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Article ; Online: Thyroid hormone treatment counteracts cellular phenotypical remodeling in diabetic organs.

Lavecchia, Angelo M / Mantzouratou, Polyxeni / Cerullo, Domenico / Locatelli, Monica / Conti, Sara / Tironi, Matteo / Sangalli, Fabio / Corna, Daniela / Zoja, Carlamaria / Remuzzi, Giuseppe / Xinaris, Christodoulos

iScience

2023 Volume 26, Issue 10, Page(s) 107826

Abstract: Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of ... ...

Abstract	Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract the cellular remodeling that occurs in diabetic cardiomyocytes, podocytes, and pancreatic beta cells. Treating diabetic rats with T3 prevents dedifferentiation, pathological growth, and ultrastructural alterations in podocytes and cardiomyocytes.
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107826
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Article ; Online: Deoxygenative Tri- and Difluoromethylthiolation of Carboxylic Acids with Benzothiazolium Reagents.

Tironi, Matteo / Maas, Lilian M / Garg, Arushi / Dix, Stefan / Götze, Jan P / Hopkinson, Matthew N

Organic letters

2020 Volume 22, Issue 22, Page(s) 8925–8930

Abstract: Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT- ... ...

Abstract	Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT-SCF
Language	English
Publishing date	2020-11-04
Publishing country	United States
Document type	Journal Article
ISSN	1523-7052
ISSN (online)	1523-7052
DOI	10.1021/acs.orglett.0c03328
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Article ; Online: Copper-dependent biological effects of particulate matter produced by brake systems on lung alveolar cells.

Figliuzzi, Marina / Tironi, Matteo / Longaretti, Lorena / Mancini, Alessandro / Teoldi, Federico / Sangalli, Fabio / Remuzzi, Andrea

Archives of toxicology

2020 Volume 94, Issue 9, Page(s) 2965–2979

Abstract: Road traffic is one of the main sources of particulate emissions into the environment and has an increasing, negative impact on the release of potentially dangerous materials. Vehicle brakes release a significant amount of wear particles, and knowledge ... ...

Abstract	Road traffic is one of the main sources of particulate emissions into the environment and has an increasing, negative impact on the release of potentially dangerous materials. Vehicle brakes release a significant amount of wear particles, and knowledge regarding their possible adverse effects is limited. One of the most dangerous elements contained in brake pads is copper (Cu), known to be toxic for human health. Therefore, our aim was to study the cell toxicity of particulate matter (PM) produced by different combinations of braking discs and pads containing different amounts of Cu. We investigated whether brake-derived microparticles have toxic effects on lung cells proportionally to their Cu content. Analyte content was measured in friction materials by XRFS and in PM2.5 captured during braking tests using SEM/EDX. The biological impact of brake-derived PM2.5 was investigated on a human epithelial alveolar cell line (A549). Cell viability, oxidative stress, mitochondrial membrane potential, apoptosis, and the pro-inflammatory response of the cells, as well as gene expression, were assessed following exposure to increasing PM2.5 concentrations (1, 10, 100, 200, and 500 µg/ml). The brake debris with the lowest Cu content did not induce significant changes in biological effects on A549 cells compared to normal controls, except for ROS production and IL6 gene expression. PM2.5 containing higher Cu quantities induced cell toxicity that correlated with Cu concentration. Our data suggest that the toxicity of PM2.5 from the brake system is mainly related to Cu content, thus confirming that eliminating Cu from brake pads will be beneficial for human health in urbanized environments.
MeSH term(s)	Air Pollutants/toxicity ; Alveolar Epithelial Cells/drug effects ; Copper/toxicity ; Humans ; Oxidative Stress ; Particulate Matter/toxicity ; Vehicle Emissions
Chemical Substances	Air Pollutants ; Particulate Matter ; Vehicle Emissions ; Copper (789U1901C5)
Language	English
Publishing date	2020-06-23
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-020-02812-4
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Article ; Online: Influence of Culture Substrates on Morphology and Function of Pulmonary Alveolar Cells In Vitro.

Campiglio, Chiara Emma / Figliuzzi, Marina / Silvani, Sara / Tironi, Matteo / Conti, Sara / Boschetti, Federica / Remuzzi, Andrea

Biomolecules

2021 Volume 11, Issue 5

Abstract: Cell's microenvironment has been shown to exert influence on cell behavior. In particular, matrix-cell interactions strongly impact cell morphology and function. The purpose of this study was to analyze the influence of different culture substrate ... ...

