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Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin. These findings identify an unanticipated role for ciguatoxin in the regulation of homeostatic plasticity in central neurons involving NaV channels and raise the possibility that some of the neurological symptoms of ciguatera might be explained by these compensatory mechanisms.

Background and Purpose Marine sponges have evolved the capacity to produce a series of very efficient chemicals to combat viruses, bacteria, and eukaryotic organisms. It has been demonstrated that several of these compounds have anti-neoplastic activity. The highly toxic sponge Crambe crambe has been the source of several molecules named crambescidins. Of these, crambescidin-816 has been shown to be cytotoxic for colon carcinoma cells. To further investigate the potential anti-carcinogenic effect of crambescidin-816, we analysed its effect on the transcription of HepG2 cells by microarray analysis followed by experiments guided by the results obtained. Experimental Approach After cytotoxicity determination, a transcriptomic analysis was performed to test the effect of crambescidin-816 on the liver-derived tumour cell HepG2. Based on the results obtained, we analysed the effect of crambescidin-816 on cell-cell adhesion, cell-matrix adhesion, and cell migration by Western blot, confocal microscopy, flow cytometry and transmission electron microscopy. Cytotoxicity and cell migration were also studied in a variety of other cell lines derived from human tumours. Key Results Crambescidin-816 had a cytotoxic effect on all the cell lines studied. It inhibited cell-cell adhesion, interfered with the formation of tight junctions, and cell-matrix adhesion, negatively affecting focal adhesions. It also altered the cytoskeleton dynamics. As a consequence of all these effects on cells crambescidin-816 inhibited cell migration. Conclusions and Implications The results indicate that crambescidin-816 is active against tumour cells and implicate a new mechanism for the anti-tumour effect of this compound.

The Mediterranean marine sponge Crambe crambe is the source of two families of guanidine alkaloids known as crambescins and crambescidins. Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study. Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities. We report herein that, while crambescin-A1 has a minor effect on these cells, CC1 protects them against oxidative injury by means of metallothionein induction even at low concentrations. Additionally, at high doses, CC1 arrests the HepG2 cell cycle in G0/G1 and thus inhibits tumor cell proliferation. The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities FEDER cofunded-grants. CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01 and Consellería de Cultura, Educación e Ordenación Universitaria, GRC2013-016, and by Axencia Galega de Innovación, Spain, ITC-20133020 SINTOX, IN852A 2013/16-3 MYTIGAL. CDTIunderISIP Programme, Spain, IDI-20130304 APTAFOOD. European Union’s 7th Framework Programme managed by Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 µAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA SI

[ES] Los datos de la Encuesta Nacional de Gestión de la Seguridad y Salud en las Empresas pone de manifiesto una escasa práctica en la investigación de casos de enfermedades profesionales o relacionadas con el trabajo. En este contexto se desarrolla este proyecto dirigido al desarrollo y ensayo de un procedimiento de investigación de casos de enfermedades profesionales o relacionadas con el trabajo, que permita orientar, armonizar y sistematizar la recogida de información en el transcurso de la investigación de este tipo de casos. En una primera fase un grupo investigadores del Instituto Valenciano de Seguridad y Salud en el Trabajo y de la Escuela Nacional de Medicina del Trabajo del Instituto de Salud Carlos III desarrollaron un procedimiento de investigación de casos de enfermedades laborales (profesionales o relacionadas con el trabajo), que se sometió mediante un taller al consenso con un grupo de expertos procedentes de distintos grupos de interés: Sindicatos, Servicios de Prevención Propios y Ajenos, Mutuas, Inspección de Trabajo, órganos técnicos de las CCAA, Sociedades de Medicina del Trabajo y Organismos Públicos de Investigación y Universidad. El procedimiento resultante se ensayó en 21 casos incidentes de enfermedades laborales, se evaluaron un total de 26 indicadores en tres dimensiones: necesidad, aplicabilidad y valoración general, medidos por una escala tipo Likert, evaluando el grado de acuerdo entre aplicadores mediante el procedimiento de estandarización del Instrumento AGREE. Los resultados ponen de manifiesto en 19 indicadores un grado de consenso superior al 80% y en 10 un grado de consenso superior al 90%, no existiendo disenso en ningunos de los indicadores analizados, lo que permite concluir que el procedimiento ensayado cubre las necesidades de información en la investigación de casos de enfermedades laborales. [EN] Data from the National Survey of Safety and Health Management at Companies evidence gaps the investigation of cases of occupational diseases. In this context this project aims to developed and test aninvestigation procedure of occupational diseases, in order to guide, harmonize and systematize the collection of information in the course of the investigation of this cases. In the first phase a group of researchers from the Safety al Occupational Health of Valencia the National School of Occupational Medicine developed a procedure for investigate cases of occupational diseases that was submitted to a consensus workshop with a group of experts from various key agents: Employees Organizations, Prevention Services, Mutuas, Labour Inspectorate, Technical Institutes from the Autonomous Communities, Societies of Occupational Medicine, Public Research Institutes and University. The resulting procedure was tested on 21 incident cases of occupational diseases, we evaluated a total of 26 indicators in three dimensions: needs, relevance and overall opinion, as measured by a Likert scale, assessing the degree of agreement between applicators by the standardization procedure of the AGREE evaluation method. The results show on 19 indicators a level of consensus upper than 80% and for others 10 indicators a level of consensus upper than 90%, there being no dissent in any of the indicators analyzed. These results leading to the conclusion that the tested procedure covers the information needs in the investigation of cases of occupational diseases. Sí