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1.
Adv Exp Med Biol ; 1325: 61-102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495530

RESUMO

Glycosphingolipids are amphiphilic plasma membrane components formed by a glycan linked to a specific lipid moiety. In this chapter we report on these compounds, on their role played in our cells to maintain the correct cell biology.In detail, we report on their structure, on their metabolic processes, on their interaction with proteins and from this, their property to modulate positively in health and negatively in disease, the cell signaling and cell biology.


Assuntos
Glicoesfingolipídeos , Lipídeos , Membrana Celular , Transdução de Sinais
2.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204326

RESUMO

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.


Assuntos
Imunomodulação , Neoplasias/imunologia , Neoplasias/metabolismo , Esfingolipídeos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Comunicação Celular , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lisofosfolipídeos/metabolismo , Neoplasias/terapia , Transdução de Sinais , Esfingolipídeos/química , Esfingolipídeos/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Resultado do Tratamento
3.
J Neurochem ; 156(4): 403-414, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33448358

RESUMO

Multiple sclerosis (MS) represents the most common demyelinating disease affecting the central nervous system (CNS) in adults as well as in children. Furthermore, in children, in addition to acquired diseases such as MS, genetically inherited diseases significantly contribute to the incidence of demyelinating disorders. Some genetic defects lead to sphingolipid alterations that are able to elicit neurological symptoms. Sphingolipids are essential for brain development, and their aberrant functionality may thus contribute to demyelinating diseases such as MS. In particular, sphingolipidoses caused by deficits of sphingolipid-metabolizing enzymes, are often associated with demyelination. Sphingolipids are not only structural molecules but also bioactive molecules involved in the regulation of cellular events such as development of the nervous system, myelination and maintenance of myelin stability. Changes in the sphingolipid metabolism deeply affect plasma membrane organization. Thus, changes in myelin sphingolipid composition might crucially contribute to the phenotype of diseases characterized by demyelinalization. Here, we review key features of several sphingolipids such as ceramide/dihydroceramide, sphingosine/dihydrosphingosine, glucosylceramide and, galactosylceramide which act in myelin formation during rat brain development and in human brain demyelination during the pathogenesis of MS, suggesting that this knowledge could be useful in identifying targets for possible therapies.


Assuntos
Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Esfingolipídeos/metabolismo , Adulto , Animais , Criança , Humanos , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia
4.
Cell Signal ; 80: 109929, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493577

RESUMO

Spontaneous segregation of cholesterol and sphingolipids as a liquid-ordered phase leads to their clustering in selected membrane areas, the lipid rafts. These specialized membrane domains enriched in gangliosides, sphingomyelin, cholesterol and selected proteins involved in signal transduction, organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating cell homeostasis. Sphingosine 1-phosphate, an important biologically active mediator, is involved in several signal transduction processes regulating a plethora of cell functions and, not only several of its downstream effectors tend to localize in lipid rafts, some of the enzymes involved in its pathway, of receptors involved in its signalling and its transporters have been often found in these membrane microdomains. Considering this, in this review we address what is currently known regarding the relationship between sphingosine 1-phosphate metabolism and signalling and plasma membrane lipid rafts.

5.
Methods Mol Biol ; 2187: 1-25, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32770498

RESUMO

Lipid rafts are membrane areas characterized by the clustering of selected membrane lipids, as the result of their phase separation forming a liquid-ordered phase floating in the lipid-disordered bulk membrane. van Meer and Simons hypothesized the existence of lipid rafts to explain the differential composition of the apical and basolateral domains of polarized epithelial cells and proposed that association of given proteins with lipid rafts along the traffic route might represent an important mechanism for protein sorting. However, great attention was paid to the lipid raft theory after Simons and Ikonen highlighted the enrichment of several proteins involved in signal transduction in "detergent-insoluble, glycolipid-enriched complexes," and postulated that lipid rafts might serve as hubs in regulating intracellular signaling. Most notably, the feature of detergent-insolubility was incorporated in the definition of lipid rafts used in 1997 by these authors. "Lipid rafts" and "detergent-resistant membranes" became almost synonymous after the publication, in 1992, of the seminal paper by Brown and Rose, describing the separation of a low-density, Triton X-100-insoluble fraction from epithelial cells, enriched in GSL and apical GPI-anchored proteins and depleted of basolateral membrane marker proteins. This paper provided a working definition of lipid rafts and a putative biochemical method for their separation. More than 2000 papers have been published using "the Triton method." Evidences obtained by the use of alternative biochemical methods for the isolation of lipid rafts and of methods enabling to analyze the dynamics of lipid rafts in intact cells highlighted the several limitations of the Triton X-100 method. On the other hand, the main findings obtained by this method have not been confuted, and the method is still widely used.In this chapter, we will discuss the most relevant methodological aspects related to the preparation of detergent-resistant membrane fractions, with a special focus on neural cells and tissues.


