Publications by authors named "Paola Bruni"

79 Publications

Phosphatidic Acid Stimulates Myoblast Proliferation through Interaction with LPA1 and LPA2 Receptors.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country, P.O. Box 644, 48980 Bilbao, Spain.

Phosphatidic acid (PA) is a bioactive phospholipid capable of regulating key biological functions, including neutrophil respiratory burst, chemotaxis, or cell growth and differentiation. However, the mechanisms whereby PA exerts these actions are not completely understood. In this work, we show that PA stimulates myoblast proliferation, as determined by measuring the incorporation of [H]thymidine into DNA and by staining the cells with crystal violet. PA induced the rapid phosphorylation of Akt and ERK1/2, and pretreatment of the cells with specific small interferin RNA (siRNA) to silence the genes encoding these kinases, or with selective pharmacologic inhibitors, blocked PA-stimulated myoblast proliferation. The mitogenic effects of PA were abolished by the preincubation of the myoblasts with pertussis toxin, a Gi protein inhibitor, suggesting the implication of Gi protein-coupled receptors in this action. Although some of the effects of PA have been associated with its possible conversion to lysoPA (LPA), treatment of the myoblasts with PA for up to 60 min did not produce any significant amount of LPA in these cells. Of interest, pharmacological blockade of the LPA receptors 1 and 2, or specific siRNA to silence the genes encoding these receptors, abolished PA-stimulated myoblast proliferation. Moreover, PA was able to compete with LPA for binding to LPA receptors, suggesting that PA can act as a ligand of LPA receptors. It can be concluded that PA stimulates myoblast proliferation through interaction with LPA1 and LPA2 receptors and the subsequent activation of the PI3K/Akt and MEK/ERK1-2 pathways, independently of LPA formation.
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http://dx.doi.org/10.3390/ijms22031452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867176PMC
February 2021

Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes.

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, 50134 Florence, Italy.

Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) plays an important role in skeletal muscle biology. S1P, generated by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK1/2), exerts most of its actions through its specific receptors, S1P. Here, we provide experimental evidence that TNFα induces atrophy and autophagy in skeletal muscle C2C12 myotubes, modulating the expression of specific markers and both active and passive membrane electrophysiological properties. NMR-metabolomics provided a clear picture of the deep remodelling of skeletal muscle fibre metabolism induced by TNFα challenge. The cytokine is responsible for the modulation of S1P signalling axis, upregulating mRNA levels of S1P and S1P and downregulating those of SK2. TNFα increases the phosphorylated form of SK1, readout of its activation. Interestingly, pharmacological inhibition of SK1 and specific antagonism of S1P prevented the increase in autophagy markers and the changes in the electrophysiological properties of C2C12 myotubes without affecting metabolic remodelling induced by the cytokine, highlighting the involvement of S1P signalling axis on TNFα-induced atrophy in skeletal muscle.
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http://dx.doi.org/10.3390/ijms22031280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866171PMC
January 2021

Genome-wide analysis of copy number alterations led to the characterisation of PDCD10 as oncogene in ovarian cancer.

Transl Oncol 2021 Mar 27;14(3):101013. Epub 2021 Jan 27.

Department of Experimental and Clinical Medicine, "Magna Graecia", University Catanzaro, Italy. Electronic address:

Copy Number Alterations (CNAs) represent the most common genetic alterations identified in ovarian cancer cells, being responsible for the extensive genomic instability observed in this cancer. Here we report the identification of CNAs in a cohort of Italian patients affected by ovarian cancer performed by SNP-based array. Our analysis allowed the identification of 201 significantly altered chromosomal bands (70 copy number gains; 131 copy number losses). The 3300 genes subjected to CNA identified here were compared to those present in the TCGA dataset. The analysis allowed the identification of 11 genes with increased CN and mRNA expression (PDCD10, EBAG9, NUDCD1, ENY2, CSNK2A1, TBC1D20, ZCCHC3, STARD3, C19orf12, POP4, UQCRFS1). PDCD10 was selected for further studies because of the highest frequency of CNA. PDCD10 was found, by immunostaining of three different Tissue Micro Arrays, to be over-expressed in the majority of ovarian primary cancer samples and in metastatic lesions. Moreover, significant correlations were found in specific subsets of patients, between increased PDCD10 expression and grade (p < 0.005), nodal involvement (p < 0.05) or advanced FIGO stage (p < 0.01). Finally, manipulation of PDCD10 expression by shRNA in ovarian cancer cells (OVCAR-5 and OVCA429) demonstrated a positive role for PDCD10 in the control of cell growth and motility in vitro and tumorigenicity in vivo. In conclusion, this study allowed the identification of novel genes subjected to copy number alterations in ovarian cancer. In particular, the results reported here point to a prominent role of PDCD10 as a bona fide oncogene.
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http://dx.doi.org/10.1016/j.tranon.2021.101013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846933PMC
March 2021

Sphingosine 1-phosphate signaling in uterine fibroids: implication in activin A pro-fibrotic effect.

Fertil Steril 2021 Jan 23. Epub 2021 Jan 23.

Department of Experimental and Clinical Biomedical Sciences "M. Serio," University of Florence, Florence, Italy.

Objective: To explore the link between sphingosine 1-phosphate (S1P) signaling and leiomyoma and the possible S1P cross-talk with the fibrotic effect of activin A.

