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SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2a

Emilia Mira, Lorena Carmona-Rodríguez, Beatriz Pérez-Villamil, Josefina Casas,María Jesús Fernández-Aceñero, Diego Martínez-Rey, Paula Martín-González, Ignacio Heras-Murillo, Mateo Paz-Cabezas, Manuel Tardáguila, Tim D. Oury, Silvia Martín-Puig, Rosa Ana Lacalle, Gemma Fabriás, Eduardo Díaz-Rubio and Santos Mañes


 One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2a (HIF-2a) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2a ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2a levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.


Wet-Chemical Etching of GaN: Underlying Mechanism of a Key Step in Blue and White LED Production

Tautz, M.; Díaz, D. D.

 ChemistrySelect 2018


 Gallium nitride (GaN) is the key material for the fabrication of blue and white light emitting diodes (LEDs). Etching of this material is applied to improve the light extraction efficiency of the product. Wet-chemical etching of GaN is commonly carried out by treatment with aqueous KOH solution at elevated temperature. Thereby, the anisotropic etching results in a highly rough surface. Hence, a remarkably higher out-coupling possibility of generated photons is feasible. On the other hand, anisotropy generally prohibits the application of a predictable and standardized etching process. In this review, both material- and process-dependent influences on the etching performance in aqueous KOH solution are classified. Herein, we critically present the factors that affect the etching rate of GaN. Moreover, the etching mechanism at the molecular level and the generation of anisotropy from the hexagonal crystal lattice are discussed. The existing gaps in the current understanding of this process maintain the field still open for further research aligned to a permanent interest of the electronic industry.


Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-â Levels in Primary Neurons from an

Ordóñez-Gutiérrez, L., Benito-Cuesta, I., Abad, J.L., Casas, J., Fábrias, G., Wandosell, F.

Pharmaceutical Research, 35 (3), art. no. 49,

Purpose: The induction of autophagy has recently been explored as a promising therapeutic strategy to combat Alzheimer’s disease. Among many other factors, there is evidence that ceramides/dihydroceramides act as mediators of autophagy, although the exact mechanisms underlying such effects are poorly understood. Here, we describe how two dihydroceramide desaturase inhibitors (XM461 and XM462) trigger autophagy and reduce amyloid secretion by neurons. Methods: Neurons isolated from wild-type and APP/PS1 transgenic mice were exposed to the two dihydroceramide desaturase inhibitors to assess their effect on these cell’s protein and lipid profiles. Results: Both dihydroceramide desaturase inhibitors increased the autophagic vesicles in wild-type neurons, reflected as an increase in LC3-II, and this was correlated with the accumulation of dihydroceramides and dihydrosphingomyelins. Exposing APP/PS1 transgenic neurons to these inhibitors also produced a 50% reduction in amyloid secretion and/or production. The lipidomic defects triggered by these dihydroceramide desaturase inhibitors were correlated with a loss of S6K activity, witnessed by the changes in S6 phosphorylation, which strongly suggested a reduction of mTORC1 activity. Conclusions: The data obtained strongly suggest that dihydroceramide desaturase 1 activity may modulate autophagy and mTORC1 activity in neurons, inhibiting amyloid secretion and S6K activity. As such, it is tantalizing to propose that dihydroceramide desaturase 1 may be an important therapeutic target to combat amyloidosis.


Evaluation of the effect of polymorphism on G-quadruplex-ligand interaction by means of spectroscopic and chromatographic techniques

Benito, S., Ferrer, A., Benabou, S., Aviñó, A., Eritja, R., Gargallo, R.

 Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 196, 185-195, 2018

 Guanine-rich sequences may fold into highly ordered structures known as G-quadruplexes. Apart from the monomeric G-quadruplex, these sequences may form multimeric structures that are not usually considered when studying interaction with ligands. This work studies the interaction of a ligand, crystal violet, with three guanine-rich DNA sequences with the capacity to form multimeric structures. These sequences correspond to short stretches found near the promoter regions of c-kit and SMARCA4 genes. Instrumental techniques (circular dichroism, molecular fluorescence, size-exclusion chromatography and electrospray ionization mass spectrometry) and multivariate data analysis were used for this purpose. The polymorphism of G-quadruplexes was characterized prior to the interaction studies. The ligand was shown to interact preferentially with the monomeric G-quadruplex; the binding stoichiometry was 1:1 and the binding constant was in the order of 105 M−1 for all three sequences. The results highlight the importance of DNA treatment prior to interaction studies.


Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates

Grijalvo, S., Alagia, A., Jorge, A.F., Eritja, R.

Genes, 9 (2), art. no. 74, 2018

Oligonucleotide-based therapy has become an alternative to classical approaches in the search of novel therapeutics involving gene-related diseases. Several mechanisms have been described in which demonstrate the pivotal role of oligonucleotide for modulating gene expression. Antisense oligonucleotides (ASOs) and more recently siRNAs and miRNAs have made important contributions either in reducing aberrant protein levels by sequence-specific targeting messenger RNAs (mRNAs) or restoring the anomalous levels of non-coding RNAs (ncRNAs) that are involved in a good number of diseases including cancer. In addition to formulation approaches which have contributed to accelerate the presence of ASOs, siRNAs and miRNAs in clinical trials; the covalent linkage between non-viral vectors and nucleic acids has also added value and opened new perspectives to the development of promising nucleic acid-based therapeutics. This review article is mainly focused on the strategies carried out for covalently modifying siRNA and miRNA molecules. Examples involving cell-penetrating peptides (CPPs), carbohydrates, polymers, lipids and aptamers are discussed for the synthesis of siRNA conjugates whereas in the case of miRNA-based drugs, this review article makes special emphasis in using antagomiRs, locked nucleic acids (LNAs), peptide nucleic acids (PNAs) as well as nanoparticles. The biomedical applications of siRNA and miRNA conjugates are also discussed.


Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex

Mir, J.F., Zagmutt, S., Lichtenstein, M.P., García-Villoria, J., Weber, M., Gracia, A., Fabriàs, G., Casas, J., López, M., Casals, N., Ribes, A., Suñol, C., Herrero, L., Serra, D.

Molecular Neurobiology, 2018

 Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and ?-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and a-ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system.


A lamellar body mimetic system for the treatment of oxazolone-induced atopic dermatitis in hairless mice

Moner, V., Fernández, E., Calpena, A.C., Garcia-Herrera, A., Cócera, M., López, O.

Journal of Dermatological Science, 2018

 Background Atopic dermatitis is a common skin disease characterized by a Th2 cell-dominant inflammatory infiltrate, elevated serum IgE levels and impaired epidermal barrier function. It is associated to abnormal epidermal lamellar body secretion, producing alteration in lipid composition and extracellular lamellar membrane organization. Objectives The oxazolone-induced atopic dermatitis in hairless mice was used to evaluate in vivo the effect of the application of a lipid system that mimics the morphology, structure and composition of epidermal lamellar bodies. Methods The skin barrier function was evaluated measuring TEWL and skin hydration in vivo. Inflammation was assessed by analysis of serum IgE levels and histological analysis. The microstructure of the intercellular lipid region was also evaluated before and after treatment. Results The skin condition was improved after 10 days of treatment indicated by decreased TEWL, decreased serum IgE levels, reduced epidermal thickness and reduced lymphocyte-dominated infiltrate. However, the treatment did no improve skin hydration. Conclusions The treatment with this lipid system seems to improve the skin condition by reinforcing the barrier function and reducing the skin inflammation. Therefore, the present study provides evidence that this lipid system combining appropriate lipid composition and morphology could be of interest for the development of future treatments for atopic dermatitis.


Hyaluronan based materials with catanionic sugar-derived surfactants as drug delivery systems

Roig, F., Blanzat, M., Solans, C., Esquena, J., García-Celma, M.J.

 Colloids and Surfaces B: Biointerfaces, 164, 218-223, 2018

 In the present work novel drug delivery systems consisting in highly porous Hyaluronan foams for the administration of a non-steroidal anti-inflammatory drug (NSAID), ketoprofen, have been obtained. A sugar-derived surfactant associated with ketoprofen was prepared and incorporated into the porous hyaluronan materials. The association between a lactose derived surfactant, Lhyd12, and ketoprofen was obtained by acid-base reaction and its physicochemical properties were studied. Tensiometric and dynamic light scattering (DLS) determinations showed the formation of catanionic surfactant aggregates, Lhyd12/ketoprofen, in aqueous solution. Furthermore, the catanionic surfactants allowed greater solubilisation of ketoprofen. Hyaluronan porous materials were developed using butanediol diglycidyl ether as crosslinking agent. The profile release of Lhyd12/ketoprofen from hyaluronan based materials shows differences as a function of the aggregation state of catanionic surfactant.


Electrochemical and AFM characterization of G-quadruplex electrochemical biosensors and applications

Chiorcea-Paquim, A.-M., Eritja, R., Oliveira-Brett, A.M.

 Journal of Nucleic Acids, 5307106, 2018

 Guanine-rich DNA sequences are able to form G-quadruplexes, being involved in important biological processes and representing smart self-assembling nanomaterials that are increasingly used in DNA nanotechnology and biosensor technology. G-quadruplex electrochemical biosensors have received particular attention, since the electrochemical response is particularly sensitive to the DNA structural changes from single-stranded, double-stranded, or hairpin into a G-quadruplex configuration. Furthermore, the development of an increased number of G-quadruplex aptamers that combine the G-quadruplex stiffness and self-assembling versatility with the aptamer high specificity of binding to a variety of molecular targets allowed the construction of biosensors with increased selectivity and sensitivity. This review discusses the recent advances on the electrochemical characterization, design, and applications of G-quadruplex electrochemical biosensors in the evaluation of metal ions, G-quadruplex ligands, and other small organic molecules, proteins, and cells. The electrochemical and atomic force microscopy characterization of G-quadruplexes is presented. The incubation time and cations concentration dependence in controlling the G-quadruplex folding, stability, and nanostructures formation at carbon electrodes are discussed. Different G-quadruplex electrochemical biosensors design strategies, based on the DNA folding into a G-quadruplex, the use of G-quadruplex aptamers, or the use of hemin/G-quadruplex DNAzymes, are revisited.


Compression of multidimensional NMR spectra allows a faster and more accurate analysis of complex samples

 Francesc Puig-Castellví,  Yolanda Pérez,  Benjamín Piña,  Romà Tauler  and  Ignacio Alfonso

 Chem. Commun., 54, 3090-3093, 2018

 We propose an approach to efficiently compress and denoise multidimensional NMR spectral data, improving their corresponding storage, handling, and analysis. This method has been tested with 2D homonuclear, 2D and 3D heteronuclear, and 2D phase-sensitive NMR spectral data and shown to be especially powerful for 2D NMR metabolomics studies.


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