12 research outputs found

    Investigation of a new tumor-associated glycosylated antigen as target for dendritic cell vaccination in pancreatic cancer

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    Glycoproteins, as valuable targets for dendritic cell (DC)-vaccination in cancers, remain an open question. Glycosylated structures, which are aberrantly modified during cancerisation, impact positively or negatively on glycoprotein immunogenicity. Here is presented an oncofetal glycovariant of bile-salt-dependent-lipase, expressed on human tumoral pancreas and efficiently processed by DC’s, inducing T-lymphocyte activation

    Exosomal Lipids Impact Notch Signaling and Induce Death of Human Pancreatic Tumoral SOJ-6 Cells

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    International audienceExosomes are of increasing interest as alternative mode of cell-to-cell communication. We previously reported that exosomes secreted by human SOJ-6 pancreatic tumor cells induce (glyco)protein ligand-independent cell death and inhibit Notch-1 pathway, this latter being particularly active during carcinogenesis and in cancer stem cells. Therefore, we asked whether exosomal lipids were key-elements for cell death and hypothesized that cholesterol-rich membrane microdomains were privileged sites of exosome interactions with tumor cells. To address these questions and based on the lipid composition of exosomes from SOJ-6 cells (Ristorcelli et al. (2008) FASEB J. 22; 3358-3369) enriched in cholesterol and sphingomyelin (lipids forming liquid-ordered phase, Lo) and depleted in phospholipids (lipids forming liquid-disordered phase, Ld), we designed Synthetic Exosome-Like Nanoparticles (SELN) with ratios Lo/Ld from 3.0 to 6.0 framing that of SOJ-6 cell exosomes. SELN decreased tumor cell survival, the higher the Lo/Ld ratio, the lower the cell survival. This decreased survival was due to activation of cell death with inhibition of Notch pathway. FRET analyses indicated fusions/exchanges of SELN with cell membranes. Fluorescent SELN co-localized with the ganglioside GM1 then with Rab5A, markers of lipid microdomains and of early endosomes, respectively. These interactions occurred at lipid microdomains of plasma and/or endosome membranes where the Notch-1 pathway matures. We thus demonstrated a major role for lipids in interactions between SELN and tumor cells, and in the ensued cell death. To our knowledge this is the first report on such effects of lipidic nanoparticles on tumor cell behavior. This may have implications in tumor progression

    Cerebral Biochemical Pathways in Experimental Autoimmune Encephalomyelitis and Adjuvant Arthritis: A Comparative Metabolomic Study

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    <div><p>Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund’s adjuvant (CFA) and spinal-cord homogenate (SC-H), whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group). Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, <em>N</em>-acetylaspartate, were decreased, and the astrocyte marker, <em>myo</em>-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE) or extra-cerebral (AA) inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and/or due to the presence of systemic proinflammatory molecules. Regardless of the nature of these mechanisms, our findings may be of interest for future clinical studies, e.g. by <em>in-vivo</em> magnetic resonance spectroscopy.</p> </div

    Significant differences in brain metabolite concentrations.

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    <p>Pairwise comparisons between rats inoculated with CFA or CFA/SC-H, and control animals. Upward (downward) arrows indicate increased (decreased) relative concentrations for the first vs. the second group compared in each column, except for C−/E-PL and PL<sub>tot</sub> (ratios and absolute concentrations, respectively). All differences shown in this table were statistically significant at the P<0.05 level in tests other than Newman-Keuls and Bonferroni, except for metabolites given in <i>italics</i> (P<0.05 in Newman-Keuls tests only), and preceded by an asterisk (P<0.1 in Bonferroni tests). For complete statistical results see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s005" target="_blank">Tables S1</a> to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s010" target="_blank">S6</a> and Section S1.3. Abbreviations: GroPtdCho, the sum of all PLs derived from PtdCho; PtdIns_sum, the sum of PtdIns and an associated PL, probably derived from PtdIns. For further abbreviations see text, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s005" target="_blank">Tables S1</a> D and S4 D.</p

    GFAP and IBA 1 immunoreactivity in brain sections.

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    <p>Images A, C and E illustrate GFAP immunoreactivity in brain sections from control, CFA and CFA/SC-H rats, respectively. Astrocytes appear similar for control and CFA rats (A and C, respectively). Reactive astrocytosis in the CFA/SC-H rat brain is depicted in image E. Images B, D and F illustrate IBA 1 immunoreactivity in brain sections from control, CFA and CFA/SC-H rats, respectively. Microglial cell size and number appear to be similar in the control and CFA rat brain (B and D, respectively). The reactive microgliosis in the CFA/SC-H rat brain is depicted in image F. Immunoreactivity for microglial cells is particularly dense in perivascular areas (lower right of image F).</p

    Absolute and relative concentrations of the most relevant water-soluble rat brain metabolites in control animals, animals injected with CFA, and animals showing clinical signs of EAE with score 4 after CFA/SC-H injection (means and standard errors).

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    <p>Unbracketed asterisks indicate statistically significant differences between the CFA or CFA/SC-H group on the one hand and the control group on the other, based on the tests given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone-0056101-t001" target="_blank">Table 1</a>. Bracketed asterisks indicate significant differences between the combined values of two groups and values of the remaining group, based on the tests given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s007" target="_blank">Tables S3</a> C. Further metabolite concentrations and statistical results are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s002" target="_blank">Figs. S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s006" target="_blank">S4</a> and in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s007" target="_blank">Tables S3</a> to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s008" target="_blank">S4</a>, including also abbreviations (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s008" target="_blank">Table S4</a> D).</p

    Pathways and potential biochemical/biological effects associated with brain metabolites of rats inoculated with CFA or CFA/SC-H.

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    <p>Metabolite levels increased (decreased) in the brains of inoculated vs. control rats are indicated by an upward (downward) arrow. For abbreviations see text, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056101#pone.0056101.s005" target="_blank">Tables S1</a> D and S4.</p

    Perivascular cell infiltrates in the CNS of CFA/SC-H rats.

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    <p>Left column: hematoxylin-eosin staining. Right column: Immunoreactivity to CD3. No cell infiltration was detected in the brain sections of control and CFA rats (A, C and B, D respectively). Perivascular cell infiltrates were found in the midbrains of the CFA/SC-H rats (E). CD3 T lymphocytes were identified in cell infiltrates in the white matter (F).</p
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