In Vitro Models for Studying Chronic Drug-Induced Liver Injury

[EN] Drug-induced liver injury (DILI) is a major clinical problem in terms of patient morbidity and mortality, cost to healthcare systems and failure of the development of new drugs. The need for consistent safety strategies capable of identifying a potential toxicity risk early in the drug discovery pipeline is key. Human DILI is poorly predicted in animals, probably due to the well-known interspecies differences in drug metabolism, pharmacokinetics, and toxicity targets. For this reason, distinct cellular models from primary human hepatocytes or hepatoma cell lines cultured as 2D monolayers to emerging 3D culture systems or the use of multi-cellular systems have been proposed for hepatotoxicity studies. In order to mimic long-term hepatotoxicity in vitro, cell models, which maintain hepatic phenotype for a suitably long period, should be used. On the other hand, repeated-dose administration is a more relevant scenario for therapeutics, providing information not only about toxicity, but also about cumulative effects and/or delayed responses. In this review, we evaluate the existing cell models for DILI prediction focusing on chronic hepatotoxicity, highlighting how better characterization and mechanistic studies could lead to advance DILI prediction.This work has been supported by the Institute of Health Carlos III (ISCIII, Plan Estatal de I+D+i 2013-2016) and co-financed by the European Regional Development Fund "A way to achieve Europe" (FEDER) through grant PI21/00223, by the Spanish Ministry of Science and Innovation Ministry-Spanish Research Agency through the Project PID2019-106000RB-C22/AEI/10.13039/501100011033, and by the Generalitat Valenciana (PROMETEO/2019/060).Donato, MT.; Gallego-Ferrer, G.; Tolosa, L. (2022). In Vitro Models for Studying Chronic Drug-Induced Liver Injury. International Journal of Molecular Sciences. 23(19):1-30. https://doi.org/10.3390/ijms231911428130231

Catálogo actualizado de los briófitos de la Región de Murcia (Sureste de España)

An updated checklist of the bryophytes of the Region of Murcia is provided. Bryophyte diversity in Murcia consists of 200 especies and 15 infraespecific taxa (77 genera) of mosses and 32 species (20 genera) of liverworts. Grimmia tergestina is confirmed in the territory. Aschisma cuynetii, Brachytheciastrum dieckii, Brachythecium albicans, Brachythecium rutabulum, Brachythecium salebrosum, Bryum alpinum, Bryum elegans, Campyliadelphus chrysophyllus, Campylopus pilifer and Didymodon eckeliae are new reported for Murcia. Bryum tenuisetum, Entosthodon attenuatus and Fissidens bryoides are excluded from the check-list.Se actualiza el catálogo de los briófitos de la Región de Murcia. Para este territorio se aceptan 200 especies y 15 taxones infraespecíficos (77 géneros) de musgos y 32 especies de hepáticas (20 géneros). Grimmia tergestina se confirma en el territorio. Aschisma cuynetii, Brachytheciastrum dieckii, Brachythecium albicans, Brachythecium rutabulum, Brachythecium salebrosum, Bryum alpinum, Bryum elegans, Campyliadelphus chrysophyllus, Campylopus pilifer y Didymodon eckeliae son nuevas citas para Murcia. Bryum tenuisetum, Entosthodon attenuatus y Fissidens bryoides se excluyen del catálogo

Bicuspid Aortic Valves With Different Spatial Orientations of the Leaflets Are Distinct Etiological Entities