Assuntos
Lipídeos de Membrana/química , Microdomínios da Membrana/química , Neurônios/química , Animais , Biomarcadores/química , Bovinos , Membrana Celular/química , Detergentes/química , Células Epiteliais/química , Camundongos , Octoxinol/química , Transporte Proteico/fisiologia , Ratos , Transdução de Sinais/fisiologia , Solubilidade
6.
EMBO J ; 39(12): e101732, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32378734

RESUMO

Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long-chain (LCFA) and very-long-chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA-GM3 increase significantly in metabolic disorders, while LCFA-GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA-GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4-mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA-GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA-GM3 and unsaturated VLCFA-GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand-molecular docking analysis supports that VLCFA-GM3 and LCFA-GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA-GM3 is a risk factor for TLR4-mediated disease progression.


Assuntos
Gangliosídeo G(M3)/metabolismo , Monócitos/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Animais , Gangliosídeo G(M3)/química , Gangliosídeo G(M3)/genética , Células HEK293 , Humanos , Camundongos , Camundongos Mutantes , Monócitos/química , Obesidade/genética , Multimerização Proteica , Receptor 4 Toll-Like/química , Receptor 4 Toll-Like/genética
7.
J Lipid Res ; 61(5): 636-654, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31871065

RESUMO

Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson's, Huntington's, and Alzheimer's diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.jlr;61/5/636/F1F1f1.

8.
Front Pharmacol ; 10: 807, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427962

RESUMO

The central nervous system is characterized by a high content of sphingolipids and by a high diversity in terms of different structures. Stage- and cell-specific sphingolipid metabolism and expression are crucial for brain development and maintenance toward adult age. On the other hand, deep dysregulation of sphingolipid metabolism, leading to altered sphingolipid pattern, is associated with the majority of neurological and neurodegenerative diseases, even those totally lacking a common etiological background. Thus, sphingolipid metabolism has always been regarded as a promising pharmacological target for the treatment of brain disorders. However, any therapeutic hypothesis applied to complex amphipathic sphingolipids, components of cellular membranes, has so far failed probably because of the high regional complexity and specificity of the different biological roles of these structures. Simpler sphingosine-based lipids, including ceramide and sphingosine 1-phosphate, are important regulators of brain homeostasis, and, thanks to the relative simplicity of their metabolic network, they seem a feasible druggable target for the treatment of brain diseases. The enzymes involved in the control of the levels of bioactive sphingoids, as well as the receptors engaged by these molecules, have increasingly allured pharmacologists and clinicians, and eventually fingolimod, a functional antagonist of sphingosine 1-phosphate receptors with immunomodulatory properties, was approved for the therapy of relapsing-remitting multiple sclerosis. Considering the importance of neuroinflammation in many other brain diseases, we would expect an extension of the use of such analogs for the treatment of other ailments in the future. Nevertheless, many aspects other than neuroinflammation are regulated by bioactive sphingoids in healthy brain and dysregulated in brain disease. In this review, we are addressing the multifaceted possibility to address the metabolism and biology of bioactive sphingosine 1-phosphate as novel targets for the development of therapeutic paradigms and the discovery of new drugs.

