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Menendez J.A.,Catalan Institute of Oncology Girona ICOGirona | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Joven J.,Rovira i Virgili University
Aging | Year: 2012

The gerosuppressant metformin operates as an efficient inhibitor of the mTOR/S6K1 gerogenic pathway due to its ability to ultimately activate the energy-sensor AMPK. If an aging-related decline in the AMPK sensitivity to cellular stress is a crucial event for mTOR-driven aging and aging-related diseases, including cancer, unraveling new proximal causes through which AMPK activation endows its gerosuppressive effects may offer not only a better understanding of metformin function but also the likely possibility of repositioning our existing gerosuppressant drugs. Here we provide our perspective on recent findings suggesting that de novo biosynthesis of purine nucleotides, which is based on the metabolism of one-carbon compounds, is a new target for metformin's actions at the crossroads of aging and cancer. © Menendez and Joven. Source


Verges M.,Girona Biomedical Research Institute IDIBGI | Verges M.,University of Girona
International Review of Cell and Molecular Biology | Year: 2016

Retromer is an evolutionary conserved protein complex required for endosome-to-Golgi retrieval of receptors for lysosomal hydrolases. It is constituted by a heterotrimer encoded by the vacuolar protein sorting (VPS) gene products Vps26, Vps35, and Vps29, which selects cargo, and a dimer of phosphoinositide-binding sorting nexins, which deforms the membrane. Recent progress in the mechanism of retromer assembly and functioning has strengthened the link between sorting at the endosome and cytoskeleton dynamics. Retromer is implicated in endosomal sorting of many cargos and plays an essential role in plant and animal development. Although it is best known for endosome sorting to the trans-Golgi network, it also intervenes in recycling to the plasma membrane. In polarized cells, such as epithelial cells and neurons, retromer may also be utilized for transcytosis and long-range transport. Considerable evidence implicates retromer in establishment and maintenance of cell polarity. That includes sorting of the apical polarity module Crumbs; regulation of retromer function by the basolateral polarity module Scribble; and retromer-dependent recycling of various cargoes to a certain surface domain, thus controlling polarized location and cell homeostasis. Importantly, altered retromer function has been linked to neurodegeneration, such as in Alzheimer's or Parkinson's disease. This review will underline how alterations in retromer localization and function may affect polarized protein transport and polarity establishment, thereby causing developmental defects and disease. © 2016 Elsevier Inc.. Source


Menendez J.A.,Catalan Institute of Oncology Girona ICO Girona | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Alarco n T.,Computational and Mathematical Biology Research Group
Frontiers in Oncology | Year: 2014

The acquisition of and departure from stemness in cancer tissues might not only be hardwired by genetic controllers, but also by the pivotal regulatory role of the cellular metabotype, which may act as a "starter dough" for cancer stemness traits. We have coined the term metabostemness to refer to the metabolic parameters causally controlling or functionally substituting the epitranscriptional orchestration of the genetic reprogramming that redirects normal and tumor cells toward less-differentiated CSC cellular states. Certain metabotypic alterations might operate as pivotal molecular events rendering a cell of origin susceptible to epigenetic rewiring required for the acquisition of aberrant stemness and, concurrently, of refractoriness to differentiation. The metabostemness attribute can remove, diminish, or modify the nature of molecular barriers present in Waddington's epigenetic landscapes, thus allowing differentiated cells to more easily (re)-enter into CSC cellular macrostates. Activation of the metabostemness trait can poise cells with chromatin states competent for rapid dedifferentiation while concomitantly setting the idoneous metabolic stage for later reprogramming stimuli to finish the journey from non-cancerous into tumor-initiating cells. Because only a few permitted metabotypes will be compatible with the operational properties owned by CSC cellular states, the metabostemness property provides a new framework through which to pharmacologically resolve the apparently impossible problem of discovering drugs aimed to target the molecular biology of the cancer stemness itself. We are embarking on one of the cancer field's biggest challenges, namely the discovery of the key metabolic features and the elite metabolites that influence chromatin structure and epigenetic circuits in charge of CSC reprogramming and the incorporation of novel metaboloepigenetic strategies that can effectively hamper cancer initiation and progression at the stem cell level. © 2014 Menendez and Alarco´n. Source


