Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r²=0.98–1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml⁻¹ of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=−0.06, P-value=2.7 × 10⁻⁴). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections

Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets. Monzio Compagnoni et al. present an iPSC-based neuronal in vitro model of multiple system atrophy. Patients' dopaminergic neurons display a dysregulation of mitochondrial functioning and autophagy, suggesting new hints for the comprehension of the pathogenesis of the disease

ll viaggio di Nixon in Cina e l'avvio e sviluppo delle relazioni Cina-USA (1972-2022), dossier della rivista Nuova Secondaria

Una rassegna, con breve introduzione dei curatori, di questioni varie nelle relazioni Cina-USA 1972-202

Crosstalk between sphingosine-1-phosphate and EGFR signalling pathways enhances human glioblastoma cell invasiveness

We show that glioblastoma multiform (GBM) cells overexpressing the constitutively active form of the epidermal growth factor receptor (EGFRvIII; EGFR+ cells) possess greater invasive properties and have higher levels of extracellular sphingosine-1-phosphate (S1P) and increased sphingosine kinase-1 (SK1) activity than the empty vector-expressing cells. Notably, the inhibition of SK1 or S1P receptors decreases the invasiveness of EGFR+ cells. Moreover, EGFR and MEK1 inhibitors reduce both SK1 activation and cell invasion suggesting that the enhanced invasiveness observed in the EGFR+ cells depends on the increased S1P secretion, downstream of the EGFRvIII-ERK-SK1-S1P pathway. Altogether, our study indicates that in glioblastoma multiform cells, EGFRvIII is connected with the S1P signaling pathway to enhance cell invasiveness and tumor progression

Sphingosine-1-P and its plasma membrane receptors in human glioma cells

Glioblastoma multiforme (GBMs), the most frequent and deadly brain tumors in humans, are characterized by extended invasiveness and cell growth. Different sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), have emerged as active mediators in the complex network of signaling pathways involved in the control of physiological and pathological cell behavior (1). Increasing evidence supports that S1P is implicated in sustaining cell invasiveness. On the other side, various growth factor receptors, such as EGFR, are frequently mutated and/or overexpressed in GBMs (2). Very importantly, S1P is able to regulate EGFR expression in lung adenocarcinoma and rat vascular smooth muscle cells suggesting the existence of a cross-talk between the S1P axis and growth factor signaling pathways induced by EGF in tumors. We investigated the crosstalk between S1P and the EGF/EGFR pathways, focusing on its role in glioma invasiveness. We used U87MG human GBMs cell line overexpressing EGF receptor (EGFR+). EGFR+ cells are characterized by increased levels of extracellular S1P and an higher expression of the active SK-1 form (phosphorylated SK-1). These cells showed increased ability to invade into Matrigel. The high chemioinvasion ability as well as spheroids sprouting were significantly inhibited in EGFR+ cells treated with SK inhibitors, or with S-FTY720-vinylphosphonate, the antagonist of S1P receptors. Moreover, we found that S1P added to the cell medium maintained the ability to drastically increase invasion in EGFR+ cells treated with SK inhibitors. At variance, S1P did not induced invasion over the basal values when glioma cells were treated with FTY720. Altogether our data strongly suggest that increased S1P secretion and signalling associated with EGFR overexpression/iperactivation play an important role in EGFR+ glioblastoma invasiveness by enhancing the invasion potential of GBM. References 1. Giussani et al. (2014) Int. J. Mol. Sci., 15, 4356 2. Zahonero et al (2014) Cell Mol Life Sci. 71, 346

Crosstalk between S1P and EGFR signalling pathways in human glioma cell invasiveness

Glioblastoma multiforme (GBMs), the most frequent and deadly brain tumor in humans, are characterized by extended invasiveness and cell growth. Further elucidation of signaling pathways responsible for the malignant phenotype and resistance to therapy will therefore represent a significant advance in GBM treatment and prognosis. Different sphingolipid metabolites, such as ceramide (Cer), and sphingosine-1-phosphate (S1P), have emerged as active mediators in the complex network of signaling pathways involved in the control of physiological and pathological cell behaviour. Increasing evidence supports that S1P is implicated in sustaining cell survival and invasiveness. On the other side, various growth factor receptors are frequently mutated and/or overexpressed in GBMs. Very importantly, S1P is able to regulate EGFR expression in lung adenocarcinoma and rat vascular smooth muscle cells. These results suggest the existence of a cross-talk between the S1P axis and growth factor signaling pathways induced by EGF in tumors. We investigated the crosstalk between S1P and the EGF/EGFR pathways, focusing on its role in glioma tumor invasiveness. We used U87MG human GBMs cell line overexpressing EGF receptor (EGFR+) or empty vector (EGFR-). EGFR+ cells are characterized by increased levels of extracellular S1P, a slightly higher sphingosine kinase-1 (SK-1) activity, and an higher expression of the active SK-1 form (phosphorylated SK-1). These cells showed increased ability to invade into Matrigel in comparison with EGFR- cells. The high chemioinvasion ability as well as spheroids sprouting were significantly inhibited in EGFR+ cells treated with SK inhibitors (SKI and PF543), or with S-FTY720-vinylphosphonate, the antagonist of S1P1\u20133-5 receptors. Moreover, we found that S1P added to the cell medium maintained the ability to drastically increase invasion in EGFR+ cells treated with SKI or PF543. At variance, S1P did not induced invasion over the basal values when glioma cells were treated with FTY720. Altogether our data strongly suggest that increased S1P secretion and signalling associated with EGFR overexpression/iperactivation play an important role in EGFR+ glioblastoma invasiveness by enhancing the invasion potential of GBM. This study was supported by Piano di sostegno alla ricerca BIOMETRA \u2013 Linea B (grant 15-6-3003005-31) to PG

The Glycosphingolipid Hydrolases in the Central Nervous System

Glycosphingolipids are a large group of complex lipids particularly abundant in the outer layer of the neuronal plasma membranes. Qualitative and quantitative changes in glycosphingolipids have been reported along neuronal differentiation and aging. Their half-life is short in the nervous system and their membrane composition and content are the result of a complex network of metabolic pathways involving both the de novo synthesis in the Golgi apparatus and the lysosomal catabolism. In particular, most of the enzymes of glycosphingolipid biosynthesis and catabolism have been found also at the plasma membrane level. Their action could be responsible for the fine tuning of the plasma membrane glycosphingolipid composition allowing the formation of highly specialized membrane areas, such as the synapses and the axonal growth cones. While the correlation between the changes of GSL pattern and the modulation of the expression/activity of different glycosyltransferases during the neuronal differentiation has been widely discussed, the role of the glycohydrolytic enzymes in this process is still little explored. For this reason, in the present review, we focus on the main glycolipid catabolic enzymes \u3b2-hexosaminidases, sialidases, \u3b2-galactosidases, and \u3b2-glucocerebrosidases in the process of the neuronal differentiation