9.
Neurochem Res ; 44(6): 1460-1474, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30569280

RESUMO

Remyelination promoting human IgMs effectively increase the number of myelinated axons in animal models of multiple sclerosis. Hence, they ultimately stimulate myelin production by oligodendrocytes (OLs); however, their exact mechanism of action remains to be elucidated, and in particular, it remains unclear whether they are directly targeting OLs, or their action is mediated by effects on other cell types. We assessed the effect of remyelination promoting antibody rHIgM22 on the proliferative response and on the ceramide/sphingosine 1-phosphate rheostat in mixed glial cell cultures (MGCs). rHIgM22 treatment caused a time-dependent increase in PDGFαR protein in MGCs. Forty-eight hours of treatment with rHIgM22 induced a dose-dependent proliferative response (evaluated as total cell number and as EdU(+) cell number) in MGCs. When the proliferation response of MGCs to rHIgM22 was analyzed as a function of the cell types, the most significant proliferative response was associated with GLAST(+) cells, i.e., astrocytes. In many cell types, the balance between different sphingolipid mediators (the "sphingolipid rheostat"), in particular ceramide and sphingosine 1-phosphate, is critical in determining the cell fate. rHIgM22 treatment in MGCs induced a moderate but significant inhibition of total acidic sphingomyelinase activity (measured in vitro on cell lysates), the main enzyme responsible for the stimulus-mediated production of ceramide, when treatment was performed in serum containing medium, but no significant differences were observed when antibody treatment was performed in the absence of serum. Moreover, rHIgM22 treatment, either in the presence or in absence of serum, had no effects on ceramide levels. On the other hand, rHIgM22 treatment for 24 h induced increased production and release of sphingosine 1-phosphate in the extracellular milieu of MGC. Release of sphingosine 1-phosphate upon rHIgM22 treatment was strongly reduced by a selective inhibitor of PDGFαR. Increased sphingosine 1-phosphate production does not seem to be mediated by regulation of the biosynthetic enzymes, sphingosine kinase 1 and 2, since protein levels of these enzymes and phosphorylation of sphingosine kinase 1 were unchanged upon rHIgM22 treatment. Instead, we observed a significant reduction in the levels of sphingosine 1-phosphate lyase 1, one of the key catabolic enzymes. Remarkably, rHIgM22 treatment under the same experimental conditions did not induce changes in the production and/or release of sphingosine 1-phosphate in pure astrocyte cultures. Taken together, these data suggest that rHIgM22 indirectly influences the proliferation of astrocytes in MGCs, by affecting the ceramide/sphingosine 1-phosphate balance. The specific cell population directly targeted by rHIgM22 remains to be identified, however our study unveils another aspect of the complexity of rHIgM22-induced remyelinating effect.


Assuntos
Astrócitos/metabolismo , Proliferação de Células/fisiologia , Imunoglobulina M/imunologia , Bainha de Mielina/metabolismo , Remielinização/efeitos dos fármacos , Esfingolipídeos/metabolismo , Animais , Ceramidas/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Recombinantes/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
J Neurochem ; 148(5): 600-611, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29959861

RESUMO

Ceramide, sphingomyelin, and glycosphingolipids (both neutral and acidic) are characterized by the presence in the lipid moiety of an aliphatic base known as sphingosine. Altogether, they are called sphingolipids and are particularly abundant in neuronal plasma membranes, where, via interactions with the other membrane lipids and membrane proteins, they play a specific role in modulating the cell signaling processes. The metabolic pathways determining the plasma membrane sphingolipid composition are thus the key point for functional changes of the cell properties. Unnatural changes of the neuronal properties are observed in sphingolipidoses, lysosomal storage diseases occurring when a lysosomal sphingolipid hydrolase is not working, leading to the accumulation of the substrate and to its distribution to all the cell membranes interacting with lysosomes. Moreover, secondary accumulation of sphingolipids is a common trait of other lysosomal storage diseases. This article is part of the Special Issue "Lysosomal Storage Disorders".


Assuntos
Doenças por Armazenamento dos Lisossomos/metabolismo , Degeneração Neural/metabolismo , Esfingolipidoses/metabolismo , Esfingolipídeos/metabolismo , Animais , Humanos , Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/metabolismo , Lisossomos/patologia , Degeneração Neural/patologia , Esfingolipidoses/patologia
12.
Glycoconj J ; 35(4): 397-402, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30145639

RESUMO

Sphingolipid metabolism is an intricate network of several interdependent and co-regulated pathways. In addition to the mainstream biosynthetic and catabolic pathways, several processes, even if less important in contributing to the final tissue sphingolipid composition from the quantitative point of view, might become relevant when sphingolipid metabolism is for any reason dysregulated and concur to the onset of neuronal pathologies. The main subcellular sites involved in the mainstream metabolic pathway are represented by the Golgi apparatus (for the biosynthesis) and by the lysosomes (for catabolism). On the other hand, the minor collateral pathways are associated with the plasma membrane and membranes of other organelles, and likely play important roles in the local regulation of membrane dynamics and contribute to maintain a perfect membrane organization functional to the physiology of the cell. In this review, we will consider few aspects of the sphingolipid metabolic pathway depending by the dynamic of the membranes that seems to become relevant in neurodegenerative diseases.


