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The Natural Phosphoinositide-Derivative Glycerophosphoinositol Inhibits the Lipopolysaccharide-Induced Inflammatory and Thrombotic Responses

publications 2017

Vessichelli M., Mariggiò S.,Varone A., Zizza P., Di Santo AM., Amore C., Dell'Elba G., Cutignano A., Fontana A., Cacciapuoti C., Di Costanzo G., Zannini MS., de Cristofaro Tiziana., Evangelista V., Corda D. (2017)

"The Natural Phosphoinositide-Derivative Glycerophosphoinositol Inhibits the Lipopolysaccharide-Induced Inflammatory and Thrombotic Responses" 

J Biol Chem. 2017 Jun 9. pii: jbc.M116.773861. doi: 10.1074/jbc.M116.773861


Abstract

 

 

 

 

Inflammatory responses are elicited through lipid products of phospholipase A2 activity that acts on the membrane phospholipids, including the phosphoinositides, to form the pro-inflammatory arachidonic acid and, in parallel, the glycerophosphoinositols. Here, we investigate the role of the glycerophosphoinositol in inflammatory response. We show that it is part of a negative-feedback loop that limits pro-inflammatory and pro-thrombotic responses in human monocytes stimulated with lipopolysaccharide. This inhibition is exerted both on the signaling cascade initiated by the lipopolysaccharide with the glycerophosphoinositol-dependent decrease in IKKα/β, p38, JNK and Erk1/2 kinases phosphorylation and at the nuclear level with decreased NF-κB translocation and binding to inflammatory gene promoters. In a model of endotoxaemia in the mouse, treatment with glycerophosphoinositol reduced TNF-α synthesis, which supports the concept that glycerophosphoinositol inhibits the de-novo synthesis of pro-inflammatory and pro-thrombotic compounds and might thus have a role as an endogenous mediator in the resolution of inflammation. As indicated, this effect of glycerophosphoinositol can also be exploited in the treatment of the manifestations of severe inflammation, by exogenous administration of the compound


 

HLA-DQ2.5 genes associated with celiac disease risk are preferentially expressed with respect to non-predisposing HLA genes: Implication for anti-gluten T cell response.

publications 2016

Pisapia L, Camarca A, Picascia S Bassi V, Barba P, Del Pozzo G, Gianfrani C.

"HLA-DQ2.5 genes associated with celiac disease risk are preferentially expressed with respect to non-predisposing
HLA genes: Im
plication foranti-gluten T cell response."

J Autoimmun. 2016 Jun;70:63-72. doi: 10.1016/j.jaut.2016.03.016. Epub 2016 Apr 12.


Abstract

HLA genes represent the main risk factor in autoimmune disorders. In celiac disease (CD), the great majority of patients carry the HLA DQA1*05 and DQB1*02 alleles, both of which encode the DQ2.5 molecule. The formation of complexes between DQ2.5 and gluten peptides on antigen-presenting cells (APCs) is necessary to activate pathogenic CD4(+) T lymphocytes. It is widely accepted that the DQ2.5 genes establish the different intensities of anti-gluten immunity, depending whether they are in a homozygous or a heterozygous configuration. Here, we demonstrated that HLA DQA1*05 and DQB1*02 gene expression is much higher than expression of non-CD-associated genes. This influences the protein levels and causes a comparable cell surface exposure of DQ2.5 heterodimers between DQ2.5 homozygous and heterozygous celiac patients. As a consequence, the magnitude of the anti-gluten CD4(+) T cell response is strictly dependent on the antigen dose and not on the DQ2.5 gene configuration of APCs. Furthermore, our findings support the concept that the expression of DQ2.5 genes is an important risk factor in celiac disease. The preferential expression of DQ2.5 alleles provides a new functional explanation of why these genes are so frequently associated with celiac disease and with other autoimmune disorders.


 


Aurora-A recruitment and centrosomal maturation are regulated by a Golgi-activated pool of Src during G2

publications 2016


Maria Luisa Barretta
Daniela SpanoChiara D’AmbrosioRomina Ines CervigniAndrea ScaloniDaniela Corda Antonino Colanzi

"Aurora-A recruitment and centrosomal maturation are regulated by a Golgi-activated pool of Src during G2"

Nature Communications 7, Article number: 11727 doi:10.1038 

 

Abstract

The Golgi apparatus is composed of stacks of cisternae laterally connected by tubules to form a ribbon-like structure. At the onset of mitosis, the Golgi ribbon is broken down into discrete stacks, which then undergo further fragmentation. This ribbon cleavage is required for G2/M transition, which thus indicates that a ‘Golgi mitotic checkpoint’ couples Golgi inheritance with cell cycle transition. We previously showed that the Golgi-checkpoint regulates the centrosomal recruitment of the mitotic kinase Aurora-A; however, how the Golgi unlinking regulates this recruitment was unknown. Here we show that, in G2, Aurora-A recruitment is promoted by activated Src at the Golgi. Our data provide evidence that Src and Aurora-A interact upon Golgi ribbon fragmentation; Src phosphorylates Aurora-A at tyrosine 148 and this specific phosphorylation is required for Aurora-A localization at the centrosomes. This process, pivotal for centrosome maturation, is a fundamental prerequisite for proper spindle formation and chromosome segregation.


 

A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

publications 2016


S. Managò, C. Valente, P. Mirabelli, D. Circolo, F. Basile, D. CordaA. C. De Luca

A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

Nature Sci. Rep. 6 24821 (2016).


Abstract

Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder that shows high mortality rates due to immature lymphocyte B-cell proliferation. B-ALL diagnosis requires identification and classification of the leukemia cells. Here, we demonstrate the use of Raman spectroscopy to discriminate normal lymphocytic B-cells from three different B-leukemia transformed cell lines (i.e., RS4;11, REH, MN60 cells) based on their biochemical features. In combination with immunofluorescence and Western blotting, we show that these Raman markers reflect the relative changes in the potential biological markers from cell surface antigens, cytoplasmic proteins, and DNA content and correlate with the lymphoblastic B-cell maturation/differentiation stages. Our study demonstrates the potential of this technique for classification of B-leukemia cells into the different differentiation/maturation stages, as well as for the identification of key biochemical changes under chemotherapeutic treatments. Finally, preliminary results from clinical samples indicate high consistency of, and potential applications for, this Raman spectroscopy approach.


 

GOLPH3 and oncogenesis: What is the molecular link?

publications 2016

Riccardo Rizzo , Seetharaman Parashuraman, Giovanni D’AngeloAlberto Luini

"GOLPH3 and oncogenesis: What is the molecular link?"

Tissue and Cell / doi:10.1016/j.tice.2016.06.008

 

Abtract

The Golgi phosphoprotein 3 (GOLPH3) is encoded by a gene that is located in a region of the human genome that is often amplified in different solid tumours. GOLPH3, an evolutionary conserved phosphatidylinositol 4-phosphate (PI4P) binding protein, is mainly localised at trans Golgi network (TGN). It regulates several cellular functions like Golgi vesicular trafficking, Golgi glycosylation and mitochondrial cardiolipin production. Recently, GOLPH3 was discovered to be part of the DNA damage response signalling pathway, with a role in cell survival following DNA damage. In this review, we will explore the cellular functions regulated by GOLPH3 and discuss if and how they contribute to the oncogenic activity of this intriguing Golgi localized oncoprotein.