Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery

AbstractThe Trypanosomatidae family, composed of unicellular parasites, causes severe vector-borne diseases that afflict human populations worldwide. Chagas disease, sleeping sickness, as well as different sorts of leishmaniases are amongst the most important infectious diseases produced by Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively. All these infections are closely related to weak health care services in low-income populations of less developed and least economically developed countries. Search for new therapeutic targets in order to hit these pathogens is of paramount priority, as no effective vaccine is currently in use against any of these parasites. Furthermore, present-day chemotherapy comprises old-fashioned drugs full of important side effects. Besides, they are prone to produce tolerance and resistance as a consequence of their continuous use for decades. DNA topoisomerases (Top) are ubiquitous enzymes responsible for solving the torsional tensions caused during replication and transcription processes, as well as in maintaining genomic stability during DNA recombination. As the inhibition of these enzymes produces cell arrest and triggers cell death, Top inhibitors are among the most effective and most widely used drugs in both cancer and antibacterial therapies. Top relaxation and decatenation activities, which are based on a common nicking–closing cycle involving one or both DNA strands, have been pointed as a promising drug target. Specific inhibitors that bind to the interface of DNA-Top complexes can stabilize Top-mediated transient DNA breaks. In addition, important structural differences have been found between Tops from the Trypanosomatidae family members and Tops from the host. Such dissimilarities make these proteins very interesting for drug design and molecular intervention. The present review is a critical update of the last findings regarding trypanosomatid’s Tops, their new structural features, their involvement both in the physiology and virulence of these parasites, as well as their use as promising targets for drug discovery

Evaluación Clínica Objetiva y Estructurada (ECOE) en el Grado en Farmacia: experiencia piloto en la Universidad de Salamanca

[ES] La Evaluación Clínica Objetiva y Estructurada (ECOE) es un tipo de examen de carácter práctico, orientado a valorar la adquisición de competencias profesionales del estudiante mediante la resolución de casos clínicos y habilidades, articulada en un circuito de estaciones o situaciones reales por las que los estudiantesrotarán de forma consecutiva en un tiempo determinado. Los resultados de su implementación en la asignatura de Prácticas tuteladas en el Grado en Farmacia de la Universidad de Salamanca confirman la idoneidad de este método de evaluación para medir la capacidad y habilidades de los futuros farmacéuticos. Los estudiantes encuentran adecuada la prueba, si bien muestran reticencias en cuanto a la novedad y al estrés que les supone enfrentarse a situaciones reales con un tiempo limitado, por lo que es necesario facilitarles recursos para su formación y entrenamiento.[EN] Objective and Structured Clinical Evaluation (OSCE) is a type of practical evaluation, aimed at assessing acquisition of professional skills of the student through the resolution of clinical cases and skills. It is comprised of a series of stations or real situations through which students rotate consecutively on a time basis. OSCE implementation results in Supervised Practices subject in Pharmacy Degree at the University of Salamanca has confirm the suitability of this evaluation methodology to measure the capacity and skills of future pharmacists. Students find this methodology adequate, although they show hesitation because of the novelty and the stress involved in facing real situations with limited time, which indicates that it is necessary to provide them with resources for training.Álvarez, R.; Sepúlveda, RA.; Valles, E.; Zarzuelo, A. (2023). Evaluación Clínica Objetiva y Estructurada (ECOE) en el Grado en Farmacia: experiencia piloto en la Universidad de Salamanca. Editorial Universitat Politècnica de València. 345-356. https://doi.org/10.4995/INRED2023.2023.1653834535

Effectiveness of pharmaceutical care in hypertensive patients of a pharmacy office in Villanueva de La Serena (Badajoz).

The main objective of this experimental study is to evaluate the effectiveness of Pharmaceutical Care in real hypertensive patients. The materials and methods used were a sample of 30 hypertensive patients assisted in a Community Pharmacy Service in Villanueva de La Serena, Badajoz. The group of patients received follow-up for a period of 6 months, from February to July 2017. Regarding the results, it was observed that after the intervention of the Pharmaceutical Care, the blood pressure figures were significantly improved, problems were detected and resolved related to medication, and increased compliance with treatments and hygienic-dietary measures together with the degree of satisfaction and trust of patients. The Pharmaceutical Care is the future of the Healthcare Pharmacy, with this research it is intended to provide clinical data to agree on an official document that serves to transfer to other professionals the effectiveness of this activity, although more prospective studies will be necessary to quantify the usefulness of the Attention Pharmaceutical in a protocolized manner, as well as updating the only consensus document published by the Ministry of Health and Consumers in 2002.El objetivo principal de este estudio experimental es evaluar la efectividad de la Atención Farmacéutica en pacientes reales hipertensos. Los materiales y métodos empleados fueron una muestra de 30 pacientes hipertensos asistidos en un Servicio de Farmacia Comunitaria en Villanueva de La Serena, Badajoz. El grupo de pacientes recibió seguimiento durante un periodo de 6 meses, de febrero a julio de 2017. Respecto a los resultados, se observó que tras la intervención de la Atención Farmacéutica mejoraron de forma significativa las cifras de presión arterial, se detectaron y resolvieron problemas relacionados con la medicación, e incrementaron el cumplimiento de los tratamientos y medidas higiénico-dietéticas junto con el grado de satisfacción y confianza de los pacientes. La Atención Farmacéutica es el futuro de la Farmacia Asistencial, con esta investigación se pretende aportar datos clínicos para consensuar un documento oficial que sirva para trasladar a otros profesionales la eficacia de esta actividad, aunque serán necesarios más estudios prospectivos que cuantifiquen la utilidad de la Atención Farmacéutica de forma protocolizada, así como actualizar el único documento de consenso publicado por el Ministerio de Sanidad y Consumo en 2002