Design: Case-control laboratory study.

Setting: University institute and university hospital.

Patient(s): Patients with uterine fibroids (n = 26).

Interventions(s): Tissue specimens of leiomyoma and normal myometrium were obtained from patients undergoing myomectomy or total hysterectomy.

Main Outcome Measure(s): Expression of mRNA levels of the enzyme involved in S1P metabolism, S1P receptors, and S1P transporter Spns2 was evaluated in matched leiomyoma/myometrium specimens and cell populations. The effects of inhibition of S1P metabolism and signaling was evaluated on activin A-induced fibrotic action in leiomyoma cell lines.

Result(s): The expression of the enzymes responsible for S1P formation, sphingosine kinase (SK) 1 and 2, and S1P, S1P, and S1P receptors was significantly augmented in leiomyomas compared with adjacent myometrium. In leiomyoma cells, but not in myometrial cells, activin A increased mRNA expression levels of SK1, SK2, and S1P. The profibrotic action of activin A was abolished when SK1/2 were inhibited or S1P were blocked. Finally, S1P augmented by itself mRNA levels of fibrotic markers (fibronectin, collagen 1A1) and activin A in leiomyomas but not in myometrial cells.

Conclusion(s): This study shows that S1P signaling is dysregulated in uterine fibroids and involved in activin A-induced fibrosis, opening new perspectives for uterine fibroid treatment.
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http://dx.doi.org/10.1016/j.fertnstert.2020.12.022DOI Listing
January 2021

Role of sphingosine 1-phosphate signalling in tissue fibrosis.

Cell Signal 2021 Feb 28;78:109861. Epub 2020 Nov 28.

Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy.

Fibrosis is characterized by the excessive accumulation of extracellular matrix components, leading to loss of tissue function in affected organs. Although the majority of fibrotic diseases have different origins, they have in common a persistent inflammatory stimulus and lymphocyte-monocyte interactions that determine the production of numerous fibrogenic cytokines. Treatment to contrast fibrosis is urgently needed, since some fibrotic diseases lead to systemic fibrosis and represent a major cause of death. In this article, the role of the bioactive sphingolipid sphingosine 1-phosphate (S1P) and its signalling pathway in the fibrosis of different tissue contexts is extensively reviewed, highlighting that it may represent an innovative and promising pharmacological therapeutic target for treating this devastating multifaceted disease. In multiple tissues S1P influences different aspects of fibrosis modulating the recruitment of inflammatory cells, as well as cell proliferation, migration and transdifferentiation into myofibroblasts, the cell type mainly involved in fibrosis development. Moreover, at the level of fibrotic lesions, S1P metabolism is profoundly influenced by multiple cross-talk with profibrotic mediators, such as transforming growth factor β, thus finely regulating the development of fibrosis. This article is part of a Special Issue entitled "Physiological and pathological roles of bioactive sphingolipids".
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http://dx.doi.org/10.1016/j.cellsig.2020.109861DOI Listing
February 2021

Sphingosine 1-phosphate receptors are dysregulated in endometriosis: possible implication in transforming growth factor β-induced fibrosis.

Fertil Steril 2021 Feb 6;115(2):501-511. Epub 2020 Sep 6.

Department of Experimental and Clinical Biomedical Sciences "M. Serio," University of Florence, Florence, Italy.

Objective: To study the molecular mechanisms involved in the appearance of the fibrotic trait in endometriosis by investigating whether the signaling pathway of the bioactive sphingolipid sphingosine 1-phosphate (S1P) was altered in endometriotic lesions.

Design: Case-control laboratory study.

Setting: University research institute and university hospital.

Patient(s): A total of 75 women, with and without endometriosis, were included in the study.

Interventions(s): Endometrial samples were obtained from women affected (n = 15 endometrioma [OMA]; n = 30 deep infiltrating endometriosis [DIE]) and not (n = 30) by endometriosis by means of laparoscopic surgery, followed by clinical and imaging investigation and checking for the expression of fibrosis markers and genes implicated in S1P metabolism and signaling by means of real-time polymerase chain reaction.

Main Outcome Measure(s): The role of the S1P signaling axis in endometriosis-associated fibrosis was studied in vitro, where RNA interference approaches were used to investigate if S1P synthesis by sphingosine kinases (SKs) and specific S1P receptors (S1PRs) are implicated in the profibrotic effect of the cytokine transforming growth factor (TGF) β1.

Result(s): mRNA expression analysis of S1PR demonstrated a deep dysregulation of S1P signaling in endometriosis, characterized by increased expression of fibrosis markers: S1P was transcriptionally more expressed in OMA, and S1P and S1P mRNA levels were significantly augmented in both OMA and DIE. SK1 and its activating protein calcium- and integrin-binding protein 1 (CIB1) were significantly up-regulated in OMA and DIE. A crucial role for the SK/S1PR axis in the profibrotic effect elicited by TGFβ1 was highlighted in vitro.

Conclusion(s): The S1P signaling axis may represent a useful biomarker or innovative pharmacologic target for endometriosis.
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http://dx.doi.org/10.1016/j.fertnstert.2020.08.012DOI Listing
February 2021

Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P receptor axis.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 09 19;1865(9):158759. Epub 2020 Jun 19.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.
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http://dx.doi.org/10.1016/j.bbalip.2020.158759DOI Listing
September 2020

Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor.

