The Mediating Role of Vision in the Relationship Between Proprioception and Postural Control in Older Adults, as Compared to Teenagers and Younger and Middle-Aged Adults

[Abstract] The aim of this study is to analyze the mediating role of vision in the relationship between conscious lower limb proprioception (dominant knee) and bipedal postural control (with eyes open and closed) in older adults, as compared with teenagers, younger adults and middle-aged adults. Methods: The sample consisted of 119 healthy, physically active participants. Postural control was assessed using the bipedal Romberg test with participants’ eyes open and closed on a force platform. Proprioception was measured through the ability to reposition the knee at 45_, measured with the Goniometer Pro application’s goniometer. Results: The results showed an indirect relationship between proprioception and postural control with closed eyes in all age groups; however, vision did not mediate this relationship. Conclusions: Older adults outperformed only teenagers on the balance test. The group of older adults was the only one that did not display differences with regard to certain variables when the test was done with open or closed eyes. It seems that age does not influence performance on proprioception tests. These findings help us to optimize the design of training programs for older adults and suggest that physical exercise is a protective factor against age-related decline.This research recieved funding from Aristos Campus Mundus 2018 proyect. ID: ACM20180

Design and synthesis of a novel non peptide CN-NFATc signaling inhibitor for tumor suppression in triple negative breast cancer

The Ca2+/calmodulin-mediated phosphatase activity of calcineurin (CN) integrates calcium-mediated signaling with gene expression programs involved in the control of essential cellular processes in health and disease, such as the immune response and the pathogenesis of cancer progression and metastasis. In addition, CN is the target of the immunosuppressive drugs cyclosporine A (CsA) and FK-506 which are the cornerstone of immunosuppressant therapy. Unfortunately, long-term administration of these drugs results in severe side effects. Herein, we describe the design, synthesis and evaluation of new synthetic compounds that are capable of inhibiting NFATc activity in a dose-dependent manner, without interfering on CN phosphatase activity. These compounds were designed using the structure-based pharmacophore model of a peptide-derived PxIxIT sequence binding to calcineurin A subunit. Moreover, these compounds inhibit NFATc-dependent cytokine gene expression, secretion and proliferation of human T CD4(+) cells. More importantly, compound 5a reduces tumor weight and shows a tendency to reduce tumor angiogenesis in an orthotopic immunocompetent mouse model of triple negative breast cancer, suggesting that 5a has tumor suppressor activity. These findings validate compound 5a as an agent with therapeutic activity against CN-NFATc and highlight its potential as a tool for drug development with therapeutic purposes

Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation

Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, M-23 displays one of the highest affinities for TTR described so far. The TTR/M-23 crystal structure confirmed the formation of unprecedented protein–ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR

Adipocyte fatty-acid binding protein is overexpressed in cirrhosis and correlates with clinical outcomes

Fatty-acid-binding proteins (FABPs) are small intracellular proteins that coordinate lipid-mediated processes by targeting metabolic and immune response pathways. The aim of the study was to investigate plasma FABPs levels and their relationship with clinical outcomes in cirrhosis. Plasma levels of L-FABP1(liver and kidney), I-FABP2(intestine), and A-FABP4(adipocyte and macrophages) were measured in 274 patients with decompensated cirrhosis. Hepatic gene expression of FABPs was assessed in liver biopsies from patients with decompensated cirrhosis and in liver cell types from mice with cirrhosis. Immunohistochemistry of A-FABP4 in human liver biopsy was also performed. Plasma levels of FABPs were increased in patients with decompensated cirrhosis compared to those of healthy subjects (L-FABP1: 25 (17-39) vs 10 (9-17) ng/mL p = 0.001, I-FABP2: 1.1 (0.5-2.1) vs 0.6 (0.4-1) ng/ mL p = 0.04 and A-FABP4: 37 (20-68) vs 16 (11-33) ng/mL p = 0.002), respectively. Increased A-FABP4 levels were associated with complications of cirrhosis, acute-on-chronic liver failure and poor survival. Hepatic A-FABP4 gene expression was upregulated in decompensated cirrhosis. Macrophages were the main liver cell that over-expressed A-FABP4 in experimental cirrhosis and increased A-FABP4 was found in macrophages of human biopsies by immunohistochemistry. A-FABP4 levels are increased in decompensated cirrhosis and correlate with poor outcomes. Liver macrophages appear to be the main source of A-FABP4 in decompensated cirrhosis

