new forms of teaching. Augmented Reality (AR) is a variant of the virtual reality where the virtual image overlaps with the real world. Augmented reality book (AR BOOK) was created as a tool for both students and instructors as part of the teaching material. In this first part, focused on the anatomy of the lower limb, the AR BOOK was used by podiatry degree students. 211 students were divided in two groups: One group studied with the AR BOOK and the other one with standard methodologies. Acquired knowledge was statistically significant increased (1,13 points compared to the traditional teaching group; p<0.0001). Some data agree with results found herein, suggesting that the use of new technologies must be considered as a interesting tool for teaching-learning process with several advantages in terms of benefits, cost or portability

Supramolecular self-assembly of a symmetric imine ligand functionalized with a dansyl fluorophore moiety

The 20th International Electronic Conference on Synthetic Organic Chemistry session Polymer and Supramolecular ChemistryWe report the synthesis and characterization of a symmetric [N4] tetradentate imine-type ligand H2L that incorporates a dansyl fluorophore group in both ligand arms. Two binding domains separated by a short arene spacer and two bulky arms with an anti conformation make this organic molecule suitable as precursor of metallosupramolecular species such as helicates. The molecular structure of H2L has been analyzed by X-ray diffraction. This technique has revealed the formation of intermolecular hydrogen bond interactions that lead to the supramolecular self-assembly of ligand molecules in the solid state and the generation of oval-shaped channels in the 3D crystal packin

miR302a and 122 are deregulated in small extracellular vesicles from ARPE-19 cells cultured with H2O2

Age related macular degeneration (AMD) is a common retina-related disease leading to blindness. Little is known on the origin of the disease, but it is well documented that oxidative stress generated in the retinal pigment epithelium and choroid neovascularization are closely involved. The study of circulating miRNAs is opening new possibilities in terms of diagnosis and therapeutics. miRNAs can travel associated to lipoproteins or inside small Extracellular Vesicles (sEVs). A number of reports indicate a signifcant deregulation of circulating miRNAs in AMD and experimental approaches, but it is unclear whether sEVs present a signifcant miRNA cargo. The present work studies miRNA expression changes in sEVs released from ARPE-19 cells under oxidative conditions (i.e. hydrogen peroxide, H2O2). H2O2 increased sEVs release from ARPE-19 cells. Moreover, 218 miRNAs could be detected in control and H2O2 induced-sEVs. Interestingly, only two of them (hsa-miR-302a and hsa-miR-122) were signifcantly under-expressed in H2O2-induced sEVs. Results herein suggest that the down regulation of miRNAs 302a and 122 might be related with previous studies showing sEVs-induced neovascularization after oxidative challenge in ARPE-19 cells.Te present project was supported by internal funds from Universidad Católica de Valencia San Vicente Mártir (2018-128-001), Centro de Investigación Traslacional San Alberto Magno de la UCV (2019-128-001), and Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana (PROMETEO/2016/094). Oltra M and Vidal-Gil L, PhD training program fellowship UCV (EDUCV-PRE-2016-005 and EDUCVPRE-2015-006 Personal Investigador en Formación UCV, respectively).Medicin

Perspectives of Therapeutic Drug Monitoring of Biological Agents in Non-Infectious Uveitis Treatment: A Review

Biological drugs, especially those targeting anti-tumour necrosis factor alpha (TNF alpha) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNF alpha drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNF alpha agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians' treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNF alpha agents in NIU are discussed

Design, optimization, and in vitro characterization of idebenone-loaded PLGA microspheres for LHON treatment

Biodegradable poly(lactic-co-glycolic acid) microspheres (PLGA MSs) are attractive delivery systems for site-specific maintained release of therapeutic active substances into the intravitreal chamber. The design, development, and characterization of idebenone-loaded PLGA microspheres by means of an oil-in-water emulsion/solvent evaporation method enabled the obtention of appropriate production yield, encapsulation efficiency and loading values. MSs revealed spherical shape, with a size range of 10–25 μm and a smooth and non-porous surface. Fourier-transform infrared spectroscopy (FTIR) spectra demonstrated no chemical interactions between idebenone and polymers. Solid-state nuclear magnetic resonance (NMR), X-ray diffractometry, differential scanning calorimetry (DSC) and thermogravimetry (TGA) analyses indicated that microencapsulation led to drug amorphization. In vitro release profiles were fitted to a biexponential kinetic profile. Idebenone-loaded PLGA MSs showed no cytotoxic effects in an organotypic tissue model. Results suggest that PLGA MSs could be an alternative intraocular system for long-term idebenone administration, showing potential therapeutic advantages as a new therapeutic approach to the Leber's Hereditary Optic Neuropathy (LHON) treatment by intravitreal administrationThis research was partially supported by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100)S