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Article ; Online: Editorial

Simona Piaggi / Marc Diederich / Alessandro Corti

Frontiers in Molecular Biosciences, Vol

The expanding functional network of glutathione transferases

2023 Volume 10

Keywords	glutathione transferases ; inflammation ; pathogenesis ; polymorphisms ; steroid biochemistry ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immune-tolerance to human iPS-derived neural progenitors xenografted into the immature cerebellum is overridden by species-specific differences in differentiation timing

Giulia Nato / Alessandro Corti / Elena Parmigiani / Elena Jachetti / Daniele Lecis / Mario Paolo Colombo / Domenico Delia / Annalisa Buffo / Lorenzo Magrassi

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 13

Abstract: Abstract We xeno-transplanted human neural precursor cells derived from induced pluripotent stem cells into the cerebellum and brainstem of mice and rats during prenatal development or the first postnatal week. The transplants survived and started to ... ...

Abstract	Abstract We xeno-transplanted human neural precursor cells derived from induced pluripotent stem cells into the cerebellum and brainstem of mice and rats during prenatal development or the first postnatal week. The transplants survived and started to differentiate up to 1 month after birth when they were rejected by both species. Extended survival and differentiation of the same cells were obtained only when they were transplanted in NOD-SCID mice. Transplants of human neural precursor cells mixed with the same cells after partial in vitro differentiation or with a cellular extract obtained from adult rat cerebellum increased survival of the xeno-graft beyond one month. These findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts induction of immune-tolerance to human antigens expressed before completion of maturation of the immune system. With further maturation the transplanted neural precursors expressed more mature antigens before the graft were rejected. Supplementation of the immature cells suspensions with more mature antigens may help to induce immune-tolerance for those antigens expressed only later by the engrafted cells.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Role of the 3Rs for Understanding and Modeling the Human Placenta

Joana Costa / Ruth Mackay / Sophie-Christine de Aguiar Greca / Alessandro Corti / Elisabete Silva / Emmanouil Karteris / Arti Ahluwalia

Journal of Clinical Medicine, Vol 10, Iss 3444, p

2021 Volume 3444

Abstract: Modeling the physiology of the human placenta is still a challenge, despite the great number of scientific advancements made in the field. Animal models cannot fully replicate the structure and function of the human placenta and pose ethical and ... ...

Abstract	Modeling the physiology of the human placenta is still a challenge, despite the great number of scientific advancements made in the field. Animal models cannot fully replicate the structure and function of the human placenta and pose ethical and financial hurdles. In addition, increasingly stricter animal welfare legislation worldwide is incentivizing the use of 3R (reduction, refinement, replacement) practices. What efforts have been made to develop alternative models for the placenta so far? How effective are they? How can we improve them to make them more predictive of human pathophysiology? To address these questions, this review aims at presenting and discussing the current models used to study phenomena at the placenta level: in vivo , ex vivo , in vitro and in silico . We describe the main achievements and opportunities for improvement of each type of model and critically assess their individual and collective impact on the pursuit of predictive studies of the placenta in line with the 3Rs and European legislation.
Keywords	placenta ; organ on a chip ; placenta on a chip ; 3Rs ; in vitro models ; in silico models ; Medicine ; R
Subject code	170
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: γ-Glutamyltransferase enzyme activity of cancer cells modulates L-γ-glutamyl-p-nitroanilide (GPNA) cytotoxicity

Alessandro Corti / Silvia Dominici / Simona Piaggi / Eugenia Belcastro / Martina Chiu / Giuseppe Taurino / Simone Pacini / Ovidio Bussolati / Alfonso Pompella

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

2019 Volume 13

Abstract: Abstract L-γ-Glutamyl-p-nitroanilide (GPNA) is widely used to inhibit the glutamine (Gln) transporter ASCT2, but recent studies have demonstrated that it is also able to inhibit other sodium-dependent and independent amino acid transporters. Moreover, ... ...