Síntesis de nuevos compuestos con actividad farmacológica diseñados a través de simulaciones computacionales

El procés d'investigació d'un fàrmac és complex i necessita de la unió d'esforços entre diferents disciplines científiques. Tot i que el descobriment i el desenvolupament de nous fàrmacs s'ha realitzat durant molts anys utilitzant únicament mètodes experimentals, en les darreres dècades el procés ha aconseguit un nivell superior d'eficiència gràcies a l'ús de mètodes computacionals com, per exemple, les simulacions de docking, de dinàmica molecular i els cribratges virtuals. Aquests mètodes computacionals permeten un estalvi de temps i de recursos en el costós procés de creació. També permeten un disseny dels compostos objectiu i de les seves rutes sintètiques de forma més eficaç. En aquesta tesi doctoral es pot observar un reflex de les tendències actuals sobre la creació de nous compostos biològicament actius, a partir de rutes sintètiques curtes i eficients per generar compostos d'estructura relativament senzilla, sobre els quals ja s'ha treballat prèviament a través d'eines computacionals. En aquest treball s'han dissenyat, sintetitzat i avaluat farmacològicament, amb resultats prometedors, compostos relacionats amb diferents temes com: (i) nous antagonistes dels receptors d'alatostatines A (ASTA-R) per aprofundir en l'estudi del mecanisme de resposta de les abelles davant de l'estrès; (ii) nous inhibidors de la senyalització Calcineurina-NFATc (CN-NFATc) per a teràpies immunosupressores i per combatre l'angiogènesi tumoral; (iii) nous estabilitzadors de la transtiretina (TTR) per combatre l'amiloïdosi peptídica per transtiretina (ATTR); i (iv) nous moduladors al·lostèrics dels receptors de cannabinoides (CBR) a partir d'anàlegs del cannabidiol (CBD).El complejo proceso de investigación de un fármaco precisa de la unión de esfuerzos entre diferentes disciplinas científicas. Aunque el descubrimiento y desarrollo de nuevos fármacos se ha realizado durante muchos años usando únicamente métodos experimentales, en las últimas décadas el proceso ha conseguido un nivel superior de eficiencia gracias al uso de métodos computacionales como, por ejemplo, las simulaciones de docking, de dinámica molecular y los cribajes virtuales. Estos métodos computacionales permiten un ahorro de tiempo y de recursos en el costoso proceso de creación. También permiten un diseño de los compuestos objetivo y de sus rutas sintéticas de forma más eficaz. En esta tesis doctoral se puede observar un reflejo de las tendencias actuales sobre la creación de nuevos compuestos biológicamente activos, a partir de rutas sintéticas cortas y eficientes para generar compuestos de estructura relativamente sencilla, sobre los que ya se ha trabajado previamente a través de herramientas computacionales. En este trabajo se han diseñado, sintetizado y evaluado farmacológicamente, con resultados prometedores, compuestos relacionados con diferentes temas como: (i) nuevos antagonistas de los receptores de alatostatinas A (ASTA-R) para profundizar en el estudio del mecanismo de repuesta de las abejas frente al estrés; (ii) nuevos inhibidores de la señalización Calcineurina-NFATc (CN-NFATc) para terapias inmunosupresoras y para frenar la angiogénesis tumoral; (iii) nuevos estabilizadores de la transtiretina (TTR) para combatir la amiloidosis peptídica por transtiretina (ATTR); y (iv) nuevos moduladores alostéricos de los receptores de cannabinoides (CBR) a partir de análogos del cannabidiol (CBD).The complex process of drug research requires the joint efforts between different scientific disciplines. Although the discovery and development of new drugs has been carried out for many years using only experimental methods, in recent decades the process has achieved a higher level of efficiency thanks to the use of computational methods such as docking simulations, molecular dynamics, pharmacophore models and virtual screenings. These computational methods save time and resources in the expensive creation process, as well as allow a more efficient design of the target compounds and their synthetic routes. In this doctoral thesis, a reflection of current trends on the creation of new biologically active compounds can be observed, based on short and efficient synthetic routes to generate compounds with a relatively simple structure, on which previous work has been carried out through computational tools. In this work, compounds related to different topics have been designed, synthesized and pharmacologically evaluated, with promising results, such as: (i) new antagonists of allatostatin A receptors (ASTA-R) to deepen the study of the response mechanism of bees against stress; (ii) new inhibitors of Calcineurin-NFATc (CN-NFATc) signalling for immunosuppressive therapies and to reduce tumour angiogenesis; (iii) new transthyretin (TTR) stabilizers against transthyretin peptide amyloidosis (ATTR); and (iv) new allosteric modulators of cannabinoid receptors (CBR) from cannabidiol (CBD) analogues

