María Tabernero

Universidad Autónoma de Madrid

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Carlota Largó

Hospital Universitario La Paz

Fulgêncio Saura-Calixto

Instituto de Ciencia y Tecnología de Alimentos y Nutrición

Víctor Caz

Hospital Universitario La Paz

Cristina Soler‐Rivas

Instituto de Investigación en Ciencias de la Alimentación

José C. E. Serrano

Universitat de Lleida

Marta Gómez de Cedrón

Madrid Institute for Advanced Studies

Jara Pérez‐Jiménez

Instituto de Ciencia y Tecnología de Alimentos y Nutrición

Roberto Martín‐Hernández

Universidad Autónoma de Madrid

Alicia Gil‐Ramírez

Instituto de Investigación en Ciencias de la Alimentación

Beatriz Sarriá

Instituto de Ciencia y Tecnología de Alimentos y Nutrición

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Consejo Superior de Investigaciones Científicas

Universidad Autónoma de Madrid

Universidad Complutense de Madrid

Instituto de Investigación en Ciencias de la Alimentación

Hospital La Paz Institute for Health Research

Hospital Universitario La Paz

Universidad de Salamanca

Instituto de Ciencia y Tecnología de Alimentos y Nutrición

Instituto de Estudios de Ciencias de la Salud de Castilla y León

Instituto de Investigación Biomédica de Salamanca

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Bioavailability of Phenolic Antioxidants Associated with Dietary Fiber: Plasma Antioxidant Capacity After Acute and Long-Term Intake in Humans

Plant Foods for Human Nutrition (2009)

Jara Pérez‐Jiménez José C. E. Serrano María Tabernero Sara Arranz M Díaz-Rubio

Flavonols

10.1007/s11130-009-0110-7

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Citations (156)

Comparative evaluation of the metabolic effects of hydroxytyrosol and its lipophilic derivatives (hydroxytyrosyl acetate and ethyl hydroxytyrosyl ether) in hypercholesterolemic rats

Food & Function (2014)

María Tabernero Beatriz Sarriá Carlota Largó Sara Martínez‐López Andrés Madrona

Hydroxytyrosol and its lipophilic derivatives reduce the metabolic imbalance induced by high-fat diets.

Hydroxytyrosol

10.1039/c3fo60677e

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Citations (58)

Effects of consuming diets containing Agave tequilana dietary fibre and jamaica calyces on body weight gain and redox status in hypercholesterolemic rats

Food Chemistry (2013)

Sonia G. Sáyago‐Ayerdi Raquel Mateos Rosa Isela Ortiz‐Basurto Carlota Largó José C. E. Serrano

Agave

Dietary fibre

10.1016/j.foodchem.2013.10.004

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Citations (44)

PO-252 Impaired glucose metabolism in human glioma stem cells upon treatment with a cell-penetrating peptide based on CONNEXIN43

ESMO Open (2018)

Sara G. Pelaz Marta Gómez de Cedrón María Tabernero Ana Ramı́rez de Molina José M. Medina

