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Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABAA receptors (GABAARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC50 of 31.5 ± 1.7 and 40.6 ± 8.2 µM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABAARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.

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Alzheimer's disease is a neurodegenerative disorder that is the leading cause of dementia in elderly patients. Amyloid-ß peptide (1-42 oligomers) has been identified as a neurotoxic factor, triggering many neuropathologic events. In this study, 15 chalcones were synthesized employing the Claisen-Schmidt condensation reaction, starting from a compound derived from fomannoxine, a natural benzodihydrofuran whose neuroprotective activity has been proven and reported, and methyl aromatic ketones with diverse patterns of halogenated substitution. As a result, chalcones were obtained, with good to excellent reaction yields from 50 to 98%. Cytotoxicity of the compounds was assessed, and their cytoprotective effect against the toxicity associated with Aß was evaluated on PC-12 cells. Out of the 15 chalcones obtained, only the 4-bromo substituted was cytotoxic at most tested concentrations. Three synthesized chalcones showed a cytoprotective effect against Aß toxicity (over 37%). The 2,4,5-trifluoro substituted chalcone was the most promising series since it showed a cytoprotective impact with more than 60 ± 5% of recovery of cellular viability; however, 3-fluoro substituted compound also exhibited important values of recovery (50 ± 6%). The fluorine substitution pattern was shown to be more effective for cytoprotective activity. Specifically, substitution with fluorine in the 3,5-positions turned out to be particularly effective for cytoprotection. Furthermore, fluorinated compounds inhibited the aggregation rate of Aß, suggesting a dual effect that can be the starting point of new molecules with therapeutic potential.

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Resumen La presente investigación, sobre el sistema familiar y participación social en mujeres campesinas adultas, tuvo por objetivo describir la participación social en el marco sistémico familiar de mujeres adultas en contexto rural. El estudio empleó metodología cualitativa, con un enfoque fenomenológico, considerando un muestreo no probabilístico de tipo intencionado a partir de cinco entrevistas semiestructuradas a mujeres adultas campesinas de las comunas de Mulchén y Parral. El análisis de datos se desarrolló con base en un análisis de contenido que refleja las dimensiones de la experiencia y observación de campo como las características del contexto más importantes. Los resultados obtenidos se visualizan a través de las categorías de sistema familiar, actividad de mujeres campesinas y participación social, elementos que dan cuenta de vínculo e intereses en común, como también roles culturales y funciones establecidas y no establecidas.

Abstract This study on family systems and social participation in rural adult women had the objective of describing social participation in the family systemic framework of adult women in a rural context. The study used a qualitative methodology, based on a phenomenological approach, considering a non-probabilistic, purposive sampling from 5 semi-structured interviews with rural adult women from the communes of Mulchén and Parral. The data analysis was carried out based on a content analysis that reflects the dimensions of the experience and field observation as the most important characteristics of the context. The results obtained are visualized through the categories of family system, rural women's activity and social participation, elements that account for common ties and interests, as well as cultural roles and established and non-established functions.

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Resumen El Servicio Mejor Niñez es un organismo público que tiene como objetivo garantizar la protección de derechos de niños, niñas y adolescentes al amparo de la Ley N.º 21302. En los últimos años, se ha visto cuestionado tanto por la opinión pública como por organismos internacionales, por incumplimiento de las funciones para la cual se creó. En esta línea, el objetivo de esta investigación se centró en la percepción de los profesionales interventores sobre la vulneración de derechos sobre niños, niñas y adolescentes en la zona centro-sur de Chile. Estas personas son profesionales en Psicología y Trabajo Social que durante años han trabajado en programas de protección de vulneración de derechos, y han desempeñado un rol protector en cuanto a la protección de estos derechos. Para ello, se utilizó un método cualitativo basado en un enfoque fenomenológico, a partir de entrevistas que permitieron conocer los significados y percepciones sobre su ejercicio profesional. Los resultados destacan la visión opuesta y extrema de los profesionales sobre el proceso de intervención (satisfactoria y frustrante), así como la diversidad de modelos o enfoques utilizados en el proceso, lo que parece indicar que no existe una sistematización teórica en cuanto a la intervención que cada programa utiliza. Se estableció una reflexión importante sobre la ejecución de políticas en infancia y adolescencia que buscan promover el desarrollo integral en el marco postpandemia por COVID-19, considerando que muchas personas menores de edad se vieron nuevamente expuestas a vulneraciones de derechos durante el proceso de pandemia.

