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Article ; Online: INTEGRATE

Marzia Di Filippo / Dario Pescini / Bruno Giovanni Galuzzi / Marcella Bonanomi / Daniela Gaglio / Eleonora Mangano / Clarissa Consolandi / Lilia Alberghina / Marco Vanoni / Chiara Damiani

PLoS Computational Biology, Vol 18, Iss 2, p e

Model-based multi-omics data integration to characterize multi-level metabolic regulation.

2022 Volume 1009337

Abstract: Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net ...

Abstract	Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net rate of the reaction) for each enzyme-controlled reaction. On the other hand, metabolic regulation controls the metabolic flux through the interactions of metabolites (substrates, cofactors, allosteric modulators) with the responsible enzyme. High-throughput data, such as metabolomics and transcriptomics data, if analyzed separately, do not accurately characterize the hierarchical regulation of metabolism outlined above. They must be integrated to disassemble the interdependence between different regulatory layers controlling metabolism. To this aim, we propose INTEGRATE, a computational pipeline that integrates metabolomics and transcriptomics data, using constraint-based stoichiometric metabolic models as a scaffold. We compute differential reaction expression from transcriptomics data and use constraint-based modeling to predict if the differential expression of metabolic enzymes directly originates differences in metabolic fluxes. In parallel, we use metabolomics to predict how differences in substrate availability translate into differences in metabolic fluxes. We discriminate fluxes regulated at the metabolic and/or gene expression level by intersecting these two output datasets. We demonstrate the pipeline using a set of immortalized normal and cancer breast cell lines. In a clinical setting, knowing the regulatory level at which a given metabolic reaction is controlled will be valuable to inform targeted, truly personalized therapies in cancer patients.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methionine Supplementation Affects Metabolism and Reduces Tumor Aggressiveness in Liver Cancer Cells

Farida Tripodi / Beatrice Badone / Marta Vescovi / Riccardo Milanesi / Simona Nonnis / Elisa Maffioli / Marcella Bonanomi / Daniela Gaglio / Gabriella Tedeschi / Paola Coccetti

Cells, Vol 9, Iss 2491, p

2020 Volume 2491

Abstract: Liver cancer is one of the most common cancer worldwide with a high mortality. Methionine is an essential amino acid required for normal development and cell growth, is mainly metabolized in the liver, and its role as an anti-cancer supplement is still ... ...

Abstract	Liver cancer is one of the most common cancer worldwide with a high mortality. Methionine is an essential amino acid required for normal development and cell growth, is mainly metabolized in the liver, and its role as an anti-cancer supplement is still controversial. Here, we evaluate the effects of methionine supplementation in liver cancer cells. An integrative proteomic and metabolomic analysis indicates a rewiring of the central carbon metabolism, with an upregulation of the tricarboxylic acid (TCA) cycle and mitochondrial adenosine triphosphate (ATP) production in the presence of high methionine and AMP-activated protein kinase (AMPK) inhibition. Methionine supplementation also reduces growth rate in liver cancer cells and induces the activation of both the AMPK and mTOR pathways. Interestingly, in high methionine concentration, inhibition of AMPK strongly impairs cell growth, cell migration, and colony formation, indicating the main role of AMPK in the control of liver cancer phenotypes. Therefore, regulation of methionine in the diet combined with AMPK inhibition could reduce liver cancer progression.
Keywords	AMPK ; TCA cycle ; migration ; growth ; proteomics ; metabolomics ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Safety Evaluation of TiO 2 Nanoparticle-Based Sunscreen UV Filters on the Development and the Immunological State of the Sea Urchin Paracentrotus lividus

Riccardo Catalano / Jérôme Labille / Daniela Gaglio / Andi Alijagic / Elisabetta Napodano / Danielle Slomberg / Andrea Campos / Annalisa Pinsino

Nanomaterials, Vol 10, Iss 2102, p

2020 Volume 2102

Abstract: Sunscreens are emulsions of water and oil that contain filters capable of protecting against the detrimental effects of ultraviolet radiation (UV). The widespread use of cosmetic products based on nanoparticulate UV filters has increased concerns ... ...