ACS Med Chem Lett 2020 May 30;11(5):913-920. Epub 2020 Mar 30.

Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, FI, Italy).

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator associated with diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, mediated by the sphingosine kinase isozymes (SK1 and SK2), is implicated in several pathophysiological conditions and diseases, including skeletal muscle fibrosis, inflammation, multiple sclerosis, and cancer. Therefore, therapeutic approaches that control S1P production have focused on the development of SK1/2 inhibitors. In this framework, we designed a series of natural monosaccharide-based compounds to enhance anchoring of the known SK1 inhibitor PF-543 at the polar head of the substrate-binding channel. Herein, we describe the structure-based design and synthesis of new glycan-containing PF-543 analogues and we demonstrate their efficiency in a TGFβ1-induced pro-fibrotic assay.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236250PMC
May 2020

Adenosine A receptors inhibit K currents and cell differentiation in cultured oligodendrocyte precursor cells and modulate sphingosine-1-phosphate signaling pathway.

Biochem Pharmacol 2020 07 3;177:113956. Epub 2020 Apr 3.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Italy.

Oligodendrocytes are the only myelinating cells in the brain and differentiate from their progenitors (OPCs) throughout adult life. However, this process fails in demyelinating pathologies. Adenosine is emerging as an important player in OPC differentiation and we recently demonstrated that adenosine A receptors inhibit cell maturation by reducing voltage-dependent K currents. No data are available to date about the A receptor (AR) subtype. The bioactive lipid mediator sphingosine-1-phosphate (S1P) and its receptors (S1P) are also crucial modulators of OPC development. An interaction between this pathway and the AR is reported in peripheral cells. We studied the role of ARs in modulating K currents and cell differentiation in OPC cultures and we investigated a possible interplay with S1P signaling. Our data indicate that the AR agonist BAY60-6583 and its new analogue P453 inhibit K currents in cultured OPC and the effect was prevented by the AR antagonist MRS1706, by K channel blockers and was differently modulated by the S1P analogue FTY720-P. An acute (10 min) exposure of OPCs to BAY60-6583 also increased the phosphorylated form of sphingosine kinase 1 (SphK1). A chronic (7 days) treatment with the same agonist decreased OPC differentiation whereas SphK1/2 inhibition exerted the opposite effect. Furthermore, AR was overexpressed during OPC differentiation, an effect prevented by the pan SphK1/2 inhibitor VPC69047. Finally, AR silenced cells showed increased cell maturation, decreased SphK1 expression and enhanced S1P lyase levels. We conclude that ARs inhibit K currents and cell differentiation and positively modulate S1P synthesis in cultured OPCs.
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http://dx.doi.org/10.1016/j.bcp.2020.113956DOI Listing
July 2020

The WD40 repeat protein, WDR36, orchestrates sphingosine kinase-1 recruitment and phospholipase C-β activation by G-coupled receptors.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 07 31;1865(7):158704. Epub 2020 Mar 31.

Institut für Allgemeine Pharmakologie und Toxikologie, Universitätsklinikum, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address:

Sphingosine kinases (SphK) catalyse the formation of sphingosine-1-phosphate (S1P) and play important roles in the cardiovascular, nervous and immune systems. We have shown before that G-coupled receptors induce a rapid and long-lasting translocation of SphK1 to the plasma membrane and cross-activation of S1P receptors. Here, we further addressed G regulation of SphK1 by analysing the influence of the WD40 repeat protein, WDR36. WDR36 has been described as a scaffold tethering Gα to phospholipase C (PLC)-β and the thromboxane A receptor-β (TPβ receptor). Overexpression of WDR36 in HEK-293 cells enhanced TPβ receptor-induced inositol phosphate production, as reported (Cartier et al. 2011), but significantly attenuated inositol phosphate production induced by muscarinic M and bradykinin B receptors. In agreement with its effect on PLCβ, WDR36 augmented TPβ receptor-induced [Ca] increases. Surprisingly, WDR36 also augmented M receptor-induced [Ca] increases, which was due to increased Ca mobilization while the Ca content of thapsigargin-sensitive stores remained unaltered. Interestingly, overexpression of WDR36 significantly delayed SphK1 translocation by G-coupled M, B and H receptors in HEK-293 cells, while TPβ receptor-induced SphK1 translocation was generally slow and not altered by WDR36 in these cells. Finally, in C2C12 myoblasts, overexpression of WDR36 delayed SphK1 translocation induced by B receptors. It is concluded that WDR36 reduces signalling of G-coupled receptors other than TPβ towards PLC and SphK1, most likely by scavenging Gα and PLCβ. Our results support a role of WDR36 in orchestration of G signalling complexes, and might help to functionally unravel its genetic association with asthma and allergy.
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http://dx.doi.org/10.1016/j.bbalip.2020.158704DOI Listing
July 2020

β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P modulation.

Oncogene 2020 01 2;39(2):368-384. Epub 2019 Sep 2.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P signaling.
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http://dx.doi.org/10.1038/s41388-019-0993-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949192PMC
January 2020

Sphingosine 1-phosphate-mediated activation of ezrin-radixin-moesin proteins contributes to cytoskeletal remodeling and changes of membrane properties in epithelial otic vesicle progenitors.