ObjectivesThe aim of this study was to decide whether bicuspid aortic valves (BAVs) with fused right and noncoronary leaflets (R-N) and BAVs with fused right and left leaflets (R-L) have different etiologies or are the product of a single diathesis.BackgroundThe BAV is the most common congenital cardiac malformation. The R-N and R-L BAVs are the most frequent BAV subtypes.MethodsThe study was carried out in adult and embryonic hearts of endothelium nitric oxide synthase knock-out mice and inbred Syrian hamsters with a high incidence of R-N and R-L BAVs, respectively. The techniques used were histochemistry, immunohistochemistry, and scanning electron microscopy.ResultsThe R-N BAVs result from a defective development of the cardiac outflow tract (OT) endocardial cushions that generates a morphologically anomalous right leaflet. The left leaflet develops normally. The R-L BAVs are the outcome of an extrafusion of the septal and parietal OT ridges that thereby engenders a sole anterior leaflet. The noncoronary leaflet forms normally.ConclusionsThe R-N and R-L BAVs are different etiological entities. The R-N BAVs are the product of a morphogenetic defect that happens before the OT septation and that probably relies on an exacerbated nitric oxide–dependent epithelial-to-mesenchymal transformation. The R-L BAVs result from the anomalous septation of the proximal portion of the OT, likely caused by a distorted behavior of neural crest cells. Care should be taken in further work on BAV genetics because R-N and R-L BAVs might rely on different genotypes. Detailed screening for R-N and R-L BAVs should be performed for a better understanding of the relationships between these BAV morphologic phenotypes and other heart disease

Virtual Excursions: a new way to explore science in class

The educational platform Virtual Science Hub (ViSH) has been developed as part of the GLOBAL excursion European project. ViSH (http://vishub.org/) is a portal where teachers and scientist interact to create virtual excursions to science infrastructures. The main motivation behind the project was to connect teachers - and in consequence their students - to scientific institutions and their wide amount of infrastructures and resources they are working with. Thus the idea of a hub was born that would allow the two worlds of scientists and teachers to connect and to innovate science teaching. The core of the ViSH?s concept design is based on virtual excursions, which allow for a number of pedagogical models to be applied. According to our internal definition a virtual excursion is a tour through some digital context by teachers and pupils on a given topic that is attractive and has an educational purpose. Inquiry-based learning, project-based and problem-based learning are the most prominent approaches that a virtual excursion may serve. The domain specific resources and scientific infrastructures currently available on the ViSH are focusing on life sciences, nano-technology, biotechnology, grid and volunteer computing. The virtual excursion approach allows an easy combination of these resources into interdisciplinary teaching scenarios. In addition, social networking features support the users in collaborating and communicating in relation to these excursions and thus create a community of interest for innovative science teaching. The design and development phases were performed following a participatory design approach. An important aspect in this process was to create design partnerships amongst all actors involved, researchers, developers, infrastructure providers, teachers, social scientists, and pedagogical experts early in the project. A joint sense of ownership was created and important changes during the conceptual phase were implemented in the ViSH due to early user feedback. Technology-wise the ViSH is based on the latest web technologies in order to make it cross-platform compatible so that it works on several operative systems such as Windows, Mac or Linux and multi-device accessible, such as desktop, tablet and mobile devices. The platform has been developed in HTML5, the latest standard for web development, assuring that it can run on any modern browser. In addition to social networking features a core element on the ViSH is the virtual excursions editor. It is a web tool that allows teachers and scientists to create rich mash-ups of learning resources provided by the e-Infrastructures (i.e. remote laboratories and live webcams). These rich mash-ups can be presented in either slides or flashcards format. Taking advantage of the web architecture supported, additional powerful components have been integrated like a recommendation engine to provide personalized suggestions about educational content or interesting users and a videoconference tool to enhance real-time collaboration like MashMeTV (http://www.mashme.tv/)

A quantitative approach to the experimental transmission success of echinostoma friedi (trematoda: echinostomatidae) in rats