Abstract	Cell's microenvironment has been shown to exert influence on cell behavior. In particular, matrix-cell interactions strongly impact cell morphology and function. The purpose of this study was to analyze the influence of different culture substrate materials on phenotype and functional properties of lung epithelial adenocarcinoma (A549) cells. A549 cells were seeded onto two different biocompatible, commercially available substrates: a polyester coverslip (Thermanox™ Coverslips), that was used as cell culture plate control, and a polydimethylsiloxane membrane (PDMS, Elastosil
Language	English
Publishing date	2021-04-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11050675
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Article: Deoxygenative Tri- and Difluoromethylthiolation of Carboxylic Acids with Benzothiazolium Reagents

Tironi, Matteo / Maas, Lilian M / Garg, Arushi / Dix, Stefan / Götze, Jan P / Hopkinson, Matthew N

Organic letters. 2020 Nov. 04, v. 22, no. 22

2020

Abstract: Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT-SCF₃ represents an attractive approach toward these SCF₃-containing compounds that avoids the ... ...

Abstract	Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT-SCF₃ represents an attractive approach toward these SCF₃-containing compounds that avoids the use of metal –SCF₃ salts or preactivated acyl electrophiles. Moreover, the in situ activation of BT-SCF₂H allows for an unprecedented nucleophilic difluoromethylthiolation reaction. DFT calculations support a mechanistic scenario involving a four-membered transition state where acyl substitution occurs without the formation of an unstable free –SCF₂H anion.
Keywords	Lewis acids ; Lewis bases ; thioesters
Language	English
Dates of publication	2020-1104
Size	p. 8925-8930.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ISSN	1523-7052
DOI	10.1021/acs.orglett.0c03328
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth.

Resovi, Andrea / Persichitti, Perla / Brunelli, Laura / Minoli, Lucia / Borsotti, Patrizia / Garattini, Giulia / Tironi, Matteo / Dugnani, Erica / Redegalli, Miriam / De Simone, Giulia / Pastorelli, Roberta / Bani, Maria Rosa / Piemonti, Lorenzo / Mosher, Deane F / Giavazzi, Raffaella / Taraboletti, Giulia / Belotti, Dorina

Journal of experimental & clinical cancer research : CR

2023 Volume 42, Issue 1, Page(s) 201

Abstract: Background: The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The ... ...

Abstract	Background: The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The identification of proteolytic events, targets and pathways would set the basis for the design of new therapeutic approaches. Methods and results: Here we demonstrate that spheroids isolated from human and murine healthy pancreas and co-transplanted orthotopically with pancreatic ductal adenocarcinoma (PDAC) in mouse pancreas inhibited tumor growth. The effect was mediated by trypsin-generated fibronectin (FN) fragments released by pancreatic spheroids. Tumor inhibition was observed also in a model of acute pancreatitis associated with trypsin activation. Mass spectrometry proteomic analysis of fragments and mAb against different FN epitopes identified the FN type III domain as responsible for the activity. By inhibiting integrin α5β1, FAK and FGFR1 signaling, the fragments induced tumor cell detachment and reduced cell proliferation. Consistent with the mutual relationship between the two pathways, FGF2 restored both FGFR1 and FAK signaling and promoted PDAC cell adhesion and proliferation. FAK and FGFR inhibitors additively inhibited PDAC growth in vitro and in orthotopic in vivo models. Conclusions: This study identifies a novel role for pancreatic trypsin and fibronectin cleavage as a mechanism of protection against cancer by the pancreatic microenvironment. The finding of a FAK-FGFR cross-talk in PDAC support the combination of FAK and FGFR inhibitors for PDAC treatment to emulate the protective effect of the normal pancreas against cancer.
MeSH term(s)	Animals ; Humans ; Mice ; Acute Disease ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Cell Proliferation ; Fibronectins/metabolism ; Pancreas/pathology ; Pancreatic Neoplasms/pathology ; Pancreatitis ; Proteomics ; Trypsin/metabolism ; Tumor Microenvironment ; Pancreatic Neoplasms
Chemical Substances	Fibronectins ; Trypsin (EC 3.4.21.4)
Language	English
Publishing date	2023-08-09
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-023-02778-y
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Article ; Online: Effect of 3D Synthetic Microscaffold Nichoid on the Morphology of Cultured Hippocampal Neurons and Astrocytes.

Musi, Clara Alice / Colnaghi, Luca / Giani, Arianna / Priori, Erica Cecilia / Marchini, Giacomo / Tironi, Matteo / Conci, Claudio / Cerullo, Giulio / Osellame, Roberto / Raimondi, Manuela Teresa / Remuzzi, Andrea / Borsello, Tiziana

Cells

2022 Volume 11, Issue 13

Abstract: The human brain is the most complex organ in biology. This complexity is due to the number and the intricate connections of brain cells and has so far limited the development of in vitro models for basic and applied brain research. We decided to create a ...