Abstract The Childhood Improvement Service is a public agency whose objective is to guarantee protection of the rights of children and adolescents with respect to the enactment of Law No. 21302. This has been questioned in recent years by both public opinion and international organizations, in relation to a failure to fulfill the functions for which it was created. In this sense, the objective of this research focused on the perception of professionals involved in children's and adolescents' rights in the central-south zone of Chile. The professionals are psychologists and social workers who have worked to protect the rights circumscribing the different types of interventions and multidisciplinary approaches carried out. For this purpose, a qualitative method was used in phase with a phenomenological approach, based on interviews that allowed ascertaining the meanings and perceptions regarding their professional practice. The results highlight the opposed and extreme views of the professionals in the intervention process (satisfactory versus frustrating), as well as the diversity of models or approaches used in the process, which seems to indicate that there is no theoretical systematization regarding the intervention applied by each program. Establishing an important reflection on the implementation of policies in childhood and adolescence that seek to promote integral development in the post-Covid-19 Pandemic framework.

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Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly affects the elderly. AD's main features have been related to cellular and molecular events, including the aberrant aggregation of the amyloid beta peptide (Aß), Ca2+ dyshomeostasis, and increased mitochondria-associated membranes (MAMs). Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose primary role is the Ca2+-dependent proteins transamidation, including the Aß peptide. TG2 activity has been closely related to cellular damage and death. We detected increased TG2 levels in neuronal cells treated with Aß oligomers (AßOs) and hippocampal slices from J20 mice using cellular and molecular approaches. In this work, we characterized the capacity of TG2 to interact and promote Aß toxic aggregates (AßTG2). AßTG2 induced an acute increase in intracellular Ca2+, miniature currents, and hiperexcitability, consistent with an increased mitochondrial Ca2+ overload, IP3R-VDAC tethering, and mitochondria-endoplasmic reticulum contacts (MERCs). AßTG2 also decreased neuronal viability and excitatory postsynaptic currents, reinforcing the idea of synaptic failure associated with MAMs dysregulation mediated by TG2. Z-DON treatment, TG2 inhibitor, reduced calcium overload, mitochondrial membrane potential loss, and synaptic failure, indicating an involvement of TG2 in a toxic cycle which increases Aß aggregation, Ca2+ overload, and MAMs upregulation. These data provide novel information regarding the role TG2 plays in synaptic function and contribute additional evidence to support the further development of TG2 inhibitors as a disease-modifying strategy for AD.

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Neurulation is a crucial process in the formation of the central nervous system (CNS), which begins with the folding and fusion of the neural plate, leading to the generation of the neural tube and subsequent development of the brain and spinal cord. Environmental and genetic factors that interfere with the neurulation process promote neural tube defects (NTDs). Connexins (Cxs) are transmembrane proteins that form gap junctions (GJs) and hemichannels (HCs) in vertebrates, allowing cell-cell (GJ) or paracrine (HCs) communication through the release of ATP, glutamate, and NAD+; regulating processes such as cell migration and synaptic transmission. Changes in the state of phosphorylation and/or the intracellular redox potential activate the opening of HCs in different cell types. Cxs such as Cx43 and Cx32 have been associated with proliferation and migration at different stages of CNS development. Here, using molecular and cellular biology techniques (permeability), we demonstrate the expression and functionality of HCs-Cxs, including Cx46 and Cx32, which are associated with the release of ATP during the neurulation process in Xenopus laevis. Furthermore, applications of FGF2 and/or changes in intracellular redox potentials (DTT), well known HCs-Cxs modulators, transiently regulated the ATP release in our model. Importantly, the blockade of HCs-Cxs by carbenoxolone (CBX) and enoxolone (ENX) reduced ATP release with a concomitant formation of NTDs. We propose two possible and highly conserved binding sites (N and E) in Cx46 that may mediate the pharmacological effect of CBX and ENX on the formation of NTDs. In summary, our results highlight the importance of ATP release mediated by HCs-Cxs during neurulation.

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GLUT1 is a facilitative glucose transporter that can transport oxidized vitamin C (i.e., dehydroascorbic acid) and complements the action of reduced vitamin C transporters. To identify the residues involved in human GLUT1's transport of dehydroascorbic acid, we performed docking studies in the 5 Å grid of the glucose-binding cavity of GLUT1. The interactions of the bicyclic hemiacetal form of dehydroascorbic acid with GLUT1 through hydrogen bonds with the -OH group of C3 and C5 were less favorable than the interactions with the sugars transported by GLUT1. The eight most relevant residues in such interactions (i.e., F26, Q161, I164, Q282, Y292, and W412) were mutated to alanine to perform functional studies for dehydroascorbic acid and the glucose analog, 2-deoxiglucose, in Xenopus laevis oocytes. All the mutants decreased the uptake of both substrates to less than 50%. The partial effect of the N317A mutant in transporting dehydroascorbic acid was associated with a 30% decrease in the Vmax compared to the wildtype GLUT1. The results show that both substrates share the eight residues studied in GLUT1, albeit with a differential contribution of N317. Our work, combining docking with functional studies, marks the first to identify structural determinants of oxidized vitamin C's transport via GLUT1.