Using a range of parameters, the ability of rats (Rattus norvegicus) to successfully transmit Echinostoma friedi to the next host was examined under experimental conditions. The concept of Experimental Transmission Success (TM), defined as the number of hosts that become successfully infected after exposure to a number of infective stages produced by a previous host per unit of inoculation at which this latter host was exposed, was introduced. Using data for the egg output and miracidium hatching and infectivity, the TM permits us to estimate the ability of a particular defintive host species to successfully transmit a parasite species. This concept may be also useful to compare the transmission fitness of a parasite in different definitive host species. Moreover, variations of the Experimental Transmission Success over the course of the infection were calculated by the use of the Weekly Experimental Transmission Success (TMW). Overall, considering the complete duration of the experiment, the TM of E. friedi using rats as definitive hosts was 0.68 infected snails/metacercaria. However, positive values of the TMW were only obtained from 2 to 4 wk post-infection, with a maximum during the third wk post-infection. When comparing the TM values of E. friedi in rats with those calculated in hamsters on the basis of previously published data, E. friedi appears to be more appropriate to move through this portion of its life cycle when using hamsters (Mesocricetus auratus) as the final host than rats.Toledo Navarro, Rafael, [email protected] ; Carpena Hernandez, Ines, [email protected] ; Espert Fernandez, Ana M., [email protected] ; Sotillo Gallego, Javier, [email protected] ; Esteban Sanchis, Jose Guillermo, [email protected]

Age protects from harmful effects produced by chronic intermittent hypoxia

Producción CientíficaObstructive sleep apnoea (OSA) affects an estimated 3–7% of the adult population, the frequency doubling at ages >60–65 years. As it evolves, OSA becomes frequently associated with cardiovascular, metabolic and neuropsychiatric pathologies defining OSA syndrome (OSAS). Exposing experimental animals to chronic intermittent hypoxia (CIH) can be used as a model of the recurrent hypoxic and O2 desaturation patterns observed in OSA patients. CIH is an important OSA event triggering associated pathologies; CIH induces carotid body (CB)-driven exaggerated sympathetic tone and overproduction of reactive oxygen species, related to the pathogenic mechanisms of associated pathologies observed in OSAS. Aiming to discover why OSAS is clinically less conspicuous in aged patients, the present study compares CIH effects in young (3–4 months) and aged (22–24 months) rats. To define potential distinctive patterns of these pathogenic mechanisms, mean arterial blood pressure as the final CIH outcome was measured. In young rats, CIH augmented CB sensory responses to hypoxia, decreased hypoxic ventilation and augmented sympathetic activity (plasma catecholamine levels and renal artery content and synthesis rate). An increased brainstem integration of CB sensory input as a trigger of sympathetic activity is suggested. CIH also caused an oxidative status decreasing aconitase/fumarase ratio and superoxide dismutase activity. In aged animals, CIH minimally affected CB responses, ventilation and sympathetic-related parameters leaving redox status unaltered. In young animals, CIH caused hypertension and in aged animals, whose baseline blood pressure was augmented, CIH did not augment it further. Plausible mechanisms of the differences and potential significance of these findings for the diagnosis and therapy of OSAS are discussed.Ministerio de Ciencia, Innovación y Universidades (grant BFU2012-37459)Instituto de Salud Carlos III (grant CIBER CB06/06/0050)Portuguese Foundation for Science and Technology (grant EXP/NEU-SCC/2813/2013

CATÁLOGO DE LOS BRIÓFITOS DE LA PROVINCIA DE MURCIA (SURESTE DE ESPAÑA)

