Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer cells

Tumor invasion and metastasis involve processes in which actin cytoskeleton rearrangement induced by Fascin1 plays a crucial role. Indeed, Fascin1 has been found overexpressed in tumors with worse prognosis. Migrastatin and its analogues target Fascin1 and inhibit its activity. However, there is need for novel and smaller Fascin1 inhibitors. The aim of this study was to assess the effect of compound G2 in colorectal cancer cell lines and compare it to migrastatin in in vitro and in vivo assays. Molecular modeling, actin-bundling, cell viability, inmunofluorescence, migration, and invasion assays were carried out in order to test anti-migratory and anti-invasive properties of compound G2. In addition, the in vivo effect of compound G2 was evaluated in a zebrafish model of invasion. HCT-116 cells exhibited the highest Fascin1 expression from eight tested colorectal cancer cell lines. Compound G2 showed important inhibitory effects on actin bundling, filopodia formation, migration, and invasion in different cell lines. Moreover, compound G2 treatment resulted in significant reduction of invasion of DLD-1 overexpressing Fascin1 and HCT-116 in zebrafish larvae xenografts; this effect being less evident in Fascin1 known-down HCT-116 cells. This study proves, for the first time, the in vitro and in vivo anti-tumoral activity of compound G2 on colorectal cancer cells and guides to design improved compound G2-based Fascin1 inhibitors. Key messages center dot Fascin is crucial for tumor invasion and metastasis and is overexpressed in bad prognostic tumors. center dot Several adverse tumors overexpress Fascin1 and lack targeted therapy. center dot Anti-fascin G2 is for the first time evaluated in colorectal carcinoma and compared with migrastatin. center dot Filopodia formation, migration activity, and invasion in vitro and in vivo assays were performed. center dot G2 blocks actin structures, migration, and invasion of colorectal cancer cells as fascin-dependent.Peer reviewe

New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells

Colorectal cancer: Antitumor antidepressant The antidepressant drug imipramine can block the activity of a protein that contributes to the progression of certain aggressive tumors. Serrated adenocarcinoma (SAC) is a form of colorectal cancer with a poor prognosis. A key factor in SAC development is the overexpression of the protein fascin1, which promotes the formation of structures that help cancer cells move around, thereby leading to metastasis. Pablo Conesa-Zamora at Santa Lucia University Hospital in Cartagena, Horacio Perez-Sanchez at the Universidad Catolica de Murcia in Guadalupe, Spain, and coworkers demonstrated that imipramine shows promise in binding to fascin1 and blocking its activity. The team analyzed over 9500 compounds as potential fascin1 blockers, identifying imipramine as a possible option. In tests on human tissues and in vivo studies using zebrafish, the drug reduced cancer invasion and metastasis. Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.Peer reviewe

Prodromal phase: Differences in prodromal symptoms, risk factors and markers of vulnerability in first episode mania versus first episode psychosis with onset in late adolescence or adulthood

Objective: This study was aimed at identifying differences in the prodromal symptoms and their duration, risk factors and markers of vulnerability in patients presenting a first episode mania (FEM) or psychosis (FEP) with onset in late adolescence or adulthood in order to guide tailored treatment strategies. Methods: Patients with a FEM or FEP underwent a clinical assessment. Prodromes were evaluated with the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R). Chi-squared tests were conducted to assess specific prodromal symptoms, risk factors or markers of vulnerability between groups. Significant prodromal symptoms were entered in a stepwise forward logistic regression model. The probabilities of a gradual versus rapid onset pattern of the prodromes were computed with logistic regression models. Results: The total sample included 108 patients (FEM = 72, FEP = 36). Social isolation was associated with the prodromal stage of a FEP whilst Increased energy or goal-directed activity with the prodrome to a FEM. Physically slowed down presented the most gradual onset whilst Increased energy presented the most rapid. The presence of obstetric complications and difficulties in writing and reading during childhood were risk factors for FEP. As for markers of vulnerability, impairment in premorbid adjustment was characteristic of FEP patients. No specific risk factor or marker of vulnerability was identified for FEM. Conclusion: Early characteristics differentiating FEP from FEM were identified. These findings might help shape early identification and preventive intervention programmes

O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

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Desarrollo y encapsulación de compuestos bioactivos de origen vegetal con efectos en el sistema cardiovascular