Thyroid hormones according to gestational age in pregnant Spanish women

<p>Abstract</p> <p>Background</p> <p>Thyroid function changes during pregnancy and maternal thyroid dysfunction have been associated with adverse outcomes. Our aim was to evaluate thyroid hormones levels in pregnant women resident in Aragon, Spain.</p> <p>Findings</p> <p>Samples for 1198 pregnant women with no apparent thyroid disorders were analyzed, using paramagnetic microparticle and chemiluminescent detection technologies, in order to determine levels of thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (Tg-Ab). Of the women in our sample, 85.22% had normal values for TPO-Ab and Tg-Ab and 14.77% had results revealing the presence of autoimmune diseases of the thyroid. The thyroid hormone reference values obtained according to gestational age (in brackets) were as follows: for free T3, values were 3.38 ± 0.52 pg/mL (<11 weeks), 3.45 ± 0.54 pg/mL (11-20 weeks), 3.32 ± 0.43 pg/mL (21-30 weeks), 3.21 ± 0.53 pg/mL (31-36 weeks), and 3.23 ± 0.41 pg/mL (>36 weeks); for free T4, values were 1.10 ± 0.14 ng/dL (<10 weeks), 1.04 ± 0.14 ng/dL (11-20 weeks), 0.93 ± 0.12 ng/dL (21-30 weeks), 0.90 ± 0.13 ng/dL (31-36 weeks), and 0.80 ± 0.21 ng/dL (>36 weeks); and for TSH, values were (μIU/mL): 1.12 ± 0.69 (<10 weeks), 1.05 ± 0.67 (11-20 weeks), 1.19 ± 0.60 (21-30 weeks), 1.38 ± 0.76 (31-36 weeks), and 1.46 ± 0.72 (>36 weeks).</p> <p>Conclusion</p> <p>Pregnant women with normal antibody values according to gestational age had values for FT4 and TSH, but not for FT3, that differed to a statistically significant degree. The values we describe can be used as reference values for the Aragon region of Spain.</p

Applications and multidisciplinary perspective on 3D printing techniques: Recent developments and future trends

In industries as diverse as automotive, aerospace, medical, energy, construction, electronics, and food, the engineering technology known as 3D printing or additive manufacturing facilitates the fabrication of rapid prototypes and the delivery of customized parts. This article explores recent advancements and emerging trends in 3D printing from a novel multidisciplinary perspective. It also provides a clear overview of the various 3D printing techniques used for producing parts and components in three dimensions. The application of these techniques in bioprinting and an up-to-date comprehensive review of their positive and negative aspects are covered, as well as the variety of materials used, with an emphasis on composites, hybrids, and smart materials. This article also provides an updated overview of 4D bioprinting technology, including biomaterial functions, bioprinting materials, and a targeted approach to various tissue engineering and regenerative medicine (TERM) applications. As a foundation for anticipated developments for TERM applications that could be useful for their successful usage in clinical settings, this article also examines present challenges and obstacles in 4D bioprinting technology. Finally, the article also outlines future regulations that will assist researchers in the manufacture of complex products and in the exploration of potential solutions to technological issues

