Arthrospira (Spirulina) platensis feeding reduces the early stage of chemically induced rat colon carcinogenesis

Sarmiento-Machado L.M and Ariane Rocha Bartolomeu A.R received fellowships from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)- Finance code 001 and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-# 2017/26217-7, respectively.Colorectal cancer is the third most diagnosed cancer worldwide and linked to dietary/lifestyle factors. Arthrospira (Spirulina) platensis (AP) contains bioactive compounds with beneficial effects in vivo/in vitro. We evaluated the effects of AP feeding against 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male Sprague Dawley rats were given subcutaneous injections of DMH (4 × 40 mg/kg body weight) (G1–G3) or vehicle (G4–G5) twice a week (weeks 3–4). During weeks 1–4, animals were fed a diet containing 1 % (G2) or 2 % (G3–G4) AP powder (w/w). After this period, all groups received a balanced diet until week 12. Some animals were euthanised after the last DMH injection (week 4) for histological, immunohistochemical (Ki-67, γ-H2AX and caspase-3) and molecular analyses (real time-PCR for 91 genes), while other animals were euthanised at week 12 for preneoplastic aberrant crypt foci (ACF) analysis. Both AP treatments (G2–G3) significantly decreased the DMH-induced increase in γ-H2AX (DNA damage) and caspase 3 (DNA damage-induced cell death) in colonic crypts at week 4. In addition, Cyp2e1 (Drug metabolism), Notch1, Notch2 and Jag1 genes (Notch pathway) and Atm, Wee1, Chek2, Mgmt, Ogg1 and Xrcc6 genes (DNA repair) were also down-regulated by 2 % AP feeding (G3) at week 4. A significant reduction in ACF development was observed in both AP-treated groups (G2–G3) at week 12. In conclusion, findings indicate that AP feeding reduced acute colonic damage after DMH, resulting in fewer preneoplastic lesions. Our study provided mechanistic insights on dietary AP-preventive effects against early colon carcinogenesis.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) 001Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2017/26217-

Una visión histórica de la proteína quinasa PKR: desde su descubrimiento y mecanismo de acción hasta sus implicaciones clínicas y terapéuticas

The protein kinase R (PKR, also called EIF2AK2) is an interferon-inducible double-stranded RNA protein kinase with multiple effects on cells. PKR plays an active part in the cellular response to numerous types of stress, with a critical role in the host's interferon-induced antiviral defence mechanisms. PKR has been extensively studied and documented for its relevance as a cell growth regulator, and more recently analysed in connection with metabolism, inflammatory processes, cancer, and neurodegenerative diseases. The present review will summarise, in chronological order, the state of the knowledge about this kinase as well as the contributions we have done at the National Centre of Biotechnology regarding the regulation and mechanisms of action of PKR. Specific mention will be made of the studies that the author leads at the University Hospital Complex of Granada, showing the importance that PKR has as a target of both conventional chemotherapeutics and novel drugs, and its potential as a biomarker and therapeutic target in various pathologies.PKR, también llamada EIF2AK, es una proteína quinasa de respuesta a ARN de doble cadena inducida por interferón que participa en múltiples efectos en las células. PKR contribuye de forma activa en la respuesta celular a numerosos tipos de estrés, teniendo una importante función en el mecanismo de defensa antiviral del hospedador inducido por los interferones. PKR ha sido estudiada intensamente a lo largo del tiempo documentando su relevancia también como modulador del crecimiento celular, y más recientemente implicándola en metabolismo, procesos inflamatorios, cáncer y enfermedades neurodegenerativas. En esta revisión se resume de forma cronológica, el conocimiento adquirido sobre esta quinasa y nuestras contribuciones en el mecanismo de acción y regulación de PKR llevadas a cabo en el Centro Nacional de Biotecnología. Además, con especial interés, se describen los estudios que la autora lidera en el Complejo Hospitalario Universitario de Granada mostrando la importancia que PKR tiene como diana molecular de quimioterapéuticos convencionales y nuevos fármacos así como su potencial como biomarcador y diana terapéutica en varias enfermedades