Las plantas y sus derivados naturales constituyen la mayor fuente de compuestos biológicamente activos, de dónde provienen el 30% de todas las moléculas del mercado farmacéutico, relacionados con la promoción de la salud. Diversos grupos de investigación han evaluado la actividad antioxidante, antimicrobiana, antiinflamatoria y cardioprotectora de compuestos bioactivos, compuestos fenólicos de algas incluidos. Por otro lado, el aceite de oliva, uno de los productos vegetales españoles más representativos de nuestra cultura gastronómica, presenta también fenoles hidrófilicos antioxidantes, entre los que destaca el hidroxitirosol (HT). Este compuesto ha sido ampliamente estudiado en la última década. Las ciclodextrinas se han empleado en microencapsulación de una gran variedad de compuestos bioactivos naturales, desde isoflavonas de soja hasta quercetina, eugenol, hidroxitirosol, etc… El principal objetivo de los agentes utilizados en la encapsulación de compuestos bioactivos es proteger dichas moléculas de interés de diferentes factores como, por ejemplo, la temperatura y aumentar su solubilidad. Con el objetivo de confirmar la presencia de compuestos fenólicos en el alga roja Gracilaria longissima, en una primera parte del proyecto, se realizarán extractos del material vegetal y se procederá a su análisis mediante técnicas de espectroscopía de masas (UHPLC-ESIQqQ-MS/MS). Posteriormente, se realizarán estudios de biodisponibilidad y se testará su bioactividad en diferentes modelos fisiopatológicos humanos in vitro. Se estudiarán diferentes mecanismos de acción propios de la patología cardiovascular (vasodilatación, estrés oxidativo, inflamación y trombogésis). Dada su estructura hidrofóbica y baja solubilidad en soluciones acuosas, se analizarán las ventajas de la encapsulación de los extractos en ensayos in vitro. En una segunda fase, y en colaboración con la empresa alimentaria B-Organic SL., se realizará un estudio clínico con voluntarios sanos que demuestre que el consumo regular de caramelos ricos en HT encapsulado puede aportar beneficios cardiovasculares como, disminuir los niveles de estrés oxidativo, la inflamación y la glucemia basal. La propuesta es ambiciosa e innovadora, ya que no se ha descrito aún la composición de oxilipinas en el género Gracilaria sp., así como estudios de biodisponibilidad ni bioactividad. Por otro lado, el uso de CDs en el proyecto aporta una aplicabilidad práctica que se hace patente en el desarrollo de un nuevo producto de interés industrial. De demostrarse los beneficios de moléculas activas del alga roja y del uso de CDs, abriremos el mercado hacia los nuevos productos saludables con potencial uso terapéutico y alimentos funcionales, apoyados en las alegaciones reconocidas por la EFSA.Ciencias de la AlimentaciónFundación Séneca70.000

Characterization of a Novel Thermostable Carboxylesterase from Geobacillus kaustophilus HTA426 Shows the Existence of a New Carboxylesterase Family▿

The gene GK3045 (741 bp) from Geobacillus kaustophilus HTA426 was cloned, sequenced, and overexpressed into Escherichia coli Rosetta (DE3). The deduced protein was a 30-kDa monomeric esterase with high homology to carboxylesterases from Geobacillus thermoleovorans NY (99% identity) and Geobacillus stearothermophilus (97% identity). This protein suffered a proteolytic cut in E. coli, and the problem was overcome by introducing a mutation in the gene (K212R) without affecting the activity. The resulting Est30 showed remarkable thermostability at 65°C, above the optimum growth temperature of G. kaustophilus HTA426. The optimum pH of the enzyme was 8.0. In addition, the purified enzyme exhibited stability against denaturing agents, like organic solvents, detergents, and urea. The protein catalyzed the hydrolysis of p-nitrophenyl esters of different acyl chain lengths, confirming the esterase activity. The sequence analysis showed that the protein contains a catalytic triad formed by Ser93, Asp192, and His222, and the Ser of the active site is located in the conserved motif Gly91-X-Ser93-X-Gly95 included in most esterases and lipases. However, this carboxylesterase showed no more than 17% sequence identity with the closest members in the eight families of microbial carboxylesterases. The three-dimensional structure was modeled by sequence alignment and compared with others carboxylesterases. The topological differences suggested the classification of this enzyme and other Geobacillus-related carboxylesterases in a new α/β hydrolase family different from IV and VI

CD36 expression and lipid metabolism following an oral glucose challenge in South Asians

