8 results on '"Alberghina, Lilia"'
Search Results
2. A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth
- Author
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Damiani, Chiara, Colombo, Riccardo, Gaglio, Daniela, Mastroianni, Fabrizia, Pescini, Dario, Westerhoff, Hans Victor, Mauri, Giancarlo, Vanoni, Marco, Alberghina, Lilia, Damiani, C, Colombo, R, Gaglio, D, Mastroianni, F, Pescini, D, Westerhoff, H, Mauri, G, Vanoni, M, Alberghina, L, Synthetic Systems Biology (SILS, FNWI), Molecular Cell Physiology, and AIMMS
- Subjects
Metabolic Processes ,0301 basic medicine ,Glucose uptake ,Glutamine ,Biochemistry ,7. Clean energy ,Glucose Metabolism ,Drug Metabolism ,Metabolic Flux Analysi ,Neoplasms ,Metabolic flux analysis ,Medicine and Health Sciences ,Amino Acids ,lcsh:QH301-705.5 ,Ecology ,Organic Compounds ,Acidic Amino Acids ,Monosaccharides ,Ketones ,Enzymes ,Flux balance analysis ,Chemistry ,Computational Theory and Mathematics ,Modeling and Simulation ,Physical Sciences ,Carbohydrate Metabolism ,Oxidoreductases ,Metabolic Networks and Pathways ,Research Article ,Chemical Elements ,Human ,Pyruvate ,Citric Acid Cycle ,Carbohydrates ,Biology ,Models, Biological ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Genetic ,Manchester Institute of Biotechnology ,Genetics ,Animals ,Humans ,Pharmacokinetics ,Computer Simulation ,Lactic Acid ,Molecular Biology ,Dehydrogenases ,Ecology, Evolution, Behavior and Systematics ,Cell Proliferation ,Pharmacology ,Organic Chemistry ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Metabolic Networks and Pathway ,Metabolism ,ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology ,Metabolic Flux Analysis ,Oxygen ,Citric acid cycle ,Metabolic pathway ,030104 developmental biology ,Glucose ,lcsh:Biology (General) ,Enzymology ,Acids ,Flux (metabolism) - Abstract
Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth., Author summary Hallmarks describing common key events in initiation, maintenance and progression of cancer have been identified. One hallmark deals with rewiring of metabolic reactions required to sustain enhanced cell proliferation. The availability of molecular, mechanistic models of cancer hallmarks will mightily improve optimized personal treatment and new drug discovery. Metabolism is the only hallmark for which it is currently possible to derive large scale mathematical models, which have predictive ability. In this paper, we exploit a constraint-based model of the core metabolism required for biomass conversion of the most relevant nutrients—glucose and glutamine—to clarify the logic of control of cancer metabolism. We newly report that, when available oxygen is not sufficient to fully oxidize available glucose and glutamine carbons–a situation compatible with that observed under normal oxygen conditions in human and in cancer cells growing in vitro—utilization of glutamine by reductive carboxylation and conversion of glucose and glutamine to lactate confer advantage for biomass production. Redox homeostasis can be maintained through the use of different alternative pathways. In conclusion, this paper offers a logic interpretation to the link between metabolic rewiring and enhanced proliferation, which may offer new approaches to targeted drug discovery and utilization.