Biochim Biophys Acta Mol Cell Res 2019 04 3;1866(4):554-565. Epub 2019 Jan 3.

Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy. Electronic address:

Hearing loss is among the most prevalent sensory impairments in humans. Cochlear implantable devices represent the current therapies for hearing loss but have various shortcomings. ERM (ezrin- radixin -moesin) are a family of adaptor proteins that link plasma membrane with actin cytoskeleton, playing a crucial role in cell morphology and in the formation of membrane protrusions. Recently, bioactive sphingolipids have emerged as regulators of ERM proteins. Sphingosine 1-phosphate (S1P) is a pleiotropic sphingolipid which regulates fundamental cellular functions such as proliferation, survival, migration as well as processes such as development and inflammation mainly via ligation to its specific receptors S1PR (S1P). Experimental findings demonstrate a key role for S1P signaling axis in the maintenance of auditory function. Preservation of cellular junctions is a fundamental function both for S1P and ERM proteins, crucial for the maintenance of cochlear integrity. In the present work, S1P was found to activate ERM in a S1P-dependent manner in murine auditory epithelial progenitors US/VOT-E36. S1P-induced ERM activation potently contributed to actin cytoskeletal remodeling and to the appearance of ionic currents and membrane passive properties changes typical of more differentiated cells. Moreover, PKC and Akt activation was found to mediate S1P-induced ERM phosphorylation. The obtained findings contribute to demonstrate the role of S1P signaling pathway in inner ear biology and to disclose potential innovative therapeutical approaches in the field of hearing loss prevention and treatment.
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http://dx.doi.org/10.1016/j.bbamcr.2018.12.007DOI Listing
April 2019

Increased Total Serum Immunoglobulin E in Children Developing Mycoplasma pneumoniae-related Extra-pulmonary Diseases.

Iran J Allergy Asthma Immunol 2018 Oct 9;17(5):490-496. Epub 2018 Oct 9.

Department of Pediatrics, IRCCS Fondazione Policlinico San Matteo e Universita' Degli Studi di Pavia, Pavia, Italy AND Department of Pediatrics, ASST Melegnano e Martesana, Vizzolo Predabissi, Milano, Italy.

Mycoplasma pneumoniae has been recognized to be involved in several extra-pulmonary diseases, but the underlying immunologic mechanisms are still largely unknown. Recently, we observed a significant elevation of serum Immunoglobulin E (IgE) in a small group of these children. Here, we assessed total serum IgE levels in children affected with Mycoplasma pneumoniae-related extra-pulmonary diseases. We prospectively collected the data of 162 children admitted to the hospital (because of respiratory infections or extra-pulmonary diseases) who were evaluated for Mycoplasma pneumoniae serology and total serum IgE levels, concomitantly. Based upon clinical and serology aspects, 3 groups of children were identified: I) with non-mycoplasma respiratory disease; II) with mycoplasma-related respiratory diseases; III) with extra-pulmonary diseases related to concomitant/recent Mycoplasma pneumoniae infection. Interestingly, children with Mycoplasma pneumoniae-related extra-pulmonary diseases showed a significant elevation of total serum IgE. In particular, patients developing Mycoplasma pneumoniae-related extra-pulmonary diseases (group III) showed significantly higher level of IgE than both previous groups (p<0.001 vs. group I; p<0.01 vs. group II). In conclusion, hospitalized children diagnosed with Mycoplasma pneumoniae-related extra-pulmonary diseases resulted to have significantly increased serum IgE compared to children developing respiratory illnesses only.
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October 2018

Bradykinin mediates myogenic differentiation in murine myoblasts through the involvement of SK1/Spns2/S1P axis.

Cell Signal 2018 05 3;45:110-121. Epub 2018 Feb 3.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale GB Morgagni 50, 50134 Firenze, Italy; Istituto interuniversitario di Miologia, IIM, Padova, Italy.

Skeletal muscle tissue retains a remarkable regenerative capacity due to the activation of resident stem cells that in pathological conditions or after tissue damage proliferate and commit themselves into myoblasts. These immature myogenic cells undergo differentiation to generate new myofibers or repair the injured ones, giving a strong contribution to muscle regeneration. Cytokines and growth factors, potently released after tissue injury by leukocytes and macrophages, are not only responsible of the induction of the initial inflammatory response, but can also affect skeletal muscle regeneration. Growth factors exploit sphingosine kinase (SK), the enzyme that catalyzes the production of sphingosine 1-phosphate (S1P), to exert their biological effects in skeletal muscle. In this paper we show for the first time that bradykinin (BK), the leading member of kinin/kallikrein system, is able to induce myogenic differentiation in C2C12 myoblasts. Moreover, evidence is provided that SK1, the specific S1P-transporter spinster homolog 2 (Spns2) and S1P receptor are involved in the action exerted by BK, since pharmacological inhibition/antagonism or specific down-regulation significantly alter BK-induced myogenic differentiation. Moreover, the molecular mechanism initiated by BK involves a rapid translocation of SK1 to plasma membrane, analyzed by time-lapse immunofluorescence analysis. The present study highlights the role of SK1/Spns2/S1P receptor 2 signaling axis in BK-induced myogenic differentiation, thus confirming the crucial involvement of this pathway in skeletal muscle cell biology.
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http://dx.doi.org/10.1016/j.cellsig.2018.02.001DOI Listing
May 2018

Lysophosphatidic Acid Signaling Axis Mediates Ceramide 1-Phosphate-Induced Proliferation of C2C12 Myoblasts.