The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer

This research was funded by MCIN/AEI/10.13039/501100011033/FEDER, grant number RTI2018-101309-B-C22 and by the Chair Doctors Galera-Requena in cancer stem cell research.The mitogen-activated protein kinase (MAPK) family is an important bridge in the transduction of extracellular and intracellular signals in different responses at the cellular level. Within this MAPK family, the p38 kinases can be found altered in various diseases, including cancer, where these kinases play a fundamental role, sometimes with antagonistic mechanisms of action, depending on several factors. In fact, this family has an immense number of functionalities, many of them yet to be discovered in terms of regulation and action in different types of cancer, being directly involved in the response to cancer therapies. To date, three main groups of MAPKs have been identified in mammals: the extracellular signal-regulated kinases (ERK), Jun N-terminal kinase (JNK), and the different isoforms of p38 (alpha, beta, gamma, delta). In this review, we highlight the mechanism of action of these kinases, taking into account their extensive regulation at the cellular level through various modifications and modulations, including a wide variety of microRNAs. We also analyze the importance of the different isoforms expressed in the different tissues and their possible role as biomarkers and molecular targets. In addition, we include the latest preclinical and clinical trials with different p38-related drugs that are ongoing with hopeful expectations in the present/future of developing precision medicine in cancer.MCIN/AEI/10.13039/501100011033/FEDER RTI2018-101309-B-C22Chair Doctors Galera-Requena in cancer stem cell researc

Caffeine and Chlorogenic Acid Combination Attenuate Early-Stage Chemically Induced Colon Carcinogenesis in Mice: Involvement of oncomiR miR-21a-5p

Colorectal cancer (CRC) is one of most common cancers worldwide, with high rates of mortality. Epidemiological findings demonstrate that coffee consumption reduces the risk of developing CRC by ~13%. In general, in vivo and in vitro findings demonstrate the antiproliferative, antioxidant and proapoptotic effects of brewed coffee or major bioavailable coffee compounds. Thus, it was assessed whether caffeine (CAF) and/or chlorogenic acid (CGA) attenuates the earlystage of chemically induced mouse colon carcinogenesis. Male Swiss mice were submitted to a 1,2-dimethylhydrazine/deoxycholic acid (DMH/DCA)-induced colon carcinogenesis model. These animals received CAF (50 mg/kg), CGA (25 mg/kg) or CAF+CGA (50 + 25 mg/kg) intragastrically for five times/week for ten weeks. CAF+CGA had the most pronounced effects on decreasing epithelial cell proliferation (Ki-67) and increasing apoptosis (cleaved caspase-3) in colonic crypts. This treatment also decreased the levels of proinflammatory cytokines IL-6, IL-17 and TNF- , and downregulated the oncomiR miR-21a-5p in the colon. Accordingly, the analysis of miR-21a-5p targets demonstrated the genes involved in the negative regulation of proliferation and inflammation, and the positive regulation of apoptosis. Ultimately, CAF+CGA attenuated preneoplastic aberrant crypt foci (ACF) development. Our findings suggest that a combination of coffee compounds reduces early-stage colon carcinogenesis by the modulation of miR-21a-5p expression, highlighting the importance of coffee intake to prevent CRC.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) 001Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2017/26217-7 2016/12015-0 2016/14420-0Junta de Andalucia RH-0139-202

HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib

Identification of novel anticancer drugs presenting more than one molecular target and efficacy against cancer stem-like cells (CSCs) subpopulations represents a therapeutic need to combat the resistance and the high risk of relapse in patients. In the present work we show how Bozepinib [(RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine], a small anti-tumor compound, demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. The cytotoxic effects of Bozepinib were observed in both breast and colon cancer cells expressing different receptor patterns. Bozepinib inhibited HER-2 signaling pathway and JNK and ERKs kinases. In addition, Bozepinib has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Moreover, the modulation of pathways involved in tumorigenesis by Bozepinib was also evident in microarrays analysis. Interestingly, Bozepinib inhibited both mamo- and colono-spheres formation and eliminated ALDH+ CSCs subpopulations at a low micromolar range similar to Salinomycin. Bozepinib induced the down-regulation of c-MYC, β-CATENIN and SOX2 proteins and the up-regulation of the GLI-3 hedgehog-signaling repressor. Finally, Bozepinib shows in vivo anti-tumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting sub-acute toxicity. These findings support further studies on the therapeutic potential of Bozepinib in cancer patients.This work was supported in part by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria, projects nº. PI10/02295, CP08/00063 and PI10/00592) and the ERDF (European Regional Development Fund)

Article Interferon-Alpha Decreases Cancer Stem Cell Properties and Modulates Exosomes in Malignant Melanoma

Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-α on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-α treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-α on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma.Ministerio de Ciencia, Innovación y Universidades (MICIU, projects noº MAT2015-62644.C2.2.RRTI2018-101309-B-C2, FEDER Funds), by the Instituto de Salud Carlos III (PIE16-00045), by Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía and European Regional Development Fund (ERDF)ref. SOMM17/6109/UGR (UCE-PP2017-3)Consejería de Salud y Familias de la Junta de Andalucía (projects noº PEMP- 0205-2020 FEDER funds)The Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963

Diseño de un curso SPOC sobre modelización matemática

Memoria ID-029. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2019-2020

Potential Impacts in the Gilthead Seabream Larviculture by Nodavirus

The nervous necrosis virus (NNV) leads to viral encephalopathy and retinopathy (VER) disease in more than 170 fish species, mainly from marine habitats. It replicates in the central nervous tissues, reaching up to 100% mortalities after a few days of infection, mainly in the larvae and juvenile stages. This is continuously spreading and affecting more species, both wild and cultured, posing a risk to the development of the aquaculture industry. In the Mediterranean Sea, it mainly affects European sea bass (Dicentrarchus labrax) and some grouper species (Epinephelus spp.). Interestingly, in the gilthead seabream (Sparus aurata), typically resistant to common NNV strains, great mortalities in hatcheries associated with typical clinical signs of VER have been confirmed to be caused by RGNNV/SJNNV reassortants. Thus, we have evaluated the susceptibility of seabream larvae to either RGNNV/SJNNV or SJNNV/RGNNV reassortants, as well as the larval immunity. Based on our results we can conclude that: (i) gilthead seabream larvae are susceptible to infection with both NNV reassortant genotypes, but mainly to RGNNV/SJNNV; (ii) virus replicated and infective particles were isolated; (iii) larval immunity was correlated with larval survival; and (iv) larval resistance and immunity were correlated with age of the larvae. Further investigations should be carried out to ascertain the risks of these new pathogens to Mediterranean larviculture

Plataforma digital "AC Innovación Docente: Comunicación y Arte" para la enseñanza virtual. Actualización y nuevos recursos

El proyecto se dirige a la actualización y mejora de la plataforma AC Innovación, dando continuidad a proyectos anteriores, centrado ahora en dos aspectos fundamentales. Por un lado, la realización de un cuestionario enfocado a los diferentes estudiantes de los grados y másteres implicados, considerados público objetivo de los mismos. El cuestionario permitirá identificar los diferentes puntos de mejora relacionados con la plataforma y los más apreciados por los estudiantes, que una vez identificados, permitirá reforzar los más valorados y mejorar los más problemáticos, dando diferentes soluciones a través de las herramientas que se consideren más adecuadas para cada punto de mejora identificado. Por otro lado, pretendemos incentivar y consolidar la actividad AC Research (seminario y publicación de trabajos de fin de grado y máster de los alumnos) vinculada a la plataforma digital adaptando el formato a la nueva realidad de la educación en abierto y la enseñanza virtual