- Published
- 2017
3. Integration of single-cell RNA-seq data into population models to characterize cancer metabolism.
- Author
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Damiani, Chiara, Maspero, Davide, Di Filippo, Marzia, Colombo, Riccardo, Pescini, Dario, Graudenzi, Alex, Westerhoff, Hans Victor, Alberghina, Lilia, Vanoni, Marco, and Mauri, Giancarlo
- Subjects
RNA sequencing ,METABOLITES ,ADENOCARCINOMA ,BREAST cancer patients ,CANCER cells - Abstract
Metabolic reprogramming is a general feature of cancer cells. Regrettably, the comprehensive quantification of metabolites in biological specimens does not promptly translate into knowledge on the utilization of metabolic pathways. By estimating fluxes across metabolic pathways, computational models hold the promise to bridge this gap between data and biological functionality. These models currently portray the average behavior of cell populations however, masking the inherent heterogeneity that is part and parcel of tumorigenesis as much as drug resistance. To remove this limitation, we propose single-cell Flux Balance Analysis (scFBA) as a computational framework to translate single-cell transcriptomes into single-cell fluxomes. We show that the integration of single-cell RNA-seq profiles of cells derived from lung adenocarcinoma and breast cancer patients into a multi-scale stoichiometric model of a cancer cell population: significantly 1) reduces the space of feasible single-cell fluxomes; 2) allows to identify clusters of cells with different growth rates within the population; 3) points out the possible metabolic interactions among cells via exchange of metabolites. The scFBA suite of MATLAB functions is available at , as well as the case study datasets. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
4. Modulation of Matrix Metalloproteinases Activity in the Ventral Horn of the Spinal Cord Re-stores Neuroglial Synaptic Homeostasis and Neurotrophic Support following Peripheral Nerve Injury.
- Author
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Cirillo, Giovanni, Colangelo, Anna Maria, De Luca, Ciro, Savarese, Leonilde, Barillari, Maria Rosaria, Alberghina, Lilia, and Papa, Michele
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MATRIX metalloproteinases ,SPINAL cord physiology ,PERIPHERAL nerve injuries ,NEUROGLIA ,HOMEOSTASIS ,SYNAPSES ,NEUROTROPHINS - Abstract
Modulation of extracellular matrix (ECM) remodeling after peripheral nerve injury (PNI) could represent a valid therapeutic strategy to prevent maladaptive synaptic plasticity in central nervous system (CNS). Inhibition of matrix metalloproteinases (MMPs) and maintaining a neurotrophic support could represent two approaches to prevent or reduce the maladaptive plastic changes in the ventral horn of spinal cord following PNI. The purpose of our study was to analyze changes in the ventral horn produced by gliopathy determined by the suffering of motor neurons following spared nerve injury (SNI) of the sciatic nerve and how the intrathecal (i.t.) administration of GM6001 (a MMPs inhibitor) or the NGF mimetic peptide BB14 modulate these events. Immunohistochemical analysis of spinal cord sections revealed that motor neuron disease following SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) response in the ventral horn of the spinal cord, indicative of reactive gliosis. These changes were paralleled by decreased glial aminoacid transporters (glutamate GLT1 and glycine GlyT1), increased levels of the neuronal glutamate transporter EAAC1, and a net increase of the Glutamate/GABA ratio, as measured by HPLC analysis. These molecular changes correlated to a significant reduction of mature NGF levels in the ventral horn. Continuous i.t. infusion of both GM6001 and BB14 reduced reactive astrogliosis, recovered the expression of neuronal and glial transporters, lowering the Glutamate/GABA ratio. Inhibition of MMPs by GM6001 significantly increased mature NGF levels, but it was absolutely ineffective in modifying the reactivity of microglia cells. Therefore, MMPs inhibition, although supplies neurotrophic support to ECM components and restores neuro-glial transporters expression, differently modulates astrocytic and microglial response after PNI. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
5. Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis.
- Author
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Palorini, Roberta, Votta, Giuseppina, Pirola, Yuri, De Vitto, Humberto, De Palma, Sara, Airoldi, Cristina, Vasso, Michele, Ricciardiello, Francesca, Lombardi, Pietro Paolo, Cirulli, Claudia, Rizzi, Raffaella, Nicotra, Francesco, Hiller, Karsten, Gelfi, Cecilia, Alberghina, Lilia, and Chiaradonna, Ferdinando
- Subjects
CYCLIC-AMP-dependent protein kinase genetics ,CANCER cells ,CELLULAR immunity ,CELL metabolism ,GLYCOLYSIS ,ANOIKIS - Abstract
Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
6. Level and Turnover of Polyadenylate-Containing Ribonucleic Acid in <em>Neurospora crass</em> in Different Steady States of Growth.
