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Dive into the research topics where Mario Mauri is active.

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Featured researches published by Mario Mauri.


The Journal of Neuroscience | 2014

Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models

Claudia Balducci; X Simona Mancini; Stefania Minniti; X Pietro La Vitola; Margherita Zotti; Giulio Sancini; Mario Mauri; Alfredo Cagnotto; X Laura Colombo; Fabio Fiordaliso; X Emanuele Grigoli; Mario Salmona; Anniina Snellman; Merja Haaparanta-Solin; Gianluigi Forloni; Massimo Masserini; Francesca Re

Alzheimers disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimers disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood–brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1–42 (−33%), assessed by ELISA, and the number and total area of plaques (−34%) detected histologically. Also, brain Aβ oligomers were reduced (−70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [11C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood–brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimers disease.


Cellular and Molecular Life Sciences | 2011

Light on the structure of thromboxane A2 receptor heterodimers

Francesca Fanelli; Mario Mauri; Valérie Capra; Francesco Raimondi; Francesca Guzzi; Manuela Ambrosio; G. Enrico Rovati; Marco Parenti

The structure-based design of a mutant form of the thromboxane A2 prostanoid receptor (TP) was instrumental in characterizing the structural determinants of the hetero-dimerization process of this G protein coupled receptor (GPCR). The results suggest that the hetero-dimeric complexes between the TPα and β isoforms are characterized by contacts between hydrophobic residues in helix 1 from both monomers. Functional characterization confirms that TPα–TPβ hetero-dimerization serves to regulate TPα function through agonist-induced internalization, with important implications in cardiovascular homeostasis. The integrated approach employed in this study can be adopted to gain structural and functional insights into the dimerization/oligomerization process of all GPCRs for which the structural model of the monomer can be achieved at reasonable atomic resolution.


Molecular and Cellular Neuroscience | 2012

Mesenchymal stem cells enhance GABAergic transmission in co-cultured hippocampal neurons

Mario Mauri; Daniela Lentini; Marta Gravati; Dana Foudah; Gerardo Biella; Barbara Costa; Mauro Toselli; Marco Parenti; Silvia Coco

Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent stem cells endowed with neurotrophic potential combined with immunological properties, making them a promising therapeutic tool for neurodegenerative disorders. However, the mechanisms through which MSCs promote the neurological recovery following injury or inflammation are still largely unknown, although cell replacement and paracrine mechanisms have been hypothesized. In order to find out what are the mechanisms of the trophic action of MSCs, as compared to glial cells, on CNS neurons, we set up a co-culture system where rat MSCs (or cortical astrocytes) were used as a feeding layer for hippocampal neurons without any direct contact between the two cell types. The analysis of hippocampal synaptogenesis, synaptic vesicle recycling and electrical activity show that MSCs were capable to support morphological and functional neuronal differentiation. The proliferation of hippocampal glial cells induced by the release of bioactive substance(s) from MSCs was necessary for neuronal survival. Furthermore, MSCs selectively increased hippocampal GABAergic pre-synapses. This effect was paralleled with a higher expression of the potassium/chloride KCC2 co-transporter and increased frequency and amplitude of mIPSCs and sIPSCs. The enhancement of GABA synapses was impaired by the treatment with K252a, a Trk/neurotrophin receptor blocker, and by TrkB receptor bodies hence suggesting the involvement of BDNF as a mediator of such effects. The results obtained here indicate that MSC-secreted factors induce glial-dependent neuronal survival and trigger an augmented GABAergic transmission in hippocampal cultures, highlighting a new effect by which MSCs could promote CNS repair. Our results suggest that MSCs may be useful in those neurological disorders characterized by an impairment of excitation versus inhibition balance.


Cellular and Molecular Life Sciences | 2010

Superactive mutants of thromboxane prostanoid receptor: functional and computational analysis of an active form alternative to constitutively active mutants

Manuela Ambrosio; Francesca Fanelli; Silvia Brocchetti; Francesco Raimondi; Mario Mauri; G. Enrico Rovati; Valérie Capra

In class A GPCRs the E/DRY motif is critical for receptor activation and function. According to experimental and computational data, R3.50 forms a double salt bridge with the adjacent E/D3.49 and E/D6.30 in helix 6, constraining the receptor in an inactive state. The disruption of this network of interactions facilitates conformational transitions that generate a signal or constitutive activity. Here we demonstrate that non-conservative substitution of either E129(3.49) or E240(6.30) of thromboxane prostanoid receptor (TP) resulted in mutants characterized by agonist-induced more efficient signaling properties, regardless of the G protein coupling. Results of computational modeling suggested a more effective interaction between Gq and the agonist-bound forms of the TP mutants, compared to the wild type. Yet, none of the mutants examined revealed any increase in basal activity, precluding their classification as constitutively active mutants. Here, we propose that these alternative active conformations might be identified as superactive mutants or SAM.