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BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-ß peptide (Aß) accumulation, where the soluble oligomers of Aß (AßOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. OBJECTIVE: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AßOs were analyzed. METHODS: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AßOs. RESULTS: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AßOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AßOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aß aggregation process inducing a decrease in AßOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. CONCLUSION: We believe that Eu represents a novel lead that reduces the Aß toxicity, opening new research venues for lignans as neuroprotective agents.

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Introducción: Los probióticos son microorganismos vivos que brindan beneficios al huésped mediante diversos mecanismos de acción. Han sido fuente de estudio en diversas patologías pediátricas, mostrando algunos resultados prometedores. Objetivo: Elaborar una revisión de la literatura sobre los mecanismos de acción y la evidencia actual que tienen los probióticos sobre la salud infantil. Materiales y métodos: Se realizó una revisión narrativa de la literatura con estrategia de búsqueda sistemática de la literatura con términos MESH acerca de los mecanismos de acción de los probióticos y su uso. Se incluyeron metaanálisis, revisiones sistemáticas y ensayos clínicos aleatorizados. Resultados: Los probióticos son una nueva herramienta terapéutica usada para mejorar la salud infantil. Se ha encontrado efecto benéfico en diarrea, en enterocolitis necrosante con una disminución significativa de la mortalidad y se ha mostrado evidencia significativa en las horas de llanto en cólico del lactante. Conclusión: Se requieren más estudios en otro tipo de enfermedades como estreñimiento y en algunos procesos alérgicos e inflamatorios. Los ensayos revisados ofrecen un panorama prometedor, pero la elección de un probiótico debe ser personalizado de acuerdo con la edad, enfermedad, cepa y dosis, dado que cada uno de ellos tiene múltiples mecanismos de acción que impactan de manera diferente en la eficacia clínica.

Introduction: Prebiotics are living microorganisms that provide benefits to the host through various mechanisms of action. They have been a source of study in various pediatric pathologies showing some promising results. Objective: To prepare a review on the mechanisms of action and current evidence that prebiotics have on child health. Materials and methods: A narrative review of the literature was carried out with a systematic literature search strategy with MESH terms about the mechanisms of action of probiotics and their use. Meta-analyzes, systematic reviews, and randomized clinical trials were included. Results: Probiotics are a new therapeutic tool used to improve children's health. A beneficial effect has been found in diarrhea, in necrotizing enterocolitis with a significant decrease in mortality and significant evidence has been shown in the hours of crying in colic in infants. Conclusion: The trials reviewed offer a promising picture, but the choice of a probiotic must be customized according to the age, disease, bacterial strain and dose, since each one has different action mechanisms and clinical effectiveness. More studies are required in some allergic and inflammatory diseases.

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The use of treated wastewater (TWW) for irrigation has gained global attention since it reduces pressure on groundwater (GW) and surface water. This study aimed to evaluate the effect of TWW on agronomic, photosynthetic, stomatal, and nutritional characteristics of barley plants. The experiment with barley was established on two bands: one band was irrigated with GW and the other with TWW. The evaluation was performed 25, 40, 60, 90, and 115 days after sowing (DAS). Results showed that irrigation with TWW increased (p < 0.01) grain yield by 54.3% and forage yield by 39.4% compared to GW irrigation. In addition, it increased plant height (PH) (p = 0.013), chlorophyll concentration index (CCI) (p = 0.006), and leaf area index (LAI) (p = 0.002). TWW also produced a positive effect (p < 0.05) in all the photosynthetic efficiency parameters evaluated. Barley plants irrigated with TWW had lower stomatal density (SD) and area (SA) (p < 0.001) than plants irrigated with GW. Plants irrigated with TWW had a higher P concentration (p < 0.05) in stems and roots and K concentration in leaves than plants irrigated with GW. We concluded that the use of TWW induced important biochemical, physiological, and agronomic changes in barley plants. Hence, the use of TWW may be a sustainable alternative for barley production in arid and semi-arid regions. This study was part of a government project, which aimed to develop a new metropolitan irrigation district with TWW. This study may contribute to the sustainability of water resources and agricultural practices in northern Mexico.

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