A check-list of the bryophytes of Murcia province is provided. Bryophyte diversity in Murcia consists of 200 taxa (74 genera) of mosses and 32 taxa (20 genera) of liverworts. Pseudocrossidium obtusulum is reported as new to the Iberian Peninsula. A total of 30 taxa are new record from Murcia: Acaulon casasianum, Astomum levieri, Bryoerythrophyllum recurvirostrum, Crossidium laevipilum, Entosthodon convexus, Grimmia dissimulata, Gymnostomum lanceolatum, Hedwigia ciliata, Orthotrichum affine, O. pumilum, O. scanicum, O. schimperi, O. striatum, O. tenellum, O. tortidontium, O. vittii, Philonotis fontana, Pleuridium acuminatum, Pohlia cruda, Pterygoneurum subsessile, Rhynchostegiella tenella, Schistidium crassipilum, Schistidium singarense, Syntrichia virescens, Tortula canescens, T. mucronifolia, Weissia brachycarpa, W. condensa var. armata, Athalamia hyalina, and Jungermannia atrovirens. Thirty eight taxa (33 mosses and 5 liverworts) are excluded from the checklist or represent doubtful reports for Murcia.Se realiza un catalogo de los briofitos de la provincia de Murcia. La diversidad briofitica de Murcia se estima en 200 taxones (74 generos) de musgos y 32 taxones de hepaticas (20 generos). Pseudocrossidium obtusulum se cita por primera vez en la Peninsula Iberica. Un total de 30 taxones son novedades para la provincia de Murcia: Acaulon casasianum, Astomum levieri, Bryoerythrophyllum recurvirostrum, Crossidium laevipilum, Entosthodon convexus, Grimmia dissimulata, Gymnostomum lanceolatum, Hedwigia ciliata, Orthotrichum affine, O. pumilum, O. scanicum, O. schimperi, O. striatum, O. tenellum, O. tortidontium, O. vittii, Philonotis fontana, Pleuridium acuminatum, Pohlia cruda, Pterygoneurum subsessile, Rhynchostegiella tenella, Schistidium crassipilum, Schistidium singarense, Syntrichia virescens, Tortula canescens, T. mucronifolia, Weissia brachycarpa, W. condensa var. armata, Athalamia hyalina y Jungermannia atrovirens. Treinta y ocho taxones (33 musgos y 5 hepaticas) se han excluido del catalogo de la provincia o se citan como dudosos

Novedades corológicas para la flora briofítica ibérica. IV

This note continues the publication on new national and regional records based on the studies of Flora Briofítica Ibérica Project. Several field trips has been carried out during the years 2004-2010, which have provided new records.Con esta nota continuamos la publicación de novedades corológicas provinciales o nacionales detectadas en los estudios realizados dentro del Proyecto Flora Briofítica Ibérica. Se han llevado a cabo diversas prospecciones y recolecciones durante los años 2004 a 2010 que han revelado novedades de interés

Contribución al conocimiento de la flora briofítica de la comarca de la Axarquía y la ZEC Sierra de Camarolos (Málaga, España)

Through the collection of samples and study of 61 localities, the bryophytic flora of the Axarquía region and the ZEC Sierra de Camarolos is studied. The bryophyte diversity is estimated at 140 species, of which 124 are mosses and 16 liverworts. Husnotiella sinuosa (Mitt.) J.A. Jiménez & M.J. Cano is recorded for the first time from Andalusia, Orthotrichum macrocephalum F. Lara, Garilleti & Mazimpaka, O. schimperi Hammar, and Tortella inflexa (Bruch) Broth. are reported for the first time from Malaga province. Most of the species in the catalogue (about 85%) are new for the studied territory.Resumen Mediante las recolecciones en un total de 61 localidades muestreadas, se lleva a cabo un estudio de la flora briofítica de la comarca de la Axarquía (Málaga) y la ZEC Sierra de Camarolos (Málaga). La diversidad briofítica se estima en 140 especies, de ellas 124 son musgos y 16 hepáticas. Husnotiella sinuosa (Mitt.) J.A. Jiménez & M.J. Cano se cita por vez primera de Andalucía, Orthotrichum macrocephalum F. Lara, Garilleti & Mazimpaka, O. schimperi Hammar y Tortella inflexa (Bruch) Broth. son novedades para la brioflora malacitana. La mayoría de las especies del catálogo (alrededor del 85%) son novedades para el territorio estudiado

The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-κB signaling

Fas apoptosis inhibitory molecule (FAIM) is a protein identified as an antagonist of Fas-induced cell death. We show that FAIM overexpression fails to rescue neurons from trophic factor deprivation, but exerts a marked neurite growth–promoting action in different neuronal systems. Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells. FAIM overexpression promoted NF-κB activation, and blocking this activation by using a super-repressor IκBα or by carrying out experiments using cortical neurons from mice that lack the p65 NF-κB subunit prevented FAIM-induced neurite outgrowth. The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras–ERK pathway. Finally, we show that FAIM interacts with both Trk and p75 neurotrophin receptor NGF receptors in a ligand-dependent manner. These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras–ERK pathway and NF-κB