Introduction Connexin43 (Cx43), the main gap junction channel-forming protein in astrocytes, is downregulated in glioma stem cells (GSCs). Restoring Cx43 in GSCs reverses their phenotype through the inhibition of c-Src and consequently reduces GSCs tumorigenicity. We have developed a cell-penetrating peptide (TAT-Cx43266–283) containing the region of Cx43 that interacts with c-Src that mimics the effect of Cx43 on GSC phenotype. GSCs reprogram their metabolism to compete for glucose resources through HIF-1-alpha, which can in turn be regulated by c-Src. Therefore, the aim of this work was to study the effect of TAT-Cx43266–283 on GSC metabolism. Material and methods G166 (human GSCs), Wistar rat organotypic brain slices, neurons and astrocytes from primary culture. 2-NBDG uptake: Cells were incubated with 146 µM 2-NBDG for 1 hour, lysed, and supernatant fluorescence intensity was measured by spectrofluorimetry and normalised to mg of protein. GSCs-brain organotypic slice co-culture Fluorescently-dyed human GSCs were injected into rat organotypic brain slices and 2-NBDG uptake was analysed by confocal microscopy. Cell energy analysis were performed on an extracellular flux analyser (Agilent Seahorse XF Technology ) using Mito Stress and Glycolysis Stress kits. Results and discussions Because TAT-Cx43266–283 inhibits Src activity in GSCs, we analysed the effect of TAT-Cx43266–283 on the rate of glucose uptake in human GSCs. Our results showed that TAT-Cx43266–283 reduced the uptake of a fluorescent glucose analogue (2-NBDG) into GSCs. Interestingly, TAT-Cx43266–283 did not significantly affect the uptake of glucose in neurons or astrocytes from primary culture, suggesting a specific effect on GSCs. Moreover, experiments using 6-NBDG, a fluorescent glucose analogue that cannot be phosphorylated by HK-2 (whose expression is regulated by HIF-1-a), showed that 6-NBDG uptake does not differ between treated and not treated GSCs. Moreover, we analysed 2-NBDG uptake on a GSCs-brain organotypic slice co-culture. Our results revealed that TAT-Cx43266–283 reduced glucose uptake in tumoral cells when they are within the brain parenchyma. More importantly, data obtained with a cell energy analysis platform (Agilent Seahorse XF Technology) showed impaired metabolism in GSCs treated with TAT-Cx43266–283, but not in neurons or astrocytes. Conclusion In vitro and ex-vivo experiments revealed that TAT-Cx43266–283 reduces the rate of glucose uptake selectively in human glioma stem cells with the subsequent decrease in metabolic activity and survival.

Cell-penetrating peptide

Carbohydrate Metabolism

10.1136/esmoopen-2018-eacr25.285

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TAT-Cx43_266-283impairs metabolic plasticity in glioma stem cells in vitro and in vivo

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Sara G. Pelaz Myriam Jaraíz-Rodríguez Rocío Talaverón Laura García-Vicente Marta Gómez de Cedrón

Abstract Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years 1 . These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies 2, 3 , and exhibit metabolic plasticity to adapt to challenging environments 4, 5 . GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43 266-283 ) that reduces tumour growth and increases survival in preclinical models 6 via c-Src inhibition 7 . Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells 8–10 , we investigated the effect of TAT-Cx43 266-283 on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43 266-283 decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43 266-283 reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43 266-283 showed decreased levels of important targets for cancer therapy, such as HK-2 11, 12 and glucose transporter 3 (GLUT-3) 13 , evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43 266-283 for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.

Hexokinase

10.1101/858563

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Effect of Dietary Docosahexaenoic Acid Supplementation on the Participation of Vasodilator Factors in Aorta from Orchidectomized Rats

PLoS ONE (2015)

Diva M. Villalpando Rocío Navarro Lara del Campo Carlota Largó David G. Muñoz

Benefits of n-3 polyunsaturated fatty acids (PUFAs) against cardiovascular diseases have been reported. Vascular tone regulation is largely mediated by endothelial factors whose release is modulated by sex hormones. Since the incidence of cardiovascular pathologies has been correlated with decreased levels of sex hormones, the aim of this study was to analyze whether a diet supplemented with the specific PUFA docosahexaenoic acid (DHA) could prevent vascular changes induced by an impaired gonadal function. For this purpose, control and orchidectomized rats were fed with a standard diet supplemented with 5% (w/w) sunflower oil or with 3% (w/w) sunflower oil plus 2% (w/w) DHA. The lipid profile, the blood pressure, the production of prostanoids and nitric oxide (NO), and the redox status of biological samples from control and orchidectomized rats, fed control or DHA-supplemented diet, were analyzed. The vasodilator response and the contribution of NO, prostanoids and hyperpolarizing mechanisms were also studied. The results showed that orchidectomy negatively affected the lipid profile, increased the production of prostanoids and reactive oxygen species (ROS), and decreased NO production and the antioxidant capacity, as well as the participation of hyperpolarizing mechanisms in the vasodilator responses. The DHA-supplemented diet of the orchidectomized rats decreased the release of prostanoids and ROS, while increasing NO production and the antioxidant capacity, and it also improved the lipid profile. Additionally, it restored the participation of hyperpolarizing mechanisms by activating potassium. Since the modifications induced by the DHA-supplemented diet were observed in the orchidectomized, but not in the healthy group, DHA seems to exert cardioprotective effects in physiopathological situations in which vascular dysfunction exists.

