1,721,083 research outputs found
Application of modern NMR techniques in the structural elucidation of bioactive natural products
No full textSphingosine -1-phosphate in the tumor niche promotes glioblastoma malignancy
No full textGlioblastoma (GBM) is the most frequent and lethal brain tumor, and is characterized by not only the presence of cancer cells but also a considerable amount of parenchymal cells. Among them, microglia and endothelial cells are recognized as crucial for both tumor growth and spread. However, the signals regulating the interplay between different cells in the GBM niche are little known. The sphingolipid metabolite sphingosine-1-phosphate (S1P) has emerged as a crucial factor in promoting GBM growth, invasion, and drug-resistance, through interaction with its specific receptors. Notwithstanding, its cellular origin in the GBM niche remains only partially known. In this study we investigated the capacity of microglia and endothelial cells of the GBM niche to act as source and/or target of S1P. We found that different cells of the GBM microenvironment, including GBM-derived tumor cells, stem cells, and endothelial cells, as well as microglia are all able to rapidly synthesize and secrete S1P. Among different cell types, GBM stem cells and GBM-derived endothelial cells were found to be particularly effective in releasing newly synthesized S1P extracellularly. Further experiments revealed that after co-culture, GBM and parenchymal cells exhibit enhanced expression of S1P receptors, and of sphingosine kinase (leading to increased S1P secretion), respectively. In addition, we found that extracellular S1P is able to induce multiple effects on different cells, by promoting growth, stemness and survival of tumor cells, migration and vasculogenesis of endothelial cells, and inflammatory properties of microglia. In conclusion, our data demonstrate that different cell types of the GBM niche and their cross-talk contribute to the S1P enrichment of the GBM microenvironment, where S1P prompts multiple processes which favor GBM progression and malignancy
Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy
Full text linkNeurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies
Different behaviour of ghost-linked acidic and neutral sialidases during human erythrocyte ageing
No full textAcidic and neutral sialidases (pH optimum 4.7 and 7.2, respectively) were assayed on human circulating erythrocytes during ageing. The assays were performed on intact erythrocytes and resealed erythrocyte ghost membranes. From young to senescent erythrocytes the acidic sialidase featured a 2.7-fold and 2.5-fold decrease in specific activity when measured on intact cells or resealed ghost membranes, whereas the neutral sialidase a 5-fold and 7-fold increase, respectively.
The Ca2+-loading procedure was employed to mimic the vesiculation process occurring during erythrocyte ageing. Under these conditions the released vesicles displayed an elevated content of acidic sialidase, almost completely linked through a glycan phosphoinositide (GPI) anchor but no neutral sialidase activity, that was completely retained by remnant erythrocytes together with almost all the starting content of sialoglycoconjugates. The loss with vesiculation of acidic sialidase with a concomitant relative increase of neutral sialidase was more marked in young than senescent erythrocytes.
The data presented suggest that during ageing erythrocytes loose acidic sialidase, and get enriched in the neutral enzyme, the vesiculation process, possibly involving GPI-anchors-rich membrane microdomains, being likely responsible for these changes. The enhanced neutral sialidase activity might account for the sialic acid loss occurring during erythrocyte ageing
Effects of a Ferulate-Derived Dihydrobenzofuran Neolignan on Angiogenesis, Steroidogenesis, and Redox Status in a Swine Cell Model
No full textIn the ongoing search for new therapeutic compounds, lignans and neolignans, which are widely distributed in plants, deserve special attention because of their interactions with several biological targets. Searching for potential antiangiogenic agents related to natural lignans/neolignans, we were attracted by a previously studied synthetic dihydrobenzofuran neolignan. We synthesized the compound by means of an eco-friendly, enzyme-mediated biomimetic coupling of the methyl ester of ferulic acid, and the present study was aimed to deeply investigate its effect in angiogenesis bioassays validated in our laboratory. In addition, a previously well-defined granulosa cell model was employed to evaluate the effect of dihydrobenzofuran neolignan on cell viability, steroidogenesis, and redox status. Present data support the antiangiogenic effect of this neolignan. Moreover, we demonstrate that, at least at the highest concentrations tested, dihydrobenzofuran neolignan affects granulosa cell viability and steroidogenesis. In addition, the compound inhibits generation of free radicals and stimulates scavenger enzyme activities. The present data, which are a further deepening of the evaluation of the biological activities of the dihydrobenzofuran lignan in well-defined cell models, are of interest and worthy of special attention
Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival
Full text linkSphingosine-1-phosphate (S1P) is a crucial mediator involved in the progression of different cancers, including glioblastoma multiforme (GBM), the most frequent and deadly human brain tumor, characterized by extensive invasiveness and rapid cell growth. Most of GBMs overexpress the epidermal growth factor receptor (EGFR), and we investigated the possible link between S1P and EGFR signaling pathways, focusing on its role in GBM survival, using the U87MG human cell line overexpressing EGFR (EGFR+). We previously demonstrated that EGFR+ cells have higher levels of extracellular S1P and increased sphingosine kinase-1 (SK1) activity than empty vector expressing cells. Notably, we demonstrated that EGFR+ cells are resistant to temozolomide (TMZ), the standard chemotherapeutic drug in GBM treatment, and the inhibition of SK1 or S1P receptors made EGFR+ cells sensitive to TMZ; moreover, exogenous S1P reverted this effect, thus involving extracellular S1P as a survival signal in TMZ resistance in GBM cells. In addition, both PI3K/AKT and MAPK inhibitors markedly reduced cell survival, suggesting that the enhanced resistance to TMZ of EGFR+ cells is dependent on the increased S1P secretion, downstream of the EGFR-ERK-SK1-S1P pathway. Altogether, our study provides evidence of a functional link between S1P and EGFR signaling pathways enhancing the survival properties of GBM cells
An unusual nitrogenous terphenyl derivative from fruiting bodies of the basidiomycete Sarcodon leucopus
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Stereochemistry and conformation of dolabellane diterpenes: an NMR and molecular mechanics study
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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