Fighting the Influenza A virus. New scaffolds and therapeutic targets

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/12071

Dimerization of highly pyramidalized 3,4,8,9-tetramethyltetracyclo[4.4.0.03,9.04,8]dec-1(6)-ene to a hydrocarbon featuring four cyclohexane rings in boat conformation

The synthesis, chemical trapping, and dimerization of a highly pyramidalized alkene is reported. Its dimer is a unique nonacycle featuring three planar cyclobutane rings, four cyclopentane rings, and four cyclohexane rings in boat conformations. The X-ray diffraction analysis showed a H-H distance between the flagpole hydrogen atoms of 1.999 and a separation of 2.619 between the two flagpole carbon atoms. The three cyclobutane rings of the dimer were thermally stabl

Acercamiento universidad-empresa químico-farmacéutica e inserción laboral y calidad

El equipo decanal de la Facultad de Farmacia de la Universidad de Barcelona tiene como una de sus prioridades implementar acciones para la mejora de las competencias profesionales de los estudiantes del Grado de Farmacia. En este marco, en el 2012 se incorporó al plan de estudios de Farmacia la asignatura optativa “prácticas en empresa”. Además, se han llevado a cabo una serie de acciones que han comprometido a empresas del sector químico-farmacéutico en este proyecto de ocupabilidad

Inhibition of 11β-HSD1, a key enzyme in the stress management, improves cognition by RL-118 drug treatment

In recent years, stress and stress-coping mechanisms constitute a growing public healthcare issue concerning modern society. Experiencing stress engenders a great complex mechanism named stress response, which consists of a rapid release of catecholamines by the sympathetic nervous system, followed by a slower response in which hormones, mainly glucocorticoids (GCs), are synthesized and released to the bloodstream. Once the stressful stimulus is perceived, the hypothalamus secretes the corticotropin-releasing hormone (CRH), which acts on the pituitary gland, activating the release of adrenocorticotropic hormone (ACTH) that binds to the adrenal glands, promoting GC secretion and conforming the hypothalamus-hypophysis-adrenal (HPA) axis. Under normal conditions, GC secretion follows a robust circadian oscillation with a peak around the onset of the active period of the day, i.e., about 1 hour before arising [1]. This basal level of GC secretion is important in exerting tonic effects upon metabolic, immune and neuronal pathways, involving gluconeogenesis stimulation, protein degradation and lipolysis increase, priming of neural regions involved in sensory processing, attention and adaptive responding, as well as accounting for immunosuppressive and anti-inflammatory actions [2]. However, when stressful exposure is prolonged, the HPA axis deregulates and GC secretion is exacerbated. This excessive GC concentration leads to several metabolic, neurological and behavioral alterations, notably cognitive impairment and affective dysfunctions. GC activity is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, which inhibition has been proved to restore metabolic and behavioral alterations, as well as enhance cognitive abilities. In fact, cortisol, the main active GC in humans, has been postulated as a potential biomarker for neurodegenerative disorders [3], like Alzheimer's disease (AD) in which aging is the major risk factor. Although it is completely assumed that stress directly influences the frailty phenotype in aged people, there are strikingly few measures to restrain stressful lifestyles in order to reduce the progression of pathological towards successful aging. Therefore, the study of stress effects on cognition and its relationship with aging is of the utmost importance to unveil what challenged we might have to cope with as a society in a not so far future

Synthesis and Antiviral Evaluation of Bisnoradamantane Sulfites and Related Compounds

The reaction of a series of 1,2-diols with thionyl chloride led to bisnoradamantane sulfites in very good yields. The reaction has also been applied to related polycyclic scaffolds. The compounds have been tested for antiviral activity but none of them showed to be active. Several attempts to generate and trap SO from these polycyclic sulfites have been unsuccessful

11β-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress

Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11β-HSD1i. Remarkably, treatment with 11β-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11β-HSD1i for the treatment of age-related cognitive decline and AD

Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N'-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds. Keywords: antibacterial; Gram-positive; N,N0-diarylureas; pentafluorosulfanyl; Staphylococcus aureus; triclocarba