Assuntos
Membrana Celular/metabolismo , Complexo de Golgi/metabolismo , Lisossomos/metabolismo , Doenças do Sistema Nervoso/metabolismo , Neurônios/metabolismo , Esfingolipídeos/metabolismo , Animais , Membrana Celular/genética , Membrana Celular/patologia , Complexo de Golgi/genética , Complexo de Golgi/patologia , Humanos , Lisossomos/genética , Lisossomos/patologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neurônios/patologia , Esfingolipídeos/genética
13.
Methods Mol Biol ; 1804: 1-17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29926402

RESUMO

In this chapter, we briefly describe the structural features of gangliosides, and focus on the peculiar chemicophysical features of gangliosides, an important class of membrane amphipathic lipids that represent an important driving force determining the organization and properties of cellular membranes.


Assuntos
Fenômenos Químicos , Gangliosídeos/química , Conformação Molecular
14.
NPJ Parkinsons Dis ; 4: 17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900402

RESUMO

During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion. The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes. The identification of typical autophagy proteins and double membranes demonstrates the organelle's autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems.

15.
FASEB J ; 32(10): 5685-5702, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29746165

RESUMO

Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose-loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids ( i.e., sphingomyelin, glucosylceramide, ceramide, and the gangliosides GM3 and GD3), at both intracellular and plasma membrane (PM) levels. In addition, we observed an increase in the lysosomal membrane protein Lamp-1 on the PM of sucrose-loaded fibroblasts and a greater release of the soluble lysosomal protein cathepsin D in their extracellular medium compared with controls. These results indicate increased fusion between lysosomes and the PM, as also suggested by the increased activity of lysosomal glycosphingolipid hydrolases on the PM of sucrose-loaded fibroblasts. The inhibition of ß-glucocerebrosidase and nonlysosomal glucosylceramidase, both involved in ceramide production resulting from glycosphingolipid catabolism on the PM, partially restored cell proliferation. Our findings indicate the existence of a new molecular mechanism underlying cell damage triggered by lysosomal impairment.-Samarani, M., Loberto, N., Soldà, G., Straniero, L., Asselta, R., Duga, S., Lunghi, G., Zucca, F. A., Mauri, L., Ciampa, M. G., Schiumarini, D., Bassi, R., Giussani, P., Chiricozzi, E., Prinetti, A., Aureli, M., Sonnino, S. A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest.


Assuntos
Pontos de Checagem do Ciclo Celular , Membrana Celular/metabolismo , Fibroblastos/metabolismo , Lisossomos/metabolismo , Esfingolipídeos/metabolismo , Catepsina D/genética , Catepsina D/metabolismo , Linhagem Celular , Membrana Celular/genética , Fibroblastos/citologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/genética , Esfingolipídeos/genética
16.
Prog Mol Biol Transl Sci ; 156: 83-120, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29747825

RESUMO

Since the structure of GM1 was elucidated 55years ago, researchers have been attracted by the sialylated glycans of gangliosides. Gangliosides head groups, protruding toward the extracellular space, significantly contribute to the cell glycocalyx; and in certain cells, such as neurons, are major determinants of the features of the cell surface. Expression of glycosyltransferases involved in the de novo biosynthesis of gangliosides is tightly regulated along cell differentiation and activation, and is regarded as the main metabolic mechanism responsible for the acquisition of cell-specific ganglioside patterns. The resulting sialooligosaccharides are characterized by a high degree of geometrical complexity and by highly dynamic properties, which seem to be functional for complex interactions with other molecules sitting on the same cellular membrane (cis-interactions) or soluble molecules present in the extracellular environment, or molecules associated with the surface of other cells (trans-interactions). There is no doubt that the multifaceted biological functions of gangliosides are largely dependent on oligosaccharide-mediated molecular interactions. However, gangliosides are amphipathic membrane lipids, and their chemicophysical, aggregational, and, consequently, biological properties are dictated by the properties of the monomers as a whole, which are not merely dependent on the structures of their polar head groups. In this chapter, we would like to focus on the peculiar chemicophysical features of gangliosides (in particular, those of the nervous system), that represent an important driving force determining the organization and properties of cellular membranes, and to emphasize the causal connections between altered ganglioside-dependent membrane organization and relevant pathological conditions.


