Cálculo retrospectivo del coeficiente de balasto horizontal a partir de mediciones de desplazamientos en pantallas del Metro de Sevilla

This paper presents an abacus with the values of the coefficient of horizontal subgrade reaction for retaining wall analysis in Seville. The aforementioned values have been extrapolated from the actual behaviour on site of the retaining walls, monitored with inclinometers, during the different excavation stages. A primary analysis is carried out initially using the calculation programs Plaxis, Rido and Cype and Chadeisson values of the coefficient of horizontal subgrade reaction. The comparison and discussion of the achieved results leads us to conclude that the usual calculations with Rido and Cype are not reliable for accurately predicting the actual behaviour of the retaining walls. Due to that a parametric analysis is carried out, varying the values of the coefficient of horizontal subgrade reaction, until finding those which mach better the measured reality. The obtained results are synthesised in an abacus so that the knowledge learnt through experience can be applied in future works.En este artículo se presenta un ábaco con los valores del coeficiente de balasto horizontal para el cálculo de pantallas en Sevilla. Dichos valores se han extrapolado a partir del comportamiento real en obra de las pantallas, medido con inclinómetros, durante las distintas fases de excavación. Se realiza de inicio un análisis primario utilizando los programas de cálculo Plaxis, Rido y Cype y los valores del coeficiente de balasto de Chadeisson. La comparación y discusión de los resultados obtenidos nos lleva a concluir que los cálculos habituales con Rido y Cype no son fiables para predecir adecuadamente el comportamiento real de las pantallas. Por eso se realiza un análisis paramétrico, variando los valores del coeficiente de balasto, hasta dar con aquéllos que mejor reproducen la realidad medida. Los resultados alcanzados se sintetizan en forma de ábaco para que lo aprendido con la experiencia pueda ser aplicado en futuros trabajos

New flavonoid \u2013 N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer\ub4s disease endowed with neurogenic properties

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid \u2013 DBMA hybrids (1\u201313) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer\u2019s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), \u3b2-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (\u3c31R/\u3c32R). After a funnel-type screening, 6,7-dimethoxychromone \u2013 DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and \u3c31R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration

Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (\uf0731R) and inhibition of key enzymes in Alzheimer\u2019s disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin- 4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in \u3c31R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and sigma-1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs

Caracterización farmacológica de derivados de melatonina y resveratrol para el potencial tratamiento de la enfermedad de Alzheimer

This study has been developed within a multidisciplinary project designed to search for multitarget compounds with NRF2 inducing capacity, by inhibiting the Keap1-NRF2 interaction, for the treatment of Alzheimer¿s disease. We have focused on melatonin and resveratrol derivatives, which additionally induce NRF2 transcription factor, master regulator of oxidative stress. For this study, two melatonin (CH213 and CH507) and one resveratrol (PL119) derivatives, which were the ones that duplicated NRF2 expression at concentrations below 10 ¿M, were selected. We found that these compounds were not neurotoxic in the human neuroblastoma cell line SH-SY5Y at the concentration of 100 ¿M. Thereafter, neuroprotection in a tau hyperphosphorylation in vitro model induced by okadaic acid (OA) was studied; compounds CH507 and PLC119 presented significant neuroprotection, while CH213 did not. Nevertheless, neuroprotection of compound CH213 against OA was studied in primary neuronal cultures achieving significant results. Additionally, their potential anti neuroinflammatory effects were studied in primary rat glial cultures exposed to LPS; in this model, only compound CH213 reduced nitric oxide production and IL-1b. CH123 was further studied in an acute model of hippocampal slices, where toxicity was induced by incubation with OA for 6 h and in organotypic hippocampal cultures of 14 months old APPTau mice; in these models, CH213 was able to provide neuroprotection and reduce oxidative stress. Finally, since QR2, also known as MT3, is overexpressed in AD patients, we sought of interest to perform a molecular docking study to evaluate how the compounds could interact with this receptor. In conclusion, CH213 is a melatonin derivative that induces NRF2 with antineuroinflammatory, antioxidant and neuroprotective properties; however, future studies in in vivo AD models need to be conducted to validate the in vitro results here obtained

New neurogenic inducers with combined activities in key targets related to Alzheimer¿s disease

Alzheimer¿s Disease (AD) is a complex multifactorial illness with no effective cure, characterized by the irreversible memory loss and global cognitive impairment. Given that the marketed drugs act only at one single target, being a symptomatic treatment, exploration of new molecules acting in different pathways is required. In this sense, we have developed a large family of multitarget directed ligands (MTDL), which interacts in different targets related to neurodegeneration, such as the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), lipoxygenase-5 (LOX-5), melatonin receptors (MT1, MT2, and MT3), and monoamine oxidases (MAO-A and MAO-B). The affinity or inhibition constants of these compounds in such targets are in the nanomolar and micromolar ranges. In general, these molecules have potent antioxidant properties (ORAC assay) and are able to penetrate into the central nervous system (CNS) by passive diffusion (PAMPA-BBB assay). Moreover, some of them are able to promote neurogenesis in vitro by inducing the maturation of neural stem cells into a neuronal phenotype. A structure-activity relationship has been stablished, reaching an optimized structure as possible candidate to treat AD, able to cross the blood brain barrier, reaching the CNS where it would act in three targets involved in the regulation of oxidative stress, as Nrf2 inducer, MT3 ligand and selective MAO B inhibitor. Furthermore, this MTDL is an effective neuroprotective and neurogenic agent.Dirección General de Investigación e Innovación de la Comunidad de Madrid y Fondo Europeo de Desarrollo Regional (B2017/BMD-3827); Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación y FEDER (SAF2015-64948-C2-1-R and RTI2018-093955-B-C21). C.H.-A. thanks Spanish Ministry of Education for a FPU fellowship (grant FPU16/01704