"Learning by doing" prácticas en empresa y otras actividades de los estudiantes de farmacia de la Universidad de Barcelona

Introducción: A principios del año 2012 se puso en marcha la asignatura Prácticas en Empresas en la Facultad de Farmacia de Barcelona, a partir de la iniciativa impulsada por el Decanato. La asignatura es optativa y consta de 12 créditos ECTS (dedicación mínima de 300 horas presenciales). Encarna García‐Montoya, Carmen Escolano, Mercè Pallàs, Pilar Pérez, Santiago Vázquez Decanato Facultad de Farmacia. Universidad de Barcelona Grupo de innovación docente: MICOMFAR (GIDUB‐13/154) Objetivos: En este trabajo se analizan los resultados derivados de las encuestas recogidas de los estudiantes y de las empresas colaboradoras para el primer semestre del curso 14/15 (68 estudiantes de 72 matriculados). El objetivo es analizar puntos de mejora y detectar “lecciones” a tener en cuenta para generalizar en la gestión de la asignatura. Metodología: En este momento al estudiante que desea cursar la asignatura se le recomienda cursar en paralelo o previamente la asignatura de libre elección: Passaport a la Professió, son 8 sesiones mensuales que ayudan al estudiante a buscar su propia oportunidad de prácticas y prepararse convenientemente. Una vez localizada la empresa que acogerá al estudiante, se firma un convenio que implica al estudiante, la empresa y la facultad. Al acabar el estudiante y el tutor de la empresa redactan un informe para la cualificación de la asignatura y un cuestionario de satisfacción (estudiante), que son analizados. Resultados y discusión: El cuestionario de satisfacción se divide en dos bloques: Procediminteo de la asignatura y Procedimientos de la empresa.Conclusión: Las prácticas en empresa constituyen una asignatura de interés para los estudiantes. La valoración realizada por los estudiantes tanto de la administración de la Facultad, como de la preparación recibida en la misma para afrontar con éxito ese periodo, así como la orientación de las coordinadoras es muy adecuada. La consideración de la atención recibida por parte de los tutores de las empresas es excelente. A modo de resumen queda indicado que el 96% de los estudiantes considera que la posición ocupada en el periodo de prácticas se ajusta a sus intereses.Conclusión: Las prácticas en empresa constituyen una asignatura de interés para los estudiantes. La valoración realizada por los estudiantes tanto de la administración de la Facultad, como de la preparación recibida en la misma para afrontar con éxito ese periodo, así como la orientación de las coordinadoras es muy adecuada. La consideración de la atención recibida por parte de los tutores de las empresas es excelente. A modo de resumen queda indicado que el 96% de los estudiantes considera que la posición ocupada en el periodo de prácticas se ajusta a sus intereses

Design and Synthesis of AMPK Activators and GDF15 Inducers

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618

The Effect of Endogenous Expression of HIV-1 gp120 on Glutamate Metabolism in Human Astrocytes

Human immunodeficiency virus (HIV) infection is a global epidemic that targets the immune system. HIV infects white blood cells and spreads throughout the entire body via blood stream and makes its way to the brain. HIV infection in the brain may lead to HIV associated neurocognitive disorders (HAND). To be able to address this problem, we have to better understand how HIV infection damages neurons. We hypothesize that gp120 causes neurotoxicity in the cells by inhibiting the conversion of glutamate to glutamine by glutaminase. As a result, glutamate concentrations will build up both inside and outside the cell causing excitatory neurotoxicity. To better understand this process, we transfected human astrocytes (U87MG cells) with mock (control), an empty vector (control), and with gp120 plasmid. Seventy-two hours post transfection, the cells were collected and run through a series of tests including SDS-PAGE/Western Blot and qRT-PCR to assess protein and mRNA levels of glutaminase and gp120. We expect production of gp120 by astrocytes to lead to a decrease in expression of glutaminase. This would inhibit the process of converting glutamate to glutamine and explain how excess of glutamate accumulates inside and outside of the cell causing neurotoxicity and cell death. In conclusion, we expect to find a direct relationship between gp120 and the glutamate metabolism in human astrocytes. Understanding the effect gp120 has on neurons will help develop more effective treatments to better fight the virus