Journal of Hematology & Oncology | 2015

In vitro and in vivo identification of ABCB1 as an efflux transporter of bosutinib

Sara Redaelli; Pietro Perini; Monica Ceccon; Rocco Piazza; Roberta Rigolio; Mario Mauri; Frank Boschelli; Athina Giannoudis; Carlo Gambacorti-Passerini

BackgroundBosutinib is a recently approved ABL inhibitor. In spite of the well-documented effectiveness of BCR-ABL inhibitors in treating chronic myeloid leukemia, development of resistance is a continuous clinical challenge. Transporters that facilitate drug uptake and efflux have been proposed as one potential source of resistance to tyrosine kinase inhibitor treatment. Our aim was to determine which carriers are responsible for bosutinib transport.MethodsK562S cells overexpressing the drug transporters ABCB1, ABCG2, and SLC22A1 were generated, characterized and used in proliferation assay and intracellular uptake and retention assay (IUR). In vivo experiments were performed in nude mice injected with K562S, K562DOX cells (overexpressing ABCB1), and K562DOX silenced for ABCB1 (K562DOX/sh P-GP).ResultsThe IUR assay using C-14 bosutinib showed that only ABCB1 was responsible for active bosutinib transport. K562DOX cells showed the lowest intracellular level of bosutinib, while K562DOX cells treated with the ABCB1 inhibitor verapamil showed intracellular bosutinib levels comparable with parental K562S. Proliferation assays demonstrated that K562DOX are resistant to bosutinib treatment while verapamil is able to restore the sensitivity to the drug. Nude mice injected with K562DOX and treated with bosutinib showed very limited response and quickly relapsed after stopping treatment while K562S as well as K562DOX/sh P-GP remained tumor-free.ConclusionsOur data suggest that the analysis of ABCB1 expression levels might help determine treatment options for patients exhibiting resistance to bosutinib.


Methods in Enzymology | 2013

Analysis of GPCR dimerization using acceptor photobleaching resonance energy transfer techniques.

Marta Busnelli; Mario Mauri; Marco Parenti; Bice Chini

The ability of GPCRs to assemble into multimeric complexes is one of the most recently studied and discussed topics for many reasons, including the possibility that GPCR assemblies show a distinct pharmacological profile offering an innovative avenue for the drug synthesis. In addition, the possible differential coupling of monomeric versus multimeric GPCRs to G proteins and other downstream partners, as well as the signaling, the regulation through desensitization and internalization, and the subcellular localization can well represent additional factors that contribute to GPCR-mediated physiopathological states. The standard biochemical techniques used to identify GPCR interactions, such as coimmunoprecipitation, have obvious limitations owing to the use of nonphysiological buffers and detergents that disrupt the natural cell environment and biological interactions and preclude the analysis of subcellular localization and compartmentalization. In the past decade, new biophysical proximity assays based on the resonance energy transfer (RET) between two chromophores allow the study of dimerization in intact living cells, thus proving more information on GPCR physiological roles. In this chapter, we detail the application of two RET techniques based on fluorescence (FRET) and bioluminescence (BRET) to the study of GPCR dimerization and describe the results that can be obtained.


Journal of Bioenergetics and Biomembranes | 2016

Plasma membrane cholesterol level and agonist-induced internalization of δ-opioid receptors; colocalization study with intracellular membrane markers of Rab family

Jana Brejchova; Miroslava Vosahlikova; Lenka Roubalova; Marco Parenti; Mario Mauri; Oleksandr Chernyavskiy; Petr Svoboda

Decrease of cholesterol level in plasma membrane of living HEK293 cells transiently expressing FLAG-δ-OR by β-cyclodextrin (β-CDX) resulted in a slight internalization of δ-OR. Massive internalization of δ-OR induced by specific agonist DADLE was diminished in cholesterol-depleted cells. These results suggest that agonist-induced internalization of δ-OR, which has been traditionally attributed exclusively to clathrin-mediated pathway, proceeds at least partially via membrane domains. Identification of internalized pools of FLAG-δ-OR by colocalization studies with proteins of Rab family indicated the decreased presence of receptors in early endosomes (Rab5), late endosomes and lysosomes (Rab7) and fast recycling vesicles (Rab4). Slow type of recycling (Rab11) was unchanged by cholesterol depletion. As expected, agonist-induced internalization of oxytocin receptors was totally suppressed in β-CDX-treated cells. Determination of average fluorescence lifetime of TMA-DPH, the polar derivative of hydrophobic membrane probe diphenylhexatriene, in live cells by FLIM indicated a significant alteration of the overall PM structure which may be interpreted as an increased “water-accessible space” within PM area. Data obtained by studies of HEK293 cells transiently expressing FLAG-δ-OR by “antibody feeding” method were extended by analysis of the effect of cholesterol depletion on distribution of FLAG-δ-OR in sucrose density gradients prepared from HEK293 cells stably expressing FLAG-δ-OR. Major part of FLAG-δ-OR was co-localized with plasma membrane marker Na,K-ATPase and β-CDX treatment resulted in shift of PM fragments containing both FLAG-δ-OR and Na,K-ATPase to higher density. Thus, the decrease in content of the major lipid constituent of PM resulted in increased density of resulting PM fragments.