- Author
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Sturani, Emmapaola, Costantini, Maria, Martegani, Enzo, and Alberghina, Lilia
- Subjects
NEUROSPORA ,RIBOSOMES ,RNA ,SORDARIACEAE ,NUCLEIC acids ,BIOCHEMISTRY - Abstract
Mycelia of Neurospora crassa in a steady state of growth in different media have a ribosomal content proportional to the rate of growth. Moreover, both the percentage of polysomes and the average ribosomal activity are about the same at all different growth rates. The content of poly- adenylated RNA was determined in three different conditions of exponential growth, which allowed growth rates that ranged from 0.26 to 0.51 duplications/h, and was found to constitute about the same fraction of total RNA (4.5–5.2 %). Using a kinetic approach, an equation was derived which allowed determination of the average half-lives of polyadenylated RNA: in each medium the cultures were labeled from the moment of the inoculation with [
32 P]orthophosphate and were then given a 10-min pulse with [5-3 H]uridine when they were in the exponential phase. It was found that the determined half-lives of polyadenylated RNA vary, depending on the growth medium, between 30 and 60 min, but with no direct correlation with the growth rate. Moreover, the rate of synthesis of polyadenylated RNA relative to that of stable RNA decreased with the growth rate. On the basis of previous data on the rates of synthesis of stable RNA, it was possible to make an evaluation of the absolute rate of synthesis of polyadenylated RNA. Whereas the rate of synthesis of stable ribosomal RNA increases as a function of the square of the number of duplications per hour, the increase in the rate of synthesis of polyadenylated RNA with the growth rate is much less consistent. It is concluded that in Neurospora the growth rate does not depend on the rate of synthesis of mRNA but rather on the rate of synthesis of rRNA, which sets both the ribosomal level and the steady-state level of mRNA. [ABSTRACT FROM AUTHOR]- Published
- 1979
- Full Text
- View/download PDF
7. Transcriptional Profiling of ubp10 Null Mutant Reveals Altered Subtelomeric Gene Expression and Insurgence of Oxidative Stress Response.
- Author
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Orlandi, Ivan, Bettiga, Maurizio, Alberghina, Lilia, and Vai, Marina
- Subjects
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SACCHAROMYCES cerevisiae , *TELOMERES , *BIOCHEMISTRY , *BIOLOGY , *CHEMISTRY , *MEDICAL sciences - Abstract
UBP10 codes for a deubiquitinating enzyme of Saccharomyces cerevisiae whose loss of function determines slow growth rate and partial impairment of silencing at telomeres and HM loci. A genome-wide analysis performed on a ubp10 disruptant revealed alterations in expression of subtelomeric genes together with a broad change in the whole transcriptional profile, closely parallel to that induced by oxidative stress. This response was accompanied by intracellular accumulation of teactire oxygen species as well as by DNA fragmentation and phosphatidylserine externalization, two markers of apoptosis. SIR4 inactivation mitigated the wide transcriptome remodeling of the ubp10 null mutant affecting particularly the stress transcriptional profile. Moreover, the ubp10sir4 disruptant did not display apoptotic markers. These results argue in favor of an involvement of deubiquitination in transcriptional control and suggest a linkage between oxidative stress and apoptotic pathway in budding yeast. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
8. Modulation of Matrix Metalloproteinases Activity in the Ventral Horn of the Spinal Cord Re-stores Neuroglial Synaptic Homeostasis and Neurotrophic Support following Peripheral Nerve Injury
- Author
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Lilia Alberghina, Giovanni Cirillo, Maria Rosaria Barillari, Michele Papa, Anna Maria Colangelo, Ciro De Luca, Leonilde Savarese, Cirillo, Giovanni, Colangelo, Anna Maria, De Luca, Ciro, Savarese, Leonilde, Barillari, Maria Rosaria, Alberghina, Lilia, Papa, Michele, Cirillo, G, Colangelo, A, De Luca, C, Savarese, L, Barillari, M, Alberghina, L, and Papa, M