Abstract	Abstract L-γ-Glutamyl-p-nitroanilide (GPNA) is widely used to inhibit the glutamine (Gln) transporter ASCT2, but recent studies have demonstrated that it is also able to inhibit other sodium-dependent and independent amino acid transporters. Moreover, GPNA is a well known substrate of the enzyme γ-glutamyltransferase (GGT). Our aim was to evaluate the effect of GGT-mediated GPNA catabolism on cell viability and Gln transport. The GGT-catalyzed hydrolysis of GPNA produced cytotoxic effects in lung cancer A549 cells, resulting from the release of metabolite p-nitroaniline (PNA) rather than from the inhibition of Gln uptake. Interestingly, compounds like valproic acid, verapamil and reversan were able to increase the cytotoxicity of GPNA and PNA, suggesting a key role of intracellular detoxification mechanisms. Our data indicate that the mechanism of action of GPNA is more complex than believed, and further confirm the poor specificity of GPNA as an inhibitor of Gln transport. Different factors may modulate the final effects of GPNA, ranging from GGT and ASCT2 expression to intracellular defenses against xenobiotics. Thus, other strategies - such as a genetic suppression of ASCT2 or the identification of new specific inhibitors - should be preferred when inhibition of ASCT2 function is required.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The beclomethasone anti-inflammatory effect occurs in cell/mediator-dependent manner and is additively enhanced by formoterol: NFkB, p38, PKA analysis

Cianchetti, Silvana / Cristina Cardini / Alessandro Corti / Marta Menegazzi / Elena Darra / Eleonora Ingrassia / Alfonso Pompella / Pierluigi Paggiaro

Life sciences. 2018 June 15, v. 203

2018

Abstract: Beclomethasone/formoterol (BDP/FOR) has been reported to be more effective than its separate components in airway disease control and in airway inflammation improvement. However, BDP/FOR effects on cytokine-induced inflammation in structural cells have ... ...

Abstract	Beclomethasone/formoterol (BDP/FOR) has been reported to be more effective than its separate components in airway disease control and in airway inflammation improvement. However, BDP/FOR effects on cytokine-induced inflammation in structural cells have not been described and whether these effects occur in a cell- and mediator-dependent manner has not been fully elucidated. We sought to evaluate BDP and/or FOR effects on endothelial ICAM-1, E-selectin, IL-8 and on bronchial epithelial ICAM-1 and IL-8. Specific intracellular signaling pathways were also investigated.Surface adhesion molecule expression and IL-8 release induced by TNF-alpha were measured by ELISA. Intracellular signaling pathways were investigated by a) EMSA and Western blot analysis to evaluate NF-κB DNA-binding and MAPK-p38 phosphorylation; b) PDTC/SB203580 as NF-κB/p38 inhibitors; c) forskolin/H-89 as PKA activator/inhibitor.BDP/FOR additively reduced endothelial E-selectin and IL-8 as well as bronchial epithelial ICAM-1 and IL-8. BDP/FOR and SB203580 showed the highest inhibitory effect on epithelial IL-8, whereas endothelial ICAM-1 was never affected by BDP/FOR and PDTC. TNF-alpha-induced NF-κB DNA-binding and MAPK-p38 phosphorylation were not influenced by BDP/FOR. Forskolin mimicked FOR effects; H-89 partially reversed the BDP/FOR inhibition in a mediator-dependent manner.The BDP/FOR inhibition degree was related to the inflammatory mediator- and cell-type considered. FOR additively enhanced BDP effects by partially involving both dependent- and independent-PKA mechanisms. Our results might contribute to highlight the strong relationship between specific molecular pathways and different sensitivity to the corticosteroid/β2-agonist effects and to clarify the molecular mechanisms underlying the BDP/FOR anti-inflammatory activity in vivo.
Keywords	Western blotting ; adhesion ; anti-inflammatory activity ; cAMP-dependent protein kinase ; disease control ; enzyme-linked immunosorbent assay ; epithelium ; forskolin ; inflammation ; intercellular adhesion molecule-1 ; interleukin-8 ; phosphorylation ; signal transduction ; transcription factor NF-kappa B ; tumor necrosis factor-alpha
Language	English
Dates of publication	2018-0615
Size	p. 27-38.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2018.04.015
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Calpain-3 impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells.

Daniele Moretti / Barbara Del Bello / Giulia Allavena / Alessandro Corti / Cinzia Signorini / Emilia Maellaro

PLoS ONE, Vol 10, Iss 2, p e

2015 Volume 0117258

Abstract: Calpain-3 is an intracellular cysteine protease, belonging to Calpain superfamily and predominantly expressed in skeletal muscle. In human melanoma cell lines and biopsies, we previously identified two novel splicing variants (hMp78 and hMp84) of Calpain- ...