Abstract	Sunscreens are emulsions of water and oil that contain filters capable of protecting against the detrimental effects of ultraviolet radiation (UV). The widespread use of cosmetic products based on nanoparticulate UV filters has increased concerns regarding their safety and compatibility with both the environment and human health. In the present work, we evaluated the effects of titanium dioxide nanoparticle (TiO 2 NP)-based UV filters with three different surface coatings on the development and immunity of the sea urchin, Paracentrotus lividus . A wide range of NP concentrations was analyzed, corresponding to different levels of dilution starting from the original cosmetic dispersion. Variations in surface coating, concentration, particle shape, and pre-dispersant medium (i.e., water or oil) influenced the embryonic development without producing a relevant developmental impairment. The most common embryonic abnormalities were related to the skeletal growth and the presence of a few cells, which were presumably involved in the particle uptake. Adult P. lividus immune cells exposed to silica-coated TiO 2 NP-based filters showed a broad metabolic plasticity based on the biosynthesis of metabolites that mediate inflammation, phagocytosis, and antioxidant response. The results presented here highlight the biosafety of the TiO 2 NP-based UV filters toward sea urchin, and the importance of developing safer-by-design sunscreens.
Keywords	cosmetic formulation ; cosmetic lifecycle ; hydrophobic compound ; nano-TiO 2 ; nano safety ; marine invertebrate ; Chemistry ; QD1-999
Subject code	290
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Two high-rate pentose-phosphate pathways in cancer cells

Vanessa Cossu / Marcella Bonanomi / Matteo Bauckneht / Silvia Ravera / Nicole Righi / Alberto Miceli / Silvia Morbelli / Anna Maria Orengo / Patrizia Piccioli / Silvia Bruno / Daniela Gaglio / Gianmario Sambuceti / Cecilia Marini

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 9

Abstract: Abstract The relevant role of pentose phosphate pathway (PPP) in cancer metabolic reprogramming has been usually outlined by studying glucose-6-phosphate dehydrogenase (G6PD). However, recent evidence suggests an unexpected role for a less characterized ... ...

Abstract	Abstract The relevant role of pentose phosphate pathway (PPP) in cancer metabolic reprogramming has been usually outlined by studying glucose-6-phosphate dehydrogenase (G6PD). However, recent evidence suggests an unexpected role for a less characterized PPP, triggered by hexose-6-phosphate dehydrogenase (H6PD) within the endoplasmic reticulum (ER). Studying H6PD biological role in breast and lung cancer, here we show that gene silencing of this reticular enzyme decreases cell content of PPP intermediates and d-ribose, to a similar extent as G6PD silencing. Decrease in overall NADPH content and increase in cell oxidative status are also comparable. Finally, either gene silencing impairs at a similar degree cell proliferating activity. This unexpected response occurs despite the absence of any cross-interference between the expression of both G6PD and H6PD. Thus, overall cancer PPP reflects the contribution of two different pathways located in the cytosol and ER, respectively. Disregarding the reticular pathway might hamper our comprehension of PPP role in cancer cell biology.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth

Chiara Damiani / Riccardo Colombo / Daniela Gaglio / Fabrizia Mastroianni / Dario Pescini / Hans Victor Westerhoff / Giancarlo Mauri / Marco Vanoni / Lilia Alberghina

PLoS Computational Biology, Vol 13, Iss 9, p e

The WarburQ effect.

2017 Volume 1005758

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 ... ...

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.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Radiosensitizing effect of curcumin-loaded lipid nanoparticles in breast cancer cells

Luigi Minafra / Nunziatina Porcino / Valentina Bravatà / Daniela Gaglio / Marcella Bonanomi / Erika Amore / Francesco Paolo Cammarata / Giorgio Russo / Carmelo Militello / Gaetano Savoca / Margherita Baglio / Boris Abbate / Giuseppina Iacoviello / Giovanna Evangelista / Maria Carla Gilardi / Maria Luisa Bondì / Giusi Irma Forte

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 16

Abstract: Abstract In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected or recurrent tumors. However, approximately ... ...