Aim: To investigate lipid metabolism and the relationship with monocyte expression of the fatty acid translocase CD36 in South Asians. Methods: An observational study of South Asians whom as an ethnic group have - a higher risk of developing diabetes. The susceptibility to diabetes is coupled with an earlier and more rapid progression of micro-, and macro-vascular complications. Twenty-nine healthy South Asian participants [mean age 34.6 (8.9) years, 76.2% male, mean body-mass index 25.0 (5.2) kg/m2] were recruited from an urban residential area of central Birmingham (United Kingdom). The main outcomes measured were post prandial (30 min) and post absorptive (120 min) changes from fasting (0 min) in circulating lipoproteins, lipds and hormones, and monocyte expression of CD36 post injection of a 75 g oral glucose challenge. The inducements of variations of monocyte CD36 expression were analysed. Results: Our results showed evident changes in monocyte CD36 expression following the glucose challenge (P < 0.001). Non-esterified fatty acids (NEFA) levels decreased progressively during the challenge (P < 0.001), in contrast to increased cholesterol (but not triglyceride) concentrations within very low density lipoprotein (VLDL) and low density lipoprotein subfractions (P < 0.01). Levels of, glucose, serum triglycerides and high density lipoprotein cholesterol remained largely unchanged. Variations of monocyte CD36 were negatively (r = -0.47, P = 0.04) associated to fat from the diet and positively to carbohydrate from the diet (r = 0.65, P < 0.001). Conclusion: These data suggest that the initiation of VLDL genesis follows the consumption of glucose within this population, inferring that the sequestration of NEFA from these particles happens due to the increased availability of CD36 receptors. While these are preliminary results, it would appear that lifestyle exposures have a role in moderating the expression of CD36

Contexto socioeconômico e atuação do BNDES na Região Sul

Bibliografia: p. 69-71O presente artigo traz uma visão abrangente da economia e da atuação do BNDES na Região Sul. Inicialmente, é abordada sua formação econômica, mediante seus diversos ciclos econômicos. Em seguida, caracteriza-se a estrutura produtiva da região, em uma abordagem setorial e regional e, por sua importância, também são apontadas questões referentes às desigualdades intrarregionais. É retratado o apoio do BNDES aos investimentos na região em período recente e, por fim, são elencadas perspectivas de investimento, em função das necessidades e potencialidades da região. Nesse contexto, a atuação do BNDES é apresentada como instrumento de promoção do desenvolvimento regional e aproveitamento de seu potencial produtivo.This paper offers a broad viewpoint on the economy and the BNDES’ operations in the South region of Brazil. First, we address economic development by analyzing its many economic cycles. Following that, we outline the production structures in the region, using a sectorial and regional approach. Here, due to their importance, we also raise some issues concerning intra-regional inequalities. We cover the BNDES’ recent support for investments in the region and, lastly, we list some investment perspectives in accordance with the region’s needs and potentials. Within this context, the BNDES’ operations are presented as an instrument to foster regional development and to make the most of this region’s production potential

Taller de Aptitud Vocacional para Arquitectura - AR206 - 202101

Descripción: El Taller de Aptitud Vocacional para Arquitectura es un curso del ciclo 0 de la carrera de Arquitectura, de carácter teórico-práctico dirigido a los estudiantes que no aprobaron o no rindieron la "Prueba de aptitud 1Vocacional para Arquitectura". En este sentido, el curso brinda el primer acercamiento a los conceptos arquitectónicos básicos y a la historia del arte y arquitectura, a través de ejercicios de diseño (maquetas, exposiciones individuales y grupales, afiches gráficos, entre otros) con los cuales el alumno se entrena (o prepara) para los talleres de diseño y los cursos de historia de la carrera. Propósito: El curso permite verificar si el perfil de los estudiantes coincide con lo necesario para el seguimiento de la Carrera de Arquitectura además de corroborar y/o reforzar las aptitudes vocacionales para la misma y de esta manera el estudiante, aumente sus probabilidades de un buen desempeño académico y la exitosa culminación de la carrera. El curso contribuye directamente al desarrollo de la competencia general de Pensamiento Innovador y la competencia específica de Diseño Fundamentado a un nivel novato (nivel 1). No tiene requisitos previos. Aprobar este curso es requisito para llevar los curso de carrera: Expresión Artística y Espacial y TI - Introducción al Diseño Arquitectónico, ambos del Ciclo 1