Int J Mol Sci 2018 Jan 4;19(1). Epub 2018 Jan 4.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.

Sphingolipids are not only crucial for membrane architecture but act as critical regulators of cell functions. The bioactive sphingolipid ceramide 1-phosphate (C1P), generated by the action of ceramide kinase, has been reported to stimulate cell proliferation, cell migration and to regulate inflammatory responses via activation of different signaling pathways. We have previously shown that skeletal muscle is a tissue target for C1P since the phosphosphingolipid plays a positive role in myoblast proliferation implying a role in muscle regeneration. Skeletal muscle displays strong capacity of regeneration thanks to the presence of quiescent adult stem cells called satellite cells that upon trauma enter into the cell cycle and start proliferating. However, at present, the exact molecular mechanism by which C1P triggers its mitogenic effect in myoblasts is lacking. Here, we report for the first time that C1P stimulates C2C12 myoblast proliferation via lysophosphatidic acid (LPA) signaling axis. Indeed, C1P subsequently to phospholipase A2 activation leads to LPA₁ and LPA₃ engagement, which in turn drive Akt (protein kinase B) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation, thus stimulating DNA synthesis. The present findings shed new light on the key role of bioactive sphingolipids in skeletal muscle and provide further support to the notion that these pleiotropic molecules might be useful therapeutic targets for skeletal muscle regeneration.
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http://dx.doi.org/10.3390/ijms19010139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796088PMC
January 2018

Pertussis manifesting as recurrent cough and wheezing in an incompletely vaccinated 8-month-old infant.

BMJ Case Rep 2017 Oct 9;2017. Epub 2017 Oct 9.

Department of Pediatrics, ASST Melegnano e Martesana, Vizzolo Predabissi, Italy.

Pertussis is an acute respiratory illness caused by , showing a re-emergence in developed countries. However, it is probably under-recognised and, as a consequence, its burden is underestimated. Here, we report the clinical case of an infant diagnosed with pertussis, despite a regular schedule of vaccination, thanks to a careful clinical evaluation, including personal and family history. In addition to pointing the attention on a precocious diagnosis of atypical cases of pertussis, this case report further raised the issue of modifying and/or implementing the immunisation strategy, considering the ongoing changes of social (eg, immigration) and sanitary (eg, vaccine coverage) background in Italy and all over the Europe.
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http://dx.doi.org/10.1136/bcr-2017-221562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652862PMC
October 2017

-induced rash and mucositis (MIRM): an unusual mild skin rash associated with severe mucosal involvement.

BMJ Case Rep 2017 May 27;2017. Epub 2017 May 27.

Pediatrics, Ospedale di Circolo di Melegnano, Vizzolo Predabissi, Italy.

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http://dx.doi.org/10.1136/bcr-2017-220749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623314PMC
May 2017

Ablation of S1P receptor protects mouse soleus from age-related drop in muscle mass, force, and regenerative capacity.

Am J Physiol Cell Physiol 2017 Jul 26;313(1):C54-C67. Epub 2017 Apr 26.

Department of Biomedical Sciences, University of Padova, Padua, Italy;

We investigated the effects of S1P deficiency on the age-related atrophy, decline in force, and regenerative capacity of soleus muscle from 23-mo-old male (old) mice. Compared with muscle from 5-mo-old (adult) mice, soleus mass and muscle fiber cross-sectional area (CSA) in old wild-type mice were reduced by ~26% and 24%, respectively. By contrast, the mass and fiber CSA of soleus muscle in old S1P-null mice were comparable to those of adult muscle. Moreover, in soleus muscle of wild-type mice, twitch and tetanic tensions diminished from adulthood to old age. A slowing of contractile properties was also observed in soleus from old wild-type mice. In S1P-null mice, neither force nor the contractile properties of soleus changed during aging. We also evaluated the regenerative capacity of soleus in old S1P-null mice by stimulating muscle regeneration through myotoxic injury. After 10 days of regeneration, the mean fiber CSA of soleus in old wild-type mice was significantly smaller (-28%) compared with that of regenerated muscle in adult mice. On the contrary, the mean fiber CSA of regenerated soleus in old S1P-null mice was similar to that of muscle in adult mice. We conclude that in the absence of S1P, soleus muscle is protected from the decrease in muscle mass and force, and the attenuation of regenerative capacity, all of which are typical characteristics of aging.
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http://dx.doi.org/10.1152/ajpcell.00027.2017DOI Listing
July 2017

NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells.

Mol Oncol 2017 05 30;11(5):517-533. Epub 2017 Mar 30.

CERM and Department of Chemistry, University of Florence, Italy.

Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR-based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
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http://dx.doi.org/10.1002/1878-0261.12048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527469PMC
May 2017

Sphingosine 1-phosphate signaling axis mediates fibroblast growth factor 2-induced proliferation and survival of murine auditory neuroblasts.