Abstract	Abstract In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected or recurrent tumors. However, approximately 90% of BC-related deaths are due to the metastatic tumor progression. Then, it is strongly desirable to improve tumor radiosensitivity using molecules with synergistic action. The main aim of this study is to develop curcumin-loaded solid nanoparticles (Cur-SLN) in order to increase curcumin bioavailability and to evaluate their radiosensitizing ability in comparison to free curcumin (free-Cur), by using an in vitro approach on BC cell lines. In addition, transcriptomic and metabolomic profiles, induced by Cur-SLN treatments, highlighted networks involved in this radiosensitization ability. The non tumorigenic MCF10A and the tumorigenic MCF7 and MDA-MB-231 BC cell lines were used. Curcumin-loaded solid nanoparticles were prepared using ethanolic precipitation and the loading capacity was evaluated by UV spectrophotometer analysis. Cell survival after treatments was evaluated by clonogenic assay. Dose–response curves were generated testing three concentrations of free-Cur and Cur-SLN in combination with increasing doses of IR (2–9 Gy). IC50 value and Dose Modifying Factor (DMF) was measured to quantify the sensitivity to curcumin and to combined treatments. A multi-“omic” approach was used to explain the Cur-SLN radiosensitizer effect by microarray and metobolomic analysis. We have shown the efficacy of the Cur-SLN formulation as radiosensitizer on three BC cell lines. The DMFs values, calculated at the isoeffect of SF = 50%, showed that the Luminal A MCF7 resulted sensitive to the combined treatments using increasing concentration of vehicled curcumin Cur-SLN (DMF: 1,78 with 10 µM Cur-SLN.) Instead, triple negative MDA-MB-231 cells were more sensitive to free-Cur, although these cells also receive a radiosensitization effect by combination with Cur-SLN (DMF: 1.38 with 10 µM Cur-SLN). The Cur-SLN radiosensitizing function, evaluated by transcriptomic and metabolomic approach, revealed anti-oxidant and anti-tumor effects. Curcumin loaded- SLN can be suggested in future preclinical and clinical studies to test its concomitant use during radiotherapy treatments with the double implications of being a radiosensitizing molecule against cancer cells, with a protective role against IR side effects.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Glutamine deprivation induces abortive s-phase rescued by deoxyribonucleotides in k-ras transformed fibroblasts.

Daniela Gaglio / Chiara Soldati / Marco Vanoni / Lilia Alberghina / Ferdinando Chiaradonna

PLoS ONE, Vol 4, Iss 3, p e

2009 Volume 4715

Abstract: Background Oncogene activation plays a role in metabolic reprogramming of cancer cells. We have previously shown that K-ras transformed fibroblasts have a stronger dependence on glycolysis and a reduced oxidative phosphorylation ability as compared to ... ...

Abstract	Background Oncogene activation plays a role in metabolic reprogramming of cancer cells. We have previously shown that K-ras transformed fibroblasts have a stronger dependence on glycolysis and a reduced oxidative phosphorylation ability as compared to their normal counterparts. Another metabolic adaptation of cancer cells, that has long been established, is their propensity to exhibit increased glutamine consumption, although the effects induced by glutamine deprivation on cancer cells are still controversial. Methodology and principal findings Here, by using nutritional perturbations and molecular physiology, we show that reduction or complete depletion of glutamine availability in K-ras transformed fibroblasts causes a strong decrease of proliferation ability and a slower re-entry of synchronized cells into the cell cycle. The reduced proliferation is accompanied by sustained expression of cyclin D and E, abortive S phase entrance and is dependent on Ras signalling deregulation, since it is rescued by expression of a dominant negative guanine nucleotide exchange factor. The growth potential of transformed cells as well as the ability to execute the G(1) to S transition is restored by adding the four deoxyribonucleotides, indicating that the arrest of proliferation of K-ras transformed cells induced by glutamine depletion is largely due to a reduced supply of DNA in the presence of signalling pathways promoting G(1) to S transition. Conclusions and significance Our results suggest that the differential effects of glutamine and glucose on cell viability are not a property of the transformed phenotype per se, but rather depend on the specific pathway being activated in transformation. For instance, myc-overexpressing cells have been reported to die under glutamine depletion and not under glucose shortage, while the opposite holds for ras-transformed fibroblasts as shown in this paper. These different responses of transformed cells to nutritional stress should be taken into account when designing anti-cancer ...
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2009-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An ensemble approach to the study of the emergence of metabolic and proliferative disorders via Flux Balance Analysis