Antiparasitic effect of synthetic aromathecins on Leishmania infantum

[EN} Background Canine leishmaniasis is a zoonotic disease caused by Leishmania infantum, being the dogs one of the major reservoirs of human visceral leishmaniasis. DNA topology is a consolidated target for drug discovery. In this regard, topoisomerase IB – one of the enzymes controlling DNA topology – has been poisoned by hundreds of compounds that increase DNA fragility and cell death. Aromathecins are novel molecules with a multiheterocyclic ring scaffold that have higher stability than camptothecins. Results Aromathecins showed strong activity against both forms of L. infantum parasites, free-living promastigotes and intra-macrophagic amastigotes harbored in ex vivo splenic explant cultures obtained from infected BALB/c mice. However, they prevented the relaxation activity of leishmanial topoisomerase IB weakly, which suggests that the inhibition of topoisomerase IB partially explains the antileishmanial effect of these compounds. The effect of aromathecins was also studied against a strain resistant to camptothecin, and results suggested that the trafficking of these compounds is not through the ABCG6 transporter. Conclusions Aromathecins are promising novel compounds against canine leishmaniasis that can circumvent potential resistances based on drug efflux pumps.SIThis research had the financial support of: Ministerio de Economía y Competitividad (MINECO, AEI, FEDER, UE) [MINECO: AGL2016–79813-C2-1R, SAF2017–83575-R]. Junta de Castilla y León cofinanced by FEDER UE [LE020P17, Grant UIC108]. The funding body does not participate in the design of the study; collection, analysis and interpretation of data and in writing the manuscript

Expression and potential role of apolipoprotein D on the death–survival balance of human colorectal cancer cells under oxidative stress conditions

Producción CientíficaPurpose Inverse correlations of apolipoprotein D (ApoD) expression with tumor growth have been shown, therefore proposing ApoD as a good prognostic marker for diverse cancer types, including colorectal cancer (CRC). Besides, ApoD expression is boosted upon oxidative stress (OS) in many pathological situations. This study aims at understanding the role of ApoD in the progression of human CRC. Methods Samples of CRC and distant normal tissue (n051) were assayed for levels of lipid peroxidation, expression profile of OS-dependent genes, and protein expression. Three single-nucleotide polymorphisms in the ApoD gene were analyzed (n0139), with no significant associations found. Finally, we assayed the effect of ApoD in proliferation and apoptosis in the CRC HT-29 cell line

Analysis of the Arabidopsis venosa4-0 mutant supports the role of VENOSA4 in dNTP metabolism

Human Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) functions as a dNTPase to maintain dNTP pool balance. In eukaryotes, the limiting step in de novo dNTP biosynthesis is catalyzed by RIBONUCLEOTIDE REDUCTASE (RNR). In Arabidopsis, the RNR1 subunit of RNR is encoded by CRINKLED LEAVES 8 (CLS8), and RNR2 by three paralogous genes, including TSO MEANING 'UGLY' IN CHINESE 2 (TSO2). In plants, DIFFERENTIAL DEVELOPMENT OF VASCULAR ASSOCIATED CELLS 1 (DOV1) catalyzes the first step of the de novo biosynthesis of purines. Here, to explore the role of VENOSA4 (VEN4), the most likely Arabidopsis ortholog of human SAMHD1, we studied the ven4‐0 point mutation, whose leaf phenotype was stronger than those of its insertional alleles. Structural predictions suggested that the E249L substitution in the mutated VEN4-0 protein rigidifies its 3D structure. The morphological phenotypes of the ven4, cls8, and dov1 single mutants were similar, and those of the ven4 tso2 and ven4 dov1 double mutants were synergistic. The ven4‐0 mutant had reduced levels of four amino acids related to dNTP biosynthesis, including glutamine and glycine, which are precursors in the de novo purine biosynthesis. Our results reveal high functional conservation between VEN4 and SAMHD1 in dNTP metabolism

Informe y valoración de los resultados globales obtenidos en el cuestionario elaborado para los alumnos de primer curso del grado de Farmacia del Curso 2014/2015

Memoria ID-0173. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2014-2015

Graphene materials with different structures prepared from the same graphite by the Hummers and Brodie methods

[EN] Graphene materials containing different functional groups were prepared from a natural graphite, by means of two different oxidation methods (Hummers and Brodie). It was observed that the differences in the structure of the resultant graphite oxides (GOs) greatly affect the structure of the graphenes resulting from their thermal exfoliation/reduction. Although the oxidation of the graphite was more effective with the modified Hummers method than with Brodie’s method (C/O of 1.8 vs 2.9, as determined by XPS), the former generated a lower residual oxygen content after thermal exfoliation/reduction and a better reconstruction of the 2D graphene structure (with fewer defects). This is explained by the presence of conjugated epoxy and hydroxyl groups in the GO obtained by Brodie’s method, which upon thermal treatment, lead to the incorporation of oxygen into the carbon lattice preventing its complete restoration. Additionally, graphene materials obtained with Brodie’s method exhibit, in general, smaller sheet size and larger surface area.The authors thank MICINN and European Union (CONSOLIDER INGENIO 2010, Ref. CSD2009-00050, MAT2010-16194) for their financial support. Dr. Patricia Alvarez thanks MICINN for her Ramon y Cajal contract.Peer reviewe