Abstract	The human brain is the most complex organ in biology. This complexity is due to the number and the intricate connections of brain cells and has so far limited the development of in vitro models for basic and applied brain research. We decided to create a new, reliable, and cost-effective in vitro system based on the Nichoid, a 3D microscaffold microfabricated by two-photon laser polymerization technology. We investigated whether these 3D microscaffold devices can create an environment allowing the manipulation, monitoring, and functional assessment of a mixed population of brain cells in vitro. With this aim, we set up a new model of hippocampal neurons and astrocytes co-cultured in the Nichoid microscaffold to generate brain micro-tissues of 30 μm thickness. After 21 days in culture, we morphologically characterized the 3D spatial organization of the hippocampal astrocytes and neurons within the microscaffold, and we compared our observations to those made using the classical 2D co-culture system. We found that the co-cultured cells colonized the entire volume of the 3D devices. Using confocal microscopy, we observed that within this period the different cell types had become well-differentiated. This was further elaborated with the use of drebrin, PSD-95, and synaptophysin antibodies that labeled the majority of neurons, both in the 2D as well as in the 3D co-cultures. Using scanning electron microscopy, we found that neurons in the 3D co-culture displayed a significantly larger amount of dendritic protrusions compared to neurons in the 2D co-culture. This latter observation indicates that neurons growing in a 3D environment may be more prone to form connections than those co-cultured in a 2D condition. Our results show that the Nichoid can be used as a 3D device to investigate the structure and morphology of neurons and astrocytes in vitro. In the future, this model can be used as a tool to study brain cell interactions in the discovery of important mechanisms governing neuronal plasticity and to determine the factors that form the basis of different human brain diseases. This system may potentially be further used for drug screening in the context of various brain diseases.
MeSH term(s)	Astrocytes ; Brain Diseases/metabolism ; Coculture Techniques ; Hippocampus ; Humans ; Neurons/metabolism
Language	English
Publishing date	2022-06-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11132008
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Article ; Online: Hybrid fibroin/polyurethane small-diameter vascular grafts: from fabrication to

Caldiroli, Alice / Pederzani, Elia / Pezzotta, Marco / Azzollini, Nadia / Fiori, Sonia / Tironi, Matteo / Rizzo, Paola / Sangalli, Fabio / Figliuzzi, Marina / Fiore, Gianfranco Beniamino / Remuzzi, Andrea / Riboldi, Stefania Adele / Soncini, Monica / Redaelli, Alberto

Biomedical materials (Bristol, England)

2022 Volume 17, Issue 5

Abstract: To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very ...

Abstract	To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very small-calibre grafts (Ø
MeSH term(s)	Animals ; Blood Vessel Prosthesis ; Fibroins ; Polyurethanes ; Rats ; Rats, Inbred Lew ; Vascular Grafting
Chemical Substances	Polyurethanes ; Fibroins (9007-76-5)
Language	English
Publishing date	2022-08-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2265222-X
ISSN	1748-605X ; 1748-6041
ISSN (online)	1748-605X
ISSN	1748-6041
DOI	10.1088/1748-605X/ac885a
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Article ; Online: C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19.

Aiello, Sistiana / Gastoldi, Sara / Galbusera, Miriam / Ruggenenti, Piero / Portalupi, Valentina / Rota, Stefano / Rubis, Nadia / Liguori, Lucia / Conti, Sara / Tironi, Matteo / Gamba, Sara / Santarsiero, Donata / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

Blood advances

2021 Volume 6, Issue 3, Page(s) 866–881

Abstract: Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, ... ...

Abstract	Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.
MeSH term(s)	Atypical Hemolytic Uremic Syndrome ; COVID-19 ; Endothelial Cells ; Humans ; Platelet Aggregation ; SARS-CoV-2
Language	English
Publishing date	2021-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021005246
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Article ; Online: Effect of the 3D Artificial Nichoid on the Morphology and Mechanobiological Response of Mesenchymal Stem Cells Cultured In Vitro.

Remuzzi, Andrea / Bonandrini, Barbara / Tironi, Matteo / Longaretti, Lorena / Figliuzzi, Marina / Conti, Sara / Zandrini, Tommaso / Osellame, Roberto / Cerullo, Giulio / Raimondi, Manuela Teresa

Cells

2020 Volume 9, Issue 8

Abstract: Stem cell fate and behavior are affected by the bidirectional communication of cells and their local microenvironment (the stem cell niche), which includes biochemical cues, as well as physical and mechanical factors. Stem cells are normally cultured in ... ...

Abstract	Stem cell fate and behavior are affected by the bidirectional communication of cells and their local microenvironment (the stem cell niche), which includes biochemical cues, as well as physical and mechanical factors. Stem cells are normally cultured in conventional two-dimensional monolayer, with a mechanical environment very different from the physiological one. Here, we compare culture of rat mesenchymal stem cells on flat culture supports and in the "Nichoid", an innovative three-dimensional substrate micro-engineered to recapitulate the architecture of the physiological niche
MeSH term(s)	Animals ; Blotting, Western ; Cell Movement/physiology ; Cell Proliferation/physiology ; Cells, Cultured ; Fluorescent Antibody Technique ; Focal Adhesions/physiology ; Male ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/ultrastructure ; Microscopy, Electron, Scanning ; Microscopy, Electron, Transmission ; Polymerase Chain Reaction ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction
Language	English
Publishing date	2020-08-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9081873
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