Giancarlo Mauri / Lilia Alberghina / Marco Vanoni / Dario Pescini / Daniela Gaglio / Sara Molinari / Riccardo Colombo / Chiara Damiani

Electronic Proceedings in Theoretical Computer Science, Vol 130, Iss Proc. Wivace 2013, Pp 92-

2013 Volume 97

Abstract: An extensive rewiring of cell metabolism supports enhanced proliferation in cancer cells. We propose a systems level approach to describe this phenomenon based on Flux Balance Analysis (FBA). The approach does not explicit a cell biomass formation ... ...

Abstract	An extensive rewiring of cell metabolism supports enhanced proliferation in cancer cells. We propose a systems level approach to describe this phenomenon based on Flux Balance Analysis (FBA). The approach does not explicit a cell biomass formation reaction to be maximized, but takes into account an ensemble of alternative flux distributions that match the cancer metabolic rewiring (CMR) phenotype description. The underlying concept is that the analysis the common/distinguishing properties of the ensemble can provide indications on how CMR is achieved and sustained and thus on how it can be controlled.
Keywords	Mathematics ; QA1-939 ; Electronic computers. Computer science ; QA75.5-76.95
Language	English
Publishing date	2013-09-01T00:00:00Z
Publisher	Open Publishing Association
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Computational Strategies for a System-Level Understanding of Metabolism

Paolo Cazzaniga / Chiara Damiani / Daniela Besozzi / Riccardo Colombo / Marco S. Nobile / Daniela Gaglio / Dario Pescini / Sara Molinari / Giancarlo Mauri / Lilia Alberghina / Marco Vanoni

Metabolites, Vol 4, Iss 4, Pp 1034-

2014 Volume 1087

Abstract: Cell metabolism is the biochemical machinery that provides energy and building blocks to sustain life. Understanding its fine regulation is of pivotal relevance in several fields, from metabolic engineering applications to the treatment of metabolic ... ...

Abstract	Cell metabolism is the biochemical machinery that provides energy and building blocks to sustain life. Understanding its fine regulation is of pivotal relevance in several fields, from metabolic engineering applications to the treatment of metabolic disorders and cancer. Sophisticated computational approaches are needed to unravel the complexity of metabolism. To this aim, a plethora of methods have been developed, yet it is generally hard to identify which computational strategy is most suited for the investigation of a specific aspect of metabolism. This review provides an up-to-date description of the computational methods available for the analysis of metabolic pathways, discussing their main advantages and drawbacks. In particular, attention is devoted to the identification of the appropriate scale and level of accuracy in the reconstruction of metabolic networks, and to the inference of model structure and parameters, especially when dealing with a shortage of experimental measurements. The choice of the proper computational methods to derive in silico data is then addressed, including topological analyses, constraint-based modeling and simulation of the system dynamics. A description of some computational approaches to gain new biological knowledge or to formulate hypotheses is finally provided.
Keywords	metabolism ; metabolome ; modeling ; systems biology ; genome-wide model ; constraint-based model ; core model ; mechanistic model ; ensemble modeling ; parameter estimation ; reverse engineering ; flux balance analysis ; network analysis ; sensitivity analysis ; control theory ; Microbiology ; QR1-502
Subject code	004
Language	English
Publishing date	2014-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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