Abstract	Calpain-3 is an intracellular cysteine protease, belonging to Calpain superfamily and predominantly expressed in skeletal muscle. In human melanoma cell lines and biopsies, we previously identified two novel splicing variants (hMp78 and hMp84) of Calpain-3 gene (CAPN3), which have a significant lower expression in vertical growth phase melanomas and, even lower, in metastases, compared to benign nevi. In the present study, in order to investigate the pathophysiological role played by the longer Calpain-3 variant, hMp84, in melanoma cells, we over-expressed it in A375 and HT-144 cells. In A375 cells, the enforced expression of hMp84 induces p53 stabilization, and modulates the expression of a few p53- and oxidative stress-related genes. Consistently, hMp84 increases the intracellular production of ROS (Reactive Oxygen Species), which lead to oxidative modification of phospholipids (formation of F2-isoprostanes) and DNA damage. Such events culminate in an adverse cell fate, as indicated by the decrease of cell proliferation and by cell death. To a different extent, either the antioxidant N-acetyl-cysteine or the p53 inhibitor, Pifithrin-α, recover cell viability and decrease ROS formation. Similarly to A375 cells, hMp84 over-expression causes inhibition of cell proliferation, cell death, and increase of both ROS levels and F2-isoprostanes also in HT-144 cells. However, in these cells no p53 accumulation occurs. In both cell lines, no significant change of cell proliferation and cell damage is observed in cells over-expressing the mutant hMp84C42S devoid of its enzymatic activity, suggesting that the catalytic activity of hMp84 is required for its detrimental effects. Since a more aggressive phenotype is expected to benefit from down-regulation of mechanisms impairing cell growth and survival, we envisage that Calpain-3 down-regulation can be regarded as a novel mechanism contributing to melanoma progression.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2015-01-01T00:00:00Z
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: Association between plasma gamma-glutamyltransferase fractions and metabolic syndrome among hypertensive patients

Maria Franzini / Ilenia Scataglini / Angelo Ricchiuti / Vanna Fierabracci / Aldo Paolicchi / Alfonso Pompella / Giulia Dell’Omo / Roberto Pedrinelli / Alessandro Corti

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 8

Abstract: Abstract Among the risk factors associated to metabolic syndrome (MetS), hypertension shows the highest prevalence in Italy. We investigated the relationship between the newly identified serum γ-glutamyltransferase (GGT) fractions, b- s- m- f-GGT, and ... ...

Abstract	Abstract Among the risk factors associated to metabolic syndrome (MetS), hypertension shows the highest prevalence in Italy. We investigated the relationship between the newly identified serum γ-glutamyltransferase (GGT) fractions, b- s- m- f-GGT, and risk factors associated to MetS in hypertensive patients. A total of ninety-five consecutive hypertensive patients were enrolled. GGT fractions were analysed by gel-filtration chromatography, and hepatic steatosis was evaluated by ultrasound. MetS was diagnosed in 36% of patients. Considering the whole group, b- and f-GGT showed the highest positive correlation with BMI, glucose, triglycerides and insulin, and the highest negative correlation with HDL cholesterol. While both serum triglycerides and insulin were independently associated with b-GGT levels, only triglycerides were independently associated with f-GGT. The values of b-GGT activity increased with steatosis grade (g0 = 1.19; g2 = 3.29; ratio g2/g0 = 2.75, p < 0.0001 linear trend). Patients with MetS showed higher levels of b-GGT, m-GGT and f-GGT [median (25th–75th) U/L: 3.19 (1.50–6.59); 0.55 (0.26–0.81); 10.3 (9.1–13.6); respectively] as compared to subjects presenting with one or two MetS criteria [1.75 (0.95–2.85), p < 0.001; 0.33 (0.19–0.60), p < 0.05; 8.8 (7.0–10.6), p < 0.001]. Our data point to a potential role for b- and f-GGT fractions in identifying MetS patients among hypertensive subjects, thus providing a minimally invasive blood-based tool for MetS diagnosis.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients

Alessandro Corti / Raina Sota / Matteo Dugo / Raffaele A. Calogero / Benedetta Terragni / Massimo Mantegazza / Silvana Franceschetti / Michela Restelli / Patrizia Gasparini / Daniele Lecis / Krystyna H. Chrzanowska / Domenico Delia

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

2019 Volume 13

Abstract: Abstract Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we ...