Menendez J.A.,Catalan Institute of Nanoscience and Nanotechnology | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Alarcon T.,Computational and Mathematical Biology Research Group | Joven J.,Rovira i Virgili University
Cell Cycle | Year: 2014

Oncometabolites are defined as small-molecule components (or enantiomers) of normal metabolism whose accumulation causes signaling dysregulation to establish a milieu that initiates carcinogenesis. In a similar manner, we propose the term "gerometabolites" to refer to small-molecule components of normal metabolism whose depletion causes signaling dysregulation to establish a milieu that drives aging. In an investigation of the pathogenic activities of the currently recognized oncometabolites R(-)-2-hydroxyglutarate (2-HG), fumarate, and succinate, which accumulate due to mutations in isocitrate dehydrogenases (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), respectively, we illustrate the fact that metabolic pseudohypoxia, the accumulation of hypoxia-inducible factor (HIFα) under normoxic conditions, and the subsequent Warburg-like reprogramming that shifts glucose metabolism from the oxidative pathway to aerobic glycolysis are the same mechanisms through which the decline of the "gerometabolite" nicotinamide adenine dinucleotide (NAD)+ reversibly disrupts nuclear-mitochondrial communication and contributes to the decline in mitochondrial function with age. From an evolutionary perspective, it is reasonable to view NAD +-driven mitochondrial homeostasis as a conserved response to changes in energy supplies and oxygen levels. Similarly, the natural ability of 2-HG to significantly alter epigenetics might reflect an evolutionarily ancient role of certain metabolites to signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency. However, when chronically altered, these responses become conserved causes of aging and cancer. Because HIFα-driven pseudohypoxia might drive the overproduction of 2-HG, the intriguing possibility exists that the decline of gerometabolites such as NAD+ could promote the chronic accumulation of oncometabolites in normal cells during aging. If the sole activation of a Warburg-like metabolic reprogramming in normal tissues might be able to significantly increase the endogenous production of bona fide etiological determinants in cancer, such as oncometabolites, this undesirable trade-off between mitochondrial dysfunction and activation of oncometabolites production might then pave the way for the epigenetic initiation of carcinogenesis in a strictly metabolic-dependent manner. Perhaps it is time to definitely adopt the view that aging and aging diseases including cancer are governed by a pivotal regulatory role of metabolic reprogramming in cell fate decisions. © 2014 Landes Bioscience. Source


Alonso M.,University of Girona | Castellanos M.,University of Girona | Castellanos M.,Girona Biomedical Research Institute IDIBGI | Besalu E.,University of Girona | And 2 more authors.
Journal of Chromatography A | Year: 2012

Needle trap devices (NTDs) are a relatively new and promising tool for headspace (HS) analysis. In this study, a dynamic HS sampling procedure is evaluated for the determination of volatile organic compounds (VOCs) in whole blood samples. A full factorial design was used to evaluate the influence of the number of cycles and incubation time and it is demonstrated that the controlling factor in the process is the number of cycles. A mathematical model can be used to determine the most appropriate number of cycles required to adsorb a prefixed amount of VOCs present in the HS phase whenever quantitative adsorption is reached in each cycle. Matrix effect is of great importance when complex biological samples, such as blood, are analyzed. The evaluation of the salting out effect showed a significant improvement in the volatilization of VOCs to the HS in this type of matrices. Moreover, a 1:4 (blood:water) dilution is required to obtain quantitative recoveries of the target analytes when external calibration is used. The method developed gives detection limits in the 0.020-0.080μgL -1 range (0.1-0.4μgL -1 range for undiluted blood samples) with appropriate repeatability values (RSD<15% at high level and <23% at LOQ level). Figure of merits of the method can be improved by using a smaller phase ratio (i.e., an increase in the blood volume and a decrease in the HS volume), which lead to lower detection limits, better repeatability values and greater sensibility. Twenty-eight blood samples have been evaluated with the proposed method and the results agree with those indicated in other studies. Benzene was the only target compound that gave significant differences between blood levels detected in volunteer non-smokers and smokers. © 2012 Elsevier B.V. Source

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