Biochemical Pharmacology | 2017

Impaired thromboxane receptor dimerization reduces signaling efficiency: A potential mechanism for reduced platelet function in vivo

Valérie Capra; Mario Mauri; Francesca Guzzi; Marta Busnelli; Maria Rosa Accomazzo; Pascale Gaussem; Shaista P. Nisar; Stuart J. Mundell; Marco Parenti; G. Enrico Rovati

Graphical abstract Figure. No caption available. ABSTRACT Thromboxane A2 is a potent mediator of inflammation and platelet aggregation exerting its effects through the activation of a G protein‐coupled receptor (GPCR), termed TP. Although the existence of dimers/oligomers in Class A GPCRs is widely accepted, their functional significance still remains controversial. Recently, we have shown that TP&agr; and TP&bgr; homo‐/hetero‐dimers interact through an interface of residues in transmembrane domain 1 (TM1) whose disruption impairs dimer formation. Here, biochemical and pharmacological characterization of this dimer deficient mutant (DDM) in living cells indicates a significant impairment in its response to agonists. Interestingly, two single loss‐of‐function TP&agr; variants, namely W29C and N42S recently identified in two heterozygous patients affected by bleeding disorders, match some of the residues mutated in our DDM. These two naturally occurring variants display a reduced potency to TP agonists and are characterized by impaired dimer formation in transfected HEK‐293T cells. These findings provide proofs that lack of homo‐dimer formation is a crucial process for reduced TP&agr; function in vivo, and might represent one molecular mechanism through which platelet TP&agr; receptor dysfunction affects the patient(s) carrying these mutations.


PLOS ONE | 2015

A Novel High-Content Immunofluorescence Assay as a Tool to Identify at the Single Cell Level γ-Globin Inducing Compounds

Marta Durlak; Cristina Fugazza; Sudharshan Elangovan; Maria Giuseppina Marini; Maria Franca Marongiu; Paolo Moi; Ivan Fraietta; Paolo Cappella; Gloria Barbarani; Isaura Font-Monclus; Mario Mauri; Sergio Ottolenghi; Fabio Gasparri; Antonella Ronchi

The identification of drugs capable of reactivating γ-globin to ameliorate β-thalassemia and Sickle Cell anemia is still a challenge, as available γ-globin inducers still have limited clinical indications. High-throughput screenings (HTS) aimed to identify new potentially therapeutic drugs require suitable first-step-screening methods combining the possibility to detect variation in the γ/β globin ratio with the robustness of a cell line. We took advantage of a K562 cell line variant expressing β-globin (β-K562) to set up a new multiplexed high-content immunofluorescence assay for the quantification of γ- and β-globin content at single-cell level. The assay was validated by using the known globin inducers hemin, hydroxyurea and butyric acid and further tested in a pilot screening that confirmed HDACs as targets for γ-globin induction (as proved by siRNA-mediated HDAC3 knockdown and by treatment with HDACs inhibitors entinostat and dacinostat) and identified Heme-oxygenases as novel candidate targets for γ-globin induction. Indeed, Heme-oxygenase2 siRNA knockdown as well as its inhibition by Tin protoporphyrin-IX (TinPPIX) greatly increased γ-globin expression. This result is particularly interesting as several metalloporphyrins have already been developed for clinical uses and could be tested (alone or in combination with other drugs) to improve pharmacological γ-globin reactivation for the treatment of β-hemoglobinopathies.


Nature Communications | 2018

SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub

Rocco Piazza; Vera Magistroni; Sara Redaelli; Mario Mauri; Luca Massimino; Alessandro Sessa; Marco Peronaci; Maciej Lalowski; Rabah Soliymani; Caterina Mezzatesta; Alessandra Pirola; Federica Banfi; Alicia Rubio; Delphine Rea; Fabio Stagno; Emilio Usala; Bruno Martino; Leonardo Campiotti; Michele Merli; Francesco Passamonti; Francesco Onida; Alessandro Morotti; Francesca Pavesi; Marco Bregni; Vania Broccoli; Marc Baumann; Carlo Gambacorti-Passerini

SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel–Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel–Giedion syndrome caused by SETBP1 mutations.SETBP1 variants occur as somatic mutations in several malignancies and as de novo germline mutations in developmental disorders. Here the authors provide evidence that SETBP1 binds to gDNA in AT-rich promoter regions to promote target gene upregulation, indicating SETBP1 functions directly to regulate transcription.

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Rocco Piazza

University of Milano-Bicocca

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Sara Redaelli

University of Milano-Bicocca

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Francesca Fanelli

University of Modena and Reggio Emilia

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Francesca Guzzi

University of Milano-Bicocca

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Francesco Raimondi

University of Modena and Reggio Emilia

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Luca Massimino

University of Milano-Bicocca

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