An Intercellular Flow of Glutathione Regulated by Interleukin 6 Links Astrocytes and the Liver in the Pathophysiology of Amyotrophic Lateral Sclerosis

Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage

Viability-based computation of spatially constrained minimum time trajectories for an autonomous underwater vehicle: implementation and experiments.

A viability algorithm is developed to compute the constrained minimum time function for general dynamical systems. The algorithm is instantiated for a specific dynamics(Dubin’s vehicle forced by a flow field) in order to numerically solve the minimum time problem. With the specific dynamics considered, the framework of hybrid systems enables us to solve the problem efficiently. The algorithm is implemented in C using epigraphical techniques to reduce the dimension of the problem. The feasibility of this optimal trajectory algorithm is tested in an experiment with a Light Autonomous Underwater Vehicle (LAUV) system. The hydrodynamics of the LAUV are analyzed in order to develop a low-dimension vehicle model. Deployment results from experiments performed in the Sacramento River in California are presented, which show good performance of the algorithm.trajectories; underwater vehicle; viability algorithm; hybrid systems; implementation;

Recent advances in the interrelationship of vegetation and climate in Spain

Póster elaborado para el WCRP Open Science Conference celebrado en Denver del 24 al 28 de octubre de 201

Association between Pterostilbene and Quercetin Inhibits Metastatic Activity of B16 Melanoma

AbstractInhibition of cancer growth by resveratrol (trans-3,5,4'trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 μM) and QUER (20 μM) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg of each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cells in the liver, a common site for metastasis development. The antimetastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival

Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1

<p>Abstract</p> <p>Background</p> <p>Bcl-2 is believed to contribute to melanoma chemoresistance. However, expression of Bcl-2 proteins may be different among melanomas. Thus correlations among expression of Bcl-2-related proteins and <it>in vivo </it>melanoma progression, and resistance to combination therapies, was investigated.</p> <p>Methods</p> <p>Human A375 melanoma was injected s.c. into immunodeficient nude mice. Protein expression was studied in tumor samples obtained by laser microdisection. Transfection of siRNA or ectopic overexpression were applied to manipulate proteins which are up- or down-regulated, preferentially, during melanoma progression. Anti-<it>bcl</it>-2 antisense oligonucleotides and chemoradiotherapy (glutathione-depleting agents, paclitaxel protein-binding particles, daunorubicin, X rays) were administered in combination.</p> <p>Results</p> <p><it>In vivo </it>A375 cells down-regulated pro-apoptotic <it>bax </it>expression; and up-regulated anti-apoptotic <it>bcl-2</it>, <it>bcl-xl</it>, and <it>mcl-1</it>, however only Bcl-2 appeared critical for long-term tumor cell survival and progression <it>in vivo</it>. Reduction of Bcl-2, combined with partial therapies, decreased melanoma growth. But only Bcl-2 targeting plus the full combination of chemoradiotherapy eradicated A375 melanoma, and led to long-term survival (> 120 days) without recurrence in 80% of mice. Tumor regression was not due to immune stimulation. Hematology and clinical chemistry data were within accepted clinical toxicities.</p> <p>Conclusion</p> <p>Strategies to target Bcl-2, may increase the effectiveness of antitumor therapies against melanomas overexpressing Bcl-2 and likely other Bcl-2-related antiapoptotic proteins.</p

The state of art of the drought studies in Spain

Póster elaborado para el WCRP Workshop on Drought Predictability and Prediction in a Changing Climate celebrado en Barcelona del 2 al 4 de marzo de 201

Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma

Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAFV600E melanoma cells. The GR content of melanoma cell lines was measured by [3H]-labeled ligand binding assay. Nuclear Nrf2 and its transcription activity was investigated by RT-PCR, western blotting, and by measuring Nrf2- and redox state-related enzyme activities and metabolites. GR knockdown was achieved using lentivirus, and GR overexpression by transfection with the NR3C1 plasmid. shRNA-induced selective Bcl-xL, Mcl-1, AKT1 or NF-κB/p65 depletion was used to test the efficacy of vemurafenib (VMF) and RU486 against BRAFV600E-mutated metastatic melanoma. During early progression of skin melanoma metastases, RU486 and VMF induced a drastic metastases regression. However, treatment at an advanced stage of growth demonstrated the development of resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of specific proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in our experimental models). We found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. Our results highlight mechanisms by which metastatic melanoma cells adapt to survive

Pterostilbene-Induced Tumor Cytotoxicity: A Lysosomal Membrane Permeabilization-Dependent Mechanism

The phenolic phytoalexin resveratrol is well known for its health-promoting and anticancer properties. Its potential benefits are, however, limited due to its low bioavailability. Pterostilbene, a natural dimethoxylated analog of resveratrol, presents higher anticancer activity than resveratrol. The mechanisms by which this polyphenol acts against cancer cells are, however, unclear. Here, we show that pterostilbene effectively inhibits cancer cell growth and stimulates apoptosis and autophagosome accumulation in cancer cells of various origins. However, these mechanisms are not determinant in cell demise. Pterostilbene promotes cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 (HSP70) content, a known stabilizer of lysosomal membranes. A375 melanoma and A549 lung cancer cells with low levels of HSP70 showed high susceptibility to pterostilbene, whereas HT29 colon and MCF7 breast cancer cells with higher levels of HSP70 were more resistant. Inhibition of HSP70 expression increased susceptibility of HT29 colon and MCF7 breast cancer cells to pterostilbene. Our data indicate that lysosomal membrane permeabilization is the main cell death pathway triggered by pterostilbene.Mena Llido, S.; Rodriguez, ML.; Ponsoda Acedo, J.; Estrela, JM.; Jaattela, M.; Ortega, ÁL. (2012). Pterostilbene-Induced Tumor Cytotoxicity: A Lysosomal Membrane Permeabilization-Dependent Mechanism. PLoS ONE. 7(9):1-12. doi:10.1371/journal.pone.0044524S1127