Biochim Biophys Acta Mol Cell Res 2017 May 7;1864(5):814-824. Epub 2017 Feb 7.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "M. Serio", viale G B Morgagni 50, 50134 Firenze, Italy.

Hearing loss affects millions of people in the world. In mammals the auditory system comprises diverse cell types which are terminally differentiated and with no regenerative potential. There is a tremendous research interest aimed at identifying cell therapy based solutions or pharmacological approaches that could be applied therapeutically alongside auditory devices to prevent hair cell and neuron loss. Sphingosine 1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that plays key role in the regulation of many physiological and pathological functions. S1P is intracellularly produced by sphingosine kinase (SK) 1 and SK2 and exerts many of its action consequently to its ligation to S1P specific receptors (S1PR), S1P. In this study, murine auditory neuroblasts named US/VOT-N33 have been used as progenitors of neurons of the spiral ganglion. We demonstrated that the fibroblast growth factor 2 (FGF2)-induced proliferative action was dependent on SK1, SK2 as well as S1P and S1P. Moreover, the pro-survival effect of FGF2 from apoptotic cell death induced by staurosporine treatment was dependent on SK but not on S1PR. Additionally, ERK1/2 and Akt signaling pathways were found to mediate the mitogenic and survival action of FGF2, respectively. Taken together, these findings demonstrate a crucial role for S1P signaling axis in the proliferation and the survival of otic vesicle neuroprogenitors, highlighting the identification of possible novel therapeutical approaches to prevent neuronal degeneration during hearing loss.
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http://dx.doi.org/10.1016/j.bbamcr.2017.02.004DOI Listing
May 2017

Postnatal cytomegalovirus infection in an infant with congenital thrombocytopenia: how it can support or mislead the diagnosis of Wiskott-Aldrich syndrome.

Infez Med 2016 Sep;24(3):237-40

Department of Paediatrics, Azienda Ospedaliera di Melegnano, Milan, Italy.

A male newborn developed a post-natal cytomegalovirus (CMV) infection, arising in the clinical setting of congenital thrombocytopenia, which was diagnosed as being alloimmune. The evidence of active CMV infection in an infant showing slow-resolution lower airways infection, persistent neonatal and low platelet volume thrombocytopenia, and diffuse eczema (associated to very high levels of serum immunoglobulin E) led to the diagnosis of Wiskott-Aldrich syndrome (WAS) before the third month of life, despite the presence of several confounding clinical factors. The correct interpretation of all clinical features supported the precocious diagnosis of WAS.
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September 2016

Paediatric Dengue Fever diagnosed through parents' epidemiologic report and preventive strategy during the acute phase of infection.

J Travel Med 2016 Jan 18;23(1). Epub 2016 Jan 18.

Department of Pediatrics, Azienda Ospedaliera di Melegnano, Vizzolo Predabissi, Milan, Italy.

In Europe, Dengue Fever is one of the most frequent imported diseases and also autochthonous cases occurred in areas where the insect vector is present. Here, we describe a child returning from Philippines and diagnosed with Dengue Fever, through the information provided by parents about an ongoing outbreak in their municipality. An appropriate clinical management in the hospital was established to monitor the occurrence of complications and to cancel the risk of dengue virus transmission in the acute phase of infection.
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http://dx.doi.org/10.1093/jtm/tav013DOI Listing
January 2016

Sequential protein expression and selective labeling for in-cell NMR in human cells.

Biochim Biophys Acta 2016 Mar 23;1860(3):527-33. Epub 2015 Dec 23.

Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy.

Background: In-cell NMR is a powerful technique to investigate proteins in living human cells at atomic resolution. Ideally, when studying functional processes involving protein-protein interactions by NMR, only one partner should be isotopically labeled. Here we show that constitutive and transient protein expression can be combined with protein silencing to obtain selective protein labeling in human cells.

Methods: We established a human cell line stably overexpressing the copper binding protein HAH1. A second protein (human superoxide dismutase 1, SOD1) was overexpressed by transient transfection and isotopically labeled. A silencing vector containing shRNA sequences against the HAH1 gene was used to decrease the rate of HAH1 synthesis during the expression of SOD1. The levels of HAH1 mRNA and protein were measured as a function of time following transfection by RT-PCR and Western Blot, and the final cell samples were analyzed by in-cell NMR.

Results: SOD1 was ectopically expressed and labeled in a time window during which HAH1 biosynthesis was strongly decreased by shRNA, thus preventing its labeling. In-cell NMR spectra confirmed that, while both proteins were present, only SOD1 was selectively labeled and could be detected by (1)H-(15)N heteronuclear NMR.

Conclusions And General Significance: We showed that controlling protein expression by specifically silencing a stably expressed protein is a useful strategy to obtain selective isotope labeling of only one protein. This approach relies on established techniques thus permitting the investigation of protein-protein interactions by NMR in human cells.
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http://dx.doi.org/10.1016/j.bbagen.2015.12.023DOI Listing
March 2016

S1P3 receptor influences key physiological properties of fast-twitch extensor digitorum longus muscle.

J Appl Physiol (1985) 2016 Jun 30;120(11):1288-300. Epub 2015 Dec 30.

