Neuroprotection by the cannabis-related products, cannabidiol and cannabigerol, and their associated mechanisms of action

The discovery and characterization of the endocannabinoid system (ECS) brought out years of research focusing on two aims. The study of its participation in the physiopathology in several diseases, including neurodegenerative disorders, and as a direct or indirect target for treating these disorders by cannabinoids or phytocannabinoids (i.e., specific compounds present in the Cannabis sativa plant). Preclinical evidence and some clinical data have shown the therapeutic potential of the most relevant phytocannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), but less for cannabigerol (CBG). In the present review, we summarized data focused on the therapeutic potential of CBD and CBG as neuroprotective agents. This property appears to be exerted by the direct or indirect activation of targets within the ECS and also by mechanisms non-mediated by the ECS. We provide information which could be useful for future CBD and CBG applications in human neurodegenerative diseases treatment.Agencia Nacional de Investigación e Innovació

3D-PP: A tool for discovering conserved three-dimensional protein patterns

Discovering conserved three-dimensional (3D) patterns among protein structures may provide valuable insights into protein classification, functional annotations or the rational design of multi-target drugs. Thus, several computational tools have been developed to discover and compare protein 3D-patterns. However, most of them only consider previously known 3D-patterns such as orthosteric binding sites or structural motifs. This fact makes necessary the development of new methods for the identification of all possible 3D-patterns that exist in protein structures (allosteric sites, enzyme-cofactor interaction motifs, among others). In this work, we present 3D-PP, a new free access web server for the discovery and recognition all similar 3D amino acid patterns among a set of proteins structures (independent of their sequence similarity). This new tool does not require any previous structural knowledge about ligands, and all data are organized in a high-performance graph database. The input can be a text file with the PDB access codes or a zip file of PDB coordinates regardless of the origin of the structural data: X-ray crystallographic experiments or in silico homology modeling. The results are presented as lists of sequence patterns that can be further analyzed within the web page. We tested the accuracy and suitability of 3D-PP using two sets of proteins coming from the Protein Data Bank: (a) Zinc finger containing and (b) Serotonin target proteins. We also evaluated its usefulness for the discovering of new 3D-patterns, using a set of protein structures coming from in silico homology modeling methodologies, all of which are overexpressed in different types of cancer. Results indicate that 3D-PP is a reliable, flexible and friendly-user tool to identify conserved structural motifs, which could be relevant to improve the knowledge about protein function or classification. The web server can be freely utilized at https://appsbio.utalca.cl/3d-pp/.Peer ReviewedPostprint (published version

Keeping Us Grounded: Academic Staff Perceptions of Service User and Carer Involvement in Health and Social Work Training

Academic staff perceptions of the value and purpose of service user and carer (SUAC) involvement within a health and social work faculty in an English university were explored in this co-produced qualitative study. Relevant research findings over the past two decades were reviewed and two SUAC researchers, plus an academic member of staff, designed the study based around fifteen semi-structured telephone interviews. Findings were that staff were very positive about the benefits brought by SUAC involvement, in respect of their own grounding, knowledge, and continuing professional development (CPD), these findings not having previously been reflected in the literature. Barriers to involvement of SUACs were found to be negligible compared to those found in recent literature, and the input of SUACs appeared to be embraced by academic staff. This changing picture has emerged at a time when managerialism and marketization affect the working conditions of staff. In times of increasing workloads, this study suggested that academics find SUAC involvement both supportive and constructively challenging. SUACs were perceived to bring fresh interdisciplinary knowledge and challenges to staff value bases alongside constructs of professionalism that staff may not be able to access elsewhere. The encouragement of interdisciplinary ways of thinking was noted to have been a serendipitous consequence of SUACs from different backgrounds inputting on courses across the faculty. Recommendations are to better ensure consistency in the use of SUACs in terms of resourcing, support, and development if such involvement is to be meaningful rather than marginalised and de-valued

A new strategy for multitarget drug discovery/repositioning through the identification of similar 3D amino acid patterns among proteins structures: The case of Tafluprost and its efects on cardiac ion channels

The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.This research was funded by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grants numbers 1191133, 1170662 and from Spanish Ministry of Economy and Competitiveness (projects SEV-2015-0493 and TIN2015-65316-P, grant BES-2016-078046), and from Generalitat de Catalunya (contracts 2017-SGR-1414 and 2017-SGR-1328). The financial support by DICYT-USACH grant 5392102RP-ACDicyt is also acknowledged. The web-server is hosted in the cluster obtained with the grant CONICYT-FONDEQUIP-EQM160063.Peer ReviewedPostprint (published version