Assuntos
Membrana Celular/química , Membrana Celular/metabolismo , Gangliosídeos/metabolismo , Microdomínios da Membrana/metabolismo , Animais , Humanos
18.
Adv Exp Med Biol ; 1112: 293-307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30637705

RESUMO

Prostate cancer (PC) is one of the most common leading causes of cancer-related death in men. Currently, the main therapeutic approaches available for PC are based on the androgen deprivation and on radiotherapy. However, despite these treatments being initially effective in cancer remission, several patients undergo recurrence, developing a most aggressive and resistant PC.Emerging evidence showed that abiraterone acetate drug will reduce PC recurrence by a mechanism independent of the inhibition of Cytochrome P450 17α-hydroxylase/17,20-lyase. Here we describe the involvement in the abiraterone-mediated PC cell death of a particular class of bioactive lipids called sphingolipids (SL). Sphingolipids are components of plasma membrane (PM) that organize macromolecular complexes involved in the control of several signaling pathways including the tumor cell death induced by radiotherapy. Here, we show for the first time that both in androgen-sensitive and insensitive PC cells abiraterone and ionizing radiation induce a reorganization of the plasma membrane SL composition. This event is triggered by activation of the PM-associated glycohydrolases that induce the production of cytotoxic ceramide by the in situ hydrolyses of glycosphingolipids. Taken together our data open a new scenario on the SL involvement in the therapy of PC.


Assuntos
Androstenos/farmacologia , Neoplasias da Próstata/patologia , Radiação Ionizante , Esfingolipídeos/química , Linhagem Celular Tumoral , Homeostase , Humanos , Masculino
19.
J Biol Chem ; 292(17): 7040-7051, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28275055

RESUMO

Gangliosides (sialic acid-containing glycosphingolipids) help regulate many important biological processes, including cell proliferation, signal transduction, and differentiation, via formation of functional microdomains in plasma membranes. The structural diversity of gangliosides arises from both the ceramide moiety and glycan portion. Recently, differing molecular species of a given ganglioside are suggested to have distinct biological properties and regulate specific and distinct biological events. Elucidation of the function of each molecular species is important and will provide new insights into ganglioside biology. Gangliosides are also suggested to be involved in skeletal muscle differentiation; however, the differential roles of ganglioside molecular species remain unclear. Here we describe striking changes in quantity and quality of gangliosides (particularly GM3) during differentiation of mouse C2C12 myoblast cells and key roles played by distinct GM3 molecular species at each step of the process.


Assuntos
Diferenciação Celular , Gangliosídeo G(M3)/química , Mioblastos/citologia , Animais , Proliferação de Células , Ceramidas/química , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Delgada , Glicoesfingolipídeos/química , Lipídeos/química , Espectrometria de Massas , Camundongos , Mioblastos/metabolismo , Ácido N-Acetilneuramínico/química , Transdução de Sinais
20.
Mol Neurobiol ; 54(2): 1564-1567, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-26867654

RESUMO

In peripheral neuropathies, such as sensorimotor neuropathies, motor neuron diseases, or the Guillain-Barré syndrome, serum antibodies recognizing saccharide units, portion of oligosaccharides, or oligosaccharide chains, have been found. These antibodies are called anti-glycosphingolipid (GSL) or anti-ganglioside antibodies. However, the information on the aglycone carrying the hydrophilic oligosaccharide remains elusive. The absolute and unique association of GSL to the onset, development and symptomatology of the peripheral neuropathies could be misleading. Here, we report some thoughts on the matter.


Assuntos
Autoanticorpos/sangue , Glicoesfingolipídeos/sangue , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/diagnóstico , Polissacarídeos/sangue , Animais , Gangliosídeos/sangue , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/diagnóstico , Humanos
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