Department of Biomedical Sciences, University of Padova, Padova, Italy; IIM, Interuniversity Institute of Myology, Italy;

To examine the role of sphingosine 1-phosphate (S1P) receptor 3 (S1P3) in modulating muscle properties, we utilized transgenic mice depleted of the receptor. Morphological analyses of extensor digitorum longus (EDL) muscle did not show evident differences between wild-type and S1P3-null mice. The body weight of 3-mo-old S1P3-null mice and the mean cross-sectional area of transgenic EDL muscle fibers were similar to those of wild-type. S1P3 deficiency enhanced the expression level of S1P1 and S1P2 receptors mRNA in S1P3-null EDL muscle. The contractile properties of S1P3-null EDL diverge from those of wild-type, largely more fatigable and less able to recover. The absence of S1P3 appears responsible for a lower availability of calcium during fatigue. S1P supplementation, expected to stimulate residual S1P receptors and signaling, reduced fatigue development of S1P3-null muscle. Moreover, in the absence of S1P3, denervated EDL atrophies less than wild-type. The analysis of atrophy-related proteins in S1P3-null EDL evidences high levels of the endogenous regulator of mitochondria biogenesis peroxisome proliferative-activated receptor-γ coactivator 1α (PGC-1α); preserving mitochondria could protect the muscle from disuse atrophy. In conclusion, the absence of S1P3 makes the muscle more sensitive to fatigue and slows down atrophy development after denervation, indicating that S1P3 is involved in the modulation of key physiological properties of the fast-twitch EDL muscle.
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http://dx.doi.org/10.1152/japplphysiol.00345.2015DOI Listing
June 2016

Urinary Schistosomiasis in an Adolescent Refugee from Africa: An Uncommon Cause of Hematuria and an Emerging Infectious Disease in Europe.

J Immigr Minor Health 2016 10;18(5):1237-1240

Department of Pediatrics, Azienda Ospedaliera di Melegnano, via Pandina 1, 20070, Vizzolo Predabissi, MI, Italy.

We report a case of urinary schistosomiasis in an adolescent refugee from Gambia (arrived to Italy illegally), who was brought to the Emergency Department of our hospital. The patient complained of gross hematuria and, in the absence of clinical evidence of bacterial urinary infection, was admitted to the pediatric ward, considering his provenience and social setting. An appropriate collection and microscopic analysis of urine samples led to the detection of bilharzia. Much attention should be paid to this emerging disease in Europe by physicians in order to recognize and treat it timely, which could prevent future and higher costs for public health systems and could reduce the potential risk of environmental spreading. In fact, there are some areas in Italy where the parasite can find its intermediate host to complete its lifecycle.
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http://dx.doi.org/10.1007/s10903-015-0272-3DOI Listing
October 2016

β-Thalassemia Intermedia Associated with Heterozygous and Isolate β-Globin Gene Mutation [IVS-II-1 (HBB: c.315G>A)].

Hemoglobin 2015 21;39(5):366-7. Epub 2015 Jul 21.

a Department of Pediatrics , Azienda Ospedaliera di Melegnano , Milan , Italy.

A 4-year-old male child of Caucasian ethnicity was investigated for moderate hemolytic and non immune-mediated anemia. The presence of splenomegaly and the elevation of Hb A(2) and Hb F and the exclusion of a defect of protein of red blood cell (RBC) membranes defined a clinical picture of β-thalassemia intermedia (β-TI). The molecular analysis showed a heterozygous IVS-II-1 (HBB: c.315G > A) mutation on the β-globin gene, in the absence of extra α-globin genes or unstable hemoglobin (Hb) chains.
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http://dx.doi.org/10.3109/03630269.2015.1062776DOI Listing
June 2016

Sphingosine 1-phosphate signaling pathway in inner ear biology. New therapeutic strategies for hearing loss?

Front Aging Neurosci 2015 23;7:60. Epub 2015 Apr 23.

Department Scienze Biomediche Sperimentali e Cliniche "Mario Serio", University of Florence Firenze, Italy.

Hearing loss is one of the most prevalent conditions around the world, in particular among people over 60 years old. Thus, an increase of this affection is predicted as result of the aging process in our population. In this context, it is important to further explore the function of molecular targets involved in the biology of inner ear sensory cells to better individuate new candidates for therapeutic application. One of the main causes of deafness resides into the premature death of hair cells and auditory neurons. In this regard, neurotrophins and growth factors such as insulin like growth factor are known to be beneficial by favoring the survival of these cells. An elevated number of published data in the last 20 years have individuated sphingolipids not only as structural components of biological membranes but also as critical regulators of key biological processes, including cell survival. Ceramide, formed by catabolism of sphingomyelin (SM) and other complex sphingolipids, is a strong inducer of apoptotic pathway, whereas sphingosine 1-phosphate (S1P), generated by cleavage of ceramide to sphingosine and phosphorylation catalyzed by two distinct sphingosine kinase (SK) enzymes, stimulates cell survival. Interestingly S1P, by acting as intracellular mediator or as ligand of a family of five distinct S1P receptors (S1P1-S1P5), is a very powerful bioactive sphingolipid, capable of triggering also other diverse cellular responses such as cell migration, proliferation and differentiation, and is critically involved in the development and homeostasis of several organs and tissues. Although new interesting data have become available, the information on S1P pathway and other sphingolipids in the biology of the inner ear is limited. Nonetheless, there are several lines of evidence implicating these signaling molecules during neurogenesis in other cell populations. In this review, we discuss the role of S1P during inner ear development, also as guidance for future studies.
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http://dx.doi.org/10.3389/fnagi.2015.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407579PMC
May 2015

Endothelial sphingosine kinase/SPNS2 axis is critical for vessel-like formation by human mesoangioblasts.