Búsqueda de sitios de unión a ligandos en receptores nicotínicos de acetilcolina humano de tipo α7 y α4(2)β2(3)

147 p.Los receptores nicotínicos de acetilcolina (nAChRs – Nicotinic Acetylcholine Receptors) son canales iónicos activados por ligando (LGIC - Ligand-Gated Ion Channels), que se encuentran presentes en la unión neuromuscular y en neuronas ubicadas en el sistema nervioso central y periférico, donde median la transmisión sináptica. En las últimas décadas, los nAChRs presentes en células neuronales se han convertido en blanco de múltiples investigaciones debido a que se ha reportado que un funcionamiento anormal de estos receptores está asociado a diversas patologías psiquiátricas y neurológicas (enfermedades de Alzheimer, Parkinson, Huntington, etc.) Numerosos intentos han sido realizados para aliviar estas enfermedades, tratando de aprovechar la unión de diversas moléculas para activar, bloquear y/o modular la funcionalidad de los distintos tipos de nAChRs. Varias de estas moléculas se unen al sitio de unión ortostérico, mientras que otros compuestos se unen a los denominados sitios alostéricos, modulando de forma positiva o negativa la acción de estos receptores.En el presente trabajo se realizó la búsqueda de sitios putativos de unión a ligando en diferentes modelos computacionales de nAChRs humanos, teniendo en cuenta la dinámica de las estructuras. Se encontraron un total de 4 sitios consensos de unión a ligando (no repetidos) para el nAChR α4β2 en estado abierto (conformación agonista), 3 sitios putativos no repetidos para el nAChR α4β2 en estado cerrado (conformación antagonista) y 5 sitios putativos de unión a ligando no repetidos para el nAChR α7 en estado abierto (conformación agonista). Posteriormente, a través de simulaciones de acoplamiento molecular proteína-ligando, se comprobó la capacidad de estos sitios para generar interacciones favorables con distintos compuestos.Palabras claves: Receptor nicotínico de acetilcolina, nAChR, Sitios de unión a ligandos . ABSTRACT: Nicotinic Acetylcholine Receptors (nAChRs) are ligand gated ionic channels (LGIC) functionally expressed in the neuromuscular junction and in neurons located in the central and peripheral nervous systems. In the last decades, neuronal nAChRs have become the focus of multiple investigations because it has been reported that their abnormal function is associated with diverse psychiatric disorders and neurological diseases (e.g. Alzheimer’s, Parkinson’s and Huntington’s diseases). Numerous attempts have been made to treat these conditions, trying to exploit the binding of several molecules that activate, block and/or modulate the function of the different types of nAChRs. Some of these drugs bind to the orthosteric binding site, while other compounds bind to the so called allosteric sites, modulating positively or negatively the actions of these receptors.In this work we searched for putative ligand binding sites in different computational models of human nAChRs, taking into account the dynamical behavior of structures. Four (not repeated) putative binding sites were found in α4β2 nAChR in the open state. Likewise, three (not repeated) binding sites for α4β2 nAChR in the closed state and three (not repeated) putative binding sites for α7 nAChR in the open state, were found. Then, through molecular docking simulations, we tested the ability of these sites to generate favorable interactions with a series of compounds over different consensus protein structures of nAChR.Key words: Nicotinic acetylcholine receptors, nAChR, Ligand Binding Sit

UFR2709, a nicotinic acetylcholine receptor antagonist, decreases ethanol intake in alcohol-preferring rats

Brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric acetylcholine-gated cation channels, have been suggested as molecular targets for the treatment of alcohol abuse and dependence. Here, we examined the effect of the competitive nAChR antagonist UFR2709 on the alcohol consumption of high-alcohol-drinking UChB rats. UChB rats were given free access to ethanol for 24-h periods in a two-bottle free-choice paradigm and their ethanol and water intake were measured. The animals were i.p injected daily for 17 days with a 10, 5, 2.5 or 1 mg/kg dose of UFR2709. Potential confounding motor effects of UFR2709 were assessed by examining the locomotor activity of animals administered the highest dose of UR2709 tested (10 mg/kg i.p.). UFR2709 reduced ethanol consumption and ethanol preference and increased water consumption in a dose-dependent manner. The most effective dose of UFR2709 was 2.5 mg/kg, which induced a 56% reduction in alcohol consumption. Administration of UFR2709 did not affect the weight or locomotor activity of the rats, suggesting that its effects on alcohol consumption and preference were mediated by specific nAChRs

Petrology of the Lower Triassic Anorogenic Granites in the High Andes (30°S.L.), Chile (チリー・ハイアンデスの下部三畳紀非造山期花崗岩類の岩石学的研究)

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