- Subjects
Male ,0301 basic medicine ,Peripheral Nerve Injuriy ,Physiology ,lcsh:Medicine ,Nervous System ,Biochemistry ,Motor Neuron Diseases ,Rats, Sprague-Dawley ,0302 clinical medicine ,Dipeptide ,Anterior Horn Cell ,Animal Cells ,Anterior Horn Cells ,Glycine Plasma Membrane Transport Proteins ,Peripheral Nerve Injuries ,Medicine and Health Sciences ,Homeostasis ,lcsh:Science ,gamma-Aminobutyric Acid ,Neurons ,Motor Neurons ,Neuronal Plasticity ,Multidisciplinary ,biology ,Glutamate receptor ,Neurochemistry ,Neurodegenerative Diseases ,Neurotransmitters ,Dipeptides ,Anatomy ,BIO/10 - BIOCHIMICA ,Synapse ,Sciatic Nerve ,Astrogliosis ,medicine.anatomical_structure ,Spinal Cord ,Neurology ,Gelatinase ,Gelatinases ,Peripheral nerve injury ,Microglia ,Glutamate ,Cellular Types ,medicine.symptom ,Astrocyte ,Research Article ,Neurotrophin ,medicine.medical_specialty ,Central nervous system ,Glutamic Acid ,Research and Analysis Methods ,Glutamate Plasma Membrane Transport Proteins ,03 medical and health sciences ,Developmental Neuroscience ,Internal medicine ,medicine ,Animals ,Glycine Plasma Membrane Transport Protein ,Nerve Growth Factor (NGF), NGF-like peptides, Astrocyte ,Immunohistochemistry Techniques ,Glutamate Plasma Membrane Transport Protein ,Biochemistry, Genetics and Molecular Biology (all) ,Animal ,reactive gliosis, neuroinflammation ,lcsh:R ,Amyotrophic Lateral Sclerosis ,Peripheral Nerve Injurie ,Biology and Life Sciences ,Tripartite Synapse ,Cell Biology ,Nerve injury ,Motor neuron ,medicine.disease ,Rats ,Histochemistry and Cytochemistry Techniques ,Neuroanatomy ,030104 developmental biology ,Endocrinology ,Agricultural and Biological Sciences (all) ,nervous system ,Cellular Neuroscience ,Astrocytes ,Synapses ,Immunologic Techniques ,biology.protein ,Rat ,lcsh:Q ,Physiological Processes ,030217 neurology & neurosurgery ,Neuroscience ,Synaptic Plasticity - Abstract
Modulation of extracellular matrix (ECM) remodeling after peripheral nerve injury (PNI) could represent a valid therapeutic strategy to prevent maladaptive synaptic plasticity in central nervous system (CNS). Inhibition of matrix metalloproteinases (MMPs) and maintaining a neurotrophic support could represent two approaches to prevent or reduce the maladaptive plastic changes in the ventral horn of spinal cord following PNI. The purpose of our study was to analyze changes in the ventral horn produced by gliopathy determined by the suffering of motor neurons following spared nerve injury (SNI) of the sciatic nerve and how the intrathecal (i.t.) administration of GM6001 (a MMPs inhibitor) or the NGF mimetic peptide BB14 modulate these events. Immunohistochemical analysis of spinal cord sections revealed that motor neuron disease following SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) response in the ventral horn of the spinal cord, indicative of reactive gliosis. These changes were paralleled by decreased glial aminoacid transporters (glutamate GLT1 and glycine GlyT1), increased levels of the neuronal glutamate transporter EAAC1, and a net increase of the Glutamate/GABA ratio, as measured by HPLC analysis. These molecular changes correlated to a significant reduction of mature NGF levels in the ventral horn. Continuous i.t. infusion of both GM6001 and BB14 reduced reactive astrogliosis, recovered the expression of neuronal and glial transporters, lowering the Glutamate/GABA ratio. Inhibition of MMPs by GM6001 significantly increased mature NGF levels, but it was absolutely ineffective in modifying the reactivity of microglia cells. Therefore, MMPs inhibition, although supplies neurotrophic support to ECM components and restores neuro-glial transporters expression, differently modulates astrocytic and microglial response after PNI. Copyright
- Published
- 2016
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