J Mol Med (Berl) 2015 Oct 9;93(10):1145-57. Epub 2015 May 9.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy.

Unlabelled: The interaction between endothelial cells and pericytes is crucial for the stabilization of newly formed vessels in angiogenesis. The comprehension of the mechanisms regulating pericyte recruitment might open therapeutical perspectives on vascular-related pathologies. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that derives from sphingomyelin catabolism and regulates biological functions in cell survival, proliferation, and differentiation. In this study, we aimed to identify the role of S1P axis in the intercellular communication between human mesenchymal progenitor mesoangioblasts (MAB) and endothelial cells (human microvascular endothelial cells (H-MVEC)) in the formation of capillary-like structures. We demonstrated that the S1P biosynthetic pathway brought about by sphingosine kinases (SK) SK1 and SK2 as well as spinster homolog 2 (SPNS2) transporter in H-MVEC is crucial for MAB migration measured by Boyden chambers and for the formation and stabilization of capillary-like structures in a 3D Matrigel culture. Moreover, the conditioned medium (CM) harvested from H-MVEC, where SK1, SK2, and SPNS2 were down-regulated, exerted a significantly diminished effect on MAB capillary morphogenesis and migration. Notably, we demonstrated that S1P1 and S1P3 receptors were positively involved in CM-induced capillary-like formation and migration, while S1P2 exerted a negative role on CM-induced migratory action of MAB. Finally, SK inhibition as well as MAB S1P1 and S1P3 down-regulation impaired H-MVEC-MAB cross-talk significantly reducing in vivo angiogenesis evaluated by Matrigel plug assay. These findings individuate novel targets for the employment of MAB in vascular-related pathologic conditions.

Key Message: • Down-regulation of SK1/2 in H-MVEC impaired vessel formation when cultured with MAB. • H-MVEC SPNS2 is critical for morphogenesis and migration induced by H-MVEC CM of MAB. • CM from SK1- and SK2-siRNA H-MVEC impaired morphogenesis and migration of MAB. • S1P1/3 were involved on CM-induced morphogenesis and migration of MAB. • Matrigel plug assay showed the role of S1P axis in MAB-endothelial cell interaction.
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http://dx.doi.org/10.1007/s00109-015-1292-0DOI Listing
October 2015

CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFβ.

Biochim Biophys Acta 2015 Feb 29;1851(2):194-202. Epub 2014 Nov 29.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy; Istituto Interuniversitario di Miologia, Italy. Electronic address:

The matricellular protein connective tissue growth factor (CTGF/CCN2) is recognized as key player in the onset of fibrosis in various tissues, including skeletal muscle. In many circumstances, CTGF has been shown to be induced by transforming growth factor beta (TGFβ) and accounting, at least in part, for its biological action. In this study it was verified that in cultured myoblasts CTGF/CCN2 causes their transdifferentiation into myofibroblasts by up-regulating the expression of fibrosis marker proteins α-smooth muscle actin and transgelin. Interestingly, it was also found that the profibrotic effect exerted by CTGF/CCN2 was mediated by the sphingosine kinase (SK)-1/S1P3 signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P3 became the S1P receptor subtype expressed at the highest degree, at least at mRNA level, and was thus capable of readdressing the sphingosine 1-phosphate signaling towards fibrosis rather than myogenic differentiation. Another interesting finding is that CTGF/CCN2 silencing prevented the TGFβ-dependent up-regulation of SK1/S1P3 signaling axis and strongly reduced the profibrotic effect exerted by TGFβ, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGFβ challenge in the transmission of at least part of its profibrotic effect. These results provide new insights into the molecular mechanism by which CTGF/CCN2 drives its biological action and strengthen the concept that SK1/S1P3 axis plays a critical role in the onset of fibrotic cell phenotype.
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http://dx.doi.org/10.1016/j.bbalip.2014.11.011DOI Listing
February 2015

A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) presenting as a somatoform disorder?

Immunol Res 2014 Dec;60(2-3):236-46

Department of Pediatrics, Azienda Ospedaliera di Melegnano, Milan, Italy,

In last centuries, vaccines reduced the incidence of several infectious diseases. In last decades, some vaccines aimed at preventing also some cancers, where viruses play a causative role. However, several adverse events have been described after vaccines, but a causal relationship has been established only in a minority of cases. Here, we describe a pseudo-neurological syndrome occurred shortly after the administration of the bivalent HPV vaccine. Some autoimmune disorders, including neurological demyelinating diseases, have been reported after HPV vaccines, but the patient showed no organic lesions. The patient was diagnosed as having a functional somatoform syndrome, which was supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA), seen the temporal link with vaccination and the presence of anti-phospholipid autoantibodies. Immunological mechanisms of vaccines-and of adjuvants-have not been completely elucidated yet, and although there is no evidence of statistical association with many post-vaccination events, a causal link with vaccine cannot be excluded in some individuals.
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http://dx.doi.org/10.1007/s12026-014-8575-3DOI Listing
December 2014