Síntesis de nuevos compuestos con actividad farmacológica diseñados a través de simulaciones computacionales

El procés d’investigació d’un fàrmac és complex i necessita de la unió d’esforços entre diferents disciplines científiques. Tot i que el descobriment i el desenvolupament de nous fàrmacs s’ha realitzat durant molts anys utilitzant únicament mètodes experimentals, en les darreres dècades el procés ha aconseguit un nivell superior d’eficiència gràcies a l’ús de mètodes computacionals com, per exemple, les simulacions de docking, de dinàmica molecular i els cribratges virtuals. Aquests mètodes computacionals permeten un estalvi de temps i de recursos en el costós procés de creació. També permeten un disseny dels compostos objectiu i de les seves rutes sintètiques de forma més eficaç. En aquesta tesi doctoral es pot observar un reflex de les tendències actuals sobre la creació de nous compostos biològicament actius, a partir de rutes sintètiques curtes i eficients per generar compostos d’estructura relativament senzilla, sobre els quals ja s’ha treballat prèviament a través d’eines computacionals. En aquest treball s’han dissenyat, sintetitzat i avaluat farmacològicament, amb resultats prometedors, compostos relacionats amb diferents temes com: (i) nous antagonistes dels receptors d’alatostatines A (ASTA-R) per aprofundir en l’estudi del mecanisme de resposta de les abelles davant de l’estrès; (ii) nous inhibidors de la senyalització Calcineurina-NFATc (CN-NFATc) per a teràpies immunosupressores i per combatre l’angiogènesi tumoral; (iii) nous estabilitzadors de la transtiretina (TTR) per combatre l’amiloïdosi peptídica per transtiretina (ATTR); i (iv) nous moduladors al·lostèrics dels receptors de cannabinoides (CBR) a partir d’anàlegs del cannabidiol (CBD).El complejo proceso de investigación de un fármaco precisa de la unión de esfuerzos entre diferentes disciplinas científicas. Aunque el descubrimiento y desarrollo de nuevos fármacos se ha realizado durante muchos años usando únicamente métodos experimentales, en las últimas décadas el proceso ha conseguido un nivel superior de eficiencia gracias al uso de métodos computacionales como, por ejemplo, las simulaciones de docking, de dinámica molecular y los cribajes virtuales. Estos métodos computacionales permiten un ahorro de tiempo y de recursos en el costoso proceso de creación. También permiten un diseño de los compuestos objetivo y de sus rutas sintéticas de forma más eficaz. En esta tesis doctoral se puede observar un reflejo de las tendencias actuales sobre la creación de nuevos compuestos biológicamente activos, a partir de rutas sintéticas cortas y eficientes para generar compuestos de estructura relativamente sencilla, sobre los que ya se ha trabajado previamente a través de herramientas computacionales. En este trabajo se han diseñado, sintetizado y evaluado farmacológicamente, con resultados prometedores, compuestos relacionados con diferentes temas como: (i) nuevos antagonistas de los receptores de alatostatinas A (ASTA-R) para profundizar en el estudio del mecanismo de repuesta de las abejas frente al estrés; (ii) nuevos inhibidores de la señalización Calcineurina-NFATc (CN-NFATc) para terapias inmunosupresoras y para frenar la angiogénesis tumoral; (iii) nuevos estabilizadores de la transtiretina (TTR) para combatir la amiloidosis peptídica por transtiretina (ATTR); y (iv) nuevos moduladores alostéricos de los receptores de cannabinoides (CBR) a partir de análogos del cannabidiol (CBD).The complex process of drug research requires the joint efforts between different scientific disciplines. Although the discovery and development of new drugs has been carried out for many years using only experimental methods, in recent decades the process has achieved a higher level of efficiency thanks to the use of computational methods such as docking simulations, molecular dynamics, pharmacophore models and virtual screenings. These computational methods save time and resources in the expensive creation process, as well as allow a more efficient design of the target compounds and their synthetic routes. In this doctoral thesis, a reflection of current trends on the creation of new biologically active compounds can be observed, based on short and efficient synthetic routes to generate compounds with a relatively simple structure, on which previous work has been carried out through computational tools. In this work, compounds related to different topics have been designed, synthesized and pharmacologically evaluated, with promising results, such as: (i) new antagonists of allatostatin A receptors (ASTA-R) to deepen the study of the response mechanism of bees against stress; (ii) new inhibitors of Calcineurin-NFATc (CN-NFATc) signalling for immunosuppressive therapies and to reduce tumour angiogenesis; (iii) new transthyretin (TTR) stabilizers against transthyretin peptide amyloidosis (ATTR); and (iv) new allosteric modulators of cannabinoid receptors (CBR) from cannabidiol (CBD) analogues.Universitat Autònoma de Barcelona. Programa de Doctorat en Químic