Sunflower oil

10.1371/journal.pone.0142039

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Citations (23)

Water-Soluble Compounds from Lentinula edodes Influencing the HMG-CoA Reductase Activity and the Expression of Genes Involved in the Cholesterol Metabolism

Journal of Agricultural and Food Chemistry (2016)

Alicia Gil‐Ramírez Víctor Caz Fhernanda Ribeiro Smiderle Roberto Martín‐Hernández Carlota Largó

A water extract from Lentinula edodes (LWE) showed HMG-CoA reductase inhibitory activity but contained no statins. NMR indicated the presence of water-soluble α- and β-glucans and fucomannogalactans. Fractions containing derivatives of these polysaccharides with molecular weight down to approximately 1 kDa still retained their inhibitory activity. Once digested LWE was applied to Caco2 in transport experiments, no significant effect was noticed on the modulation of cholesterol-related gene expression. But, when the lower compartment of the Caco2 monolayer was applied to HepG2, some genes were modulated (after 24 h). LWE was also administrated to normo- and hypercholesterolemic mice, and no significant lowering of serum cholesterol levels was observed; but reduction of triglycerides in liver was observed. However, LWE supplementation modulated the transcriptional profile of some genes involved in the cholesterol metabolism similarly to simvastatin, suggesting that it could hold potential as a hypolipidemic/hypocholesterolemic extract, although further dose-dependent studies should be carried out.

Lentinula

Hydroxymethylglutaryl-CoA reductase

10.1021/acs.jafc.5b05571

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Citations (36)

Erratum to “Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43266-283” [EBioMedicine 62, December 2020] DOI: https://doi.org/10.1016/j.ebiom.2020.103134

EBioMedicine (2021)

Sara G. Pelaz Myriam Jaraíz-Rodríguez Andrea Álvarez-Vázquez Rocío Talaverón Laura García-Vicente

The publisher regrets that due to a production error, a wrong image for HK-1 in Fig. 3, panel d, was used by mistake. The correct image for panel d is as below:The publisher apologises for any inconvenience caused. The publisher regrets that due to a production error, a wrong image for HK-1 in Fig. 3, panel d, was used by mistake. The correct image for panel d is as below: The publisher apologises for any inconvenience caused. Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43266-283The reduced ability of TAT-Cx43266-283–treated GSCs to survive in metabolically challenging settings, such as those with restricted nutrient availability or the ever-changing in vivo environment, allows us to conclude that the advantageous metabolic plasticity of GSCs can be therapeutically exploited through the specific and cell-selective inhibition of c-Src by TAT-Cx43266-283. Full-Text PDF Open Access

Mistake

Ex vivo

10.1016/j.ebiom.2021.103752

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fDWI predicts obesity development in rats

Blanca Lizarbe Pilar López‐Larrubia Sebastián Cerdán Víctor Caz María Tabernero

Trabajo presentado al 29th Annual Scientific Meeting of European Society for Magnetic Resonance In Medicine and Biology, celebrado en Lisboa (Portugal) del 4 al 6 de Octubre de 2012.

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The antioxidant capacity of cocoa products: contribution to the Spanish diet

International Journal of Food Science & Technology (2006)

María Tabernero José C. E. Serrano Fulgêncio Saura-Calixto

Summary Chocolate and soluble cocoa powders are dietary sources of antioxidants. The literature reports antioxidant capacity (AC) derived from aqueous‐organic extracts of cocoa polyphenols; however, the residue of these extracts contains appreciable amounts of nonextractable polyphenols (condensed tannins or proanthocyanidins), which may become bioactive antioxidants after colonic fermentation. The objective of this work was to determine the total AC of cocoa products including both extractable and nonextractable polyphenols. Three methods were used: ferric reducing/antioxidant power, 2,2,‐diphenyl‐1‐picrylhydrazyl and 2,2′‐azinobis (3‐ethylbenzothiazoline‐6‐sulfonic acid) cations’ free‐radical scavenging capacity. With this last method, AC ranged from 42 to 79 and from 22 to 60 μ mol Trolox per gram of sample for extractable and nonextractable polyphenols, respectively. Addition of milk reduces the AC of cocoa products by about 30%. On the other hand, it was estimated that cocoa products account for about 10% of the total AC of the Spanish diet.

Trolox

10.1111/j.1365-2621.2006.01239.x

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Citations (40)