Abstract	Abstract Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency. We found that Top1cc trapping by CPT induces an ATM-dependent DDR as well as an ATM-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and ATM status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of ATM. In unperturbed A-T neurons a set of genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in A-T patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Gamma-glutamyltransferase fractions in human plasma and bile

Irene Fornaciari / Vanna Fierabracci / Alessandro Corti / Hassan Aziz Elawadi / Evelina Lorenzini / Michele Emdin / Aldo Paolicchi / Maria Franzini

PLoS ONE, Vol 9, Iss 2, p e

characteristic and biogenesis.

2014 Volume 88532

Abstract: Total plasma gamma-glutamyltransferase (GGT) activity is a sensitive, non-specific marker of liver dysfunction. Four GGT fractions (b-, m-, s-, f-GGT) were described in plasma and their differential specificity in the diagnosis of liver diseases was ... ...

Abstract	Total plasma gamma-glutamyltransferase (GGT) activity is a sensitive, non-specific marker of liver dysfunction. Four GGT fractions (b-, m-, s-, f-GGT) were described in plasma and their differential specificity in the diagnosis of liver diseases was suggested. Nevertheless fractional GGT properties have not been investigated yet. The aim of this study was to characterize the molecular nature of fractional GGT in both human plasma and bile. Plasma was obtained from healthy volunteers; whereas bile was collected from patients undergoing liver transplantation. Molecular weight (MW), density, distribution by centrifugal sedimentation and sensitivity to both detergent (deoxycholic acid) and protease (papain) were evaluated. A partial purification of b-GGT was obtained by ultracentrifugation. Plasma b-GGT fraction showed a MW of 2000 kDa and a density between 1.063-1.210 g/ml. Detergent converted b-GGT into s-GGT, whereas papain alone did not produce any effect. Plasma m-GGT and s-GGT showed a MW of 1,000 and 200 kDa, and densities between 1.006-1.063 g/ml and 1.063-1.210 g/ml respectively. Both fractions were unaffected by deoxycholic acid, while GGT activity was recovered into f-GGT peak after papain treatment. Plasma f-GGT showed a MW of 70 kDa and a density higher than 1.21 g/ml. We identified only two chromatographic peaks, in bile, showing similar characteristics as plasma b- and f-GGT fractions. These evidences, together with centrifugal sedimentation properties and immunogold electronic microscopy data, indicate that b-GGT is constituted of membrane microvesicles in both bile and plasma, m-GGT and s-GGT might be constituted of bile-acid micelles, while f-GGT represents the free-soluble form of the enzyme.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2014-01-01T00:00:00Z
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: Contribution by polymorphonucleate granulocytes to elevated gamma-glutamyltransferase in cystic fibrosis sputum.

Alessandro Corti / Maria Franzini / Silvana Cianchetti / Gabriella Bergamini / Evelina Lorenzini / Paola Melotti / Aldo Paolicchi / Pierluigi Paggiaro / Alfonso Pompella

PLoS ONE, Vol 7, Iss 4, p e

2012 Volume 34772

Abstract: BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder characterized by a chronic neutrophilic airways inflammation, increasing levels of oxidative stress and reduced levels of antioxidants such as glutathione (GSH). Gamma- ... ...

Abstract	BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder characterized by a chronic neutrophilic airways inflammation, increasing levels of oxidative stress and reduced levels of antioxidants such as glutathione (GSH). Gamma-glutamyltransferase (GGT), an enzyme induced by oxidative stress and involved in the catabolism of GSH and its derivatives, is increased in the airways of CF patients with inflammation, but the possible implications of its increase have not yet been investigated in detail. PRINCIPAL FINDINGS: The present study was aimed to evaluate the origin and the biochemical characteristics of the GGT detectable in CF sputum. We found GGT activity both in neutrophils and in the fluid, the latter significantly correlating with myeloperoxidase expression. In neutrophils, GGT was associated with intracellular granules. In the fluid, gel-filtration chromatography showed the presence of two distinct GGT fractions, the first corresponding to the human plasma b-GGT fraction, the other to the free enzyme. The same fractions were also observed in the supernatant of ionomycin and fMLP-activated neutrophils. Western blot analysis confirmed the presence of a single band of GGT immunoreactive peptide in the CF sputum samples and in isolated neutrophils. CONCLUSIONS: In conclusion, our data indicate that neutrophils are able to transport and release GGT, thus increasing GGT activity in CF sputum. The prompt release of GGT may have consequences on all GGT substrates, including major inflammatory mediators such as S-nitrosoglutathione and leukotrienes, and could participate in early modulation of inflammatory response.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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