Reduction of stress responses in honey bees by synthetic ligands targeting an allatostatin receptor

Altres ajuts: French Research Agency, ANR-13-ADAP-0002-01Honey bees are of great economic and ecological importance, but are facing multiple stressors that can jeopardize their pollination efficiency and survival. Therefore, understanding the physiological bases of their stress response may help defining treatments to improve their resilience. We took an original approach to design molecules with this objective. We took advantage of the previous identified neuropeptide allatostatin A (ASTA) and its receptor (ASTA-R) as likely mediators of the honey bee response to a biologically relevant stressor, exposure to an alarm pheromone compound. A first series of ASTA-R ligands were identified through in silico screening using a homology 3D model of the receptor and in vitro binding experiments. One of these (A8) proved also efficient in vivo, as it could counteract two behavioral effects of pheromone exposure, albeit only in the millimolar range. This putative antagonist was used as a template for the chemical synthesis of a second generation of potential ligands. Among these, two compounds showed improved efficiency in vivo (in the micromolar range) as compared to A8 despite no major improvement in their affinity for the receptor in vitro. These new ligands are thus promising candidates for alleviating stress in honey bees

Design of negative and positive allosteric modulators of the cannabinoid CB2 Receptor derived from the natural product cannabidiol

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility

PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties

The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR

Adipocyte fatty-acid binding protein is overexpressed in cirrhosis and correlates with clinical outcomes

Fatty-acid-binding proteins (FABPs) are small intracellular proteins that coordinate lipid-mediated processes by targeting metabolic and immune response pathways. The aim of the study was to investigate plasma FABPs levels and their relationship with clinical outcomes in cirrhosis. Plasma levels of L-FABP1(liver and kidney), I-FABP2(intestine), and A-FABP4(adipocyte and macrophages) were measured in 274 patients with decompensated cirrhosis. Hepatic gene expression of FABPs was assessed in liver biopsies from patients with decompensated cirrhosis and in liver cell types from mice with cirrhosis. Immunohistochemistry of A-FABP4 in human liver biopsy was also performed. Plasma levels of FABPs were increased in patients with decompensated cirrhosis compared to those of healthy subjects (L-FABP1: 25 (17-39) vs 10 (9-17) ng/mL p = 0.001, I-FABP2: 1.1 (0.5-2.1) vs 0.6 (0.4-1) ng/ mL p = 0.04 and A-FABP4: 37 (20-68) vs 16 (11-33) ng/mL p = 0.002), respectively. Increased A-FABP4 levels were associated with complications of cirrhosis, acute-on-chronic liver failure and poor survival. Hepatic A-FABP4 gene expression was upregulated in decompensated cirrhosis. Macrophages were the main liver cell that over-expressed A-FABP4 in experimental cirrhosis and increased A-FABP4 was found in macrophages of human biopsies by immunohistochemistry. A-FABP4 levels are increased in decompensated cirrhosis and correlate with poor outcomes. Liver macrophages appear to be the main source of A-FABP4 in decompensated cirrhosis