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[PMID]: 29196263 [Au] Autor: Bousquet PA; Sandvik JA; Jeppesen Edin NF; Krengel U [Ad] Endereço: Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, NO-0315 Oslo, Norway. Electronic address: paula.bousquet@kjemi.uio.no. [Ti] Título: Hypothesis: Hypoxia induces de novo synthesis of NeuGc gangliosides in humans through CMAH domain substitute. [So] Source: Biochem Biophys Res Commun;495(1):1562-1566, 2018 01 01. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Immunotherapy is a growing field in cancer research. A privileged tumor-associated antigen that has received much attention is N-glycolyl (NeuGc) GM3. This ganglioside is present in several types of cancer, but is almost undetectable in human healthy tissues. However, its non-hydroxylated variant, NeuAc GM3, is abundant in all mammals. Due to a deletion in the human gene encoding the key enzyme for synthesis of NeuGc, humans, in contrast to other mammals, cannot synthesize NeuGc GM3. Therefore the presence of this ganglioside in human cancer cells represents an enigma. It has been shown that hypoxic conditions trigger the expression of NeuGc gangliosides, which not only serve as attractive targets for cancer therapy, but also as diagnostic and prognostic tumor marker. Here, we confirm hypoxia-induced expression of the NeuGc GM3 ganglioside also in HeLa cells and reveal several candidate proteins, in particular GM3 synthase and subunit B of respiratory complex II (SDHB), that may be involved in the generation of NeuGc GM3 by SILAC-based proteome analysis. These findings have the potential to significantly advance our understanding of how this enigmatic tumor-associated antigen is produced in humans, and also suggest a possible mechanism of action of anti-tumor antibodies that recognize hypoxia markers, such as 14F7. [Mh] Termos MeSH primário: Gangliosídeo G(M3)/metabolismo Oxigenases de Função Mista/metabolismo Modelos Biológicos Oxigênio/metabolismo Hipóxia Tumoral/fisiologia [Mh] Termos MeSH secundário: Substituição de Aminoácidos Células HeLa Seres Humanos Domínios Proteicos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (G(M3) Ganglioside); EC 1.- (Mixed Function Oxygenases); EC 1.14.18.2 (CMPacetylneuraminate monooxygenase); S88TT14065 (Oxygen) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180105 [Lr] Data última revisão: 180105 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171203 [St] Status: MEDLINE

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[PMID]: 28275055 [Au] Autor: Go S; Go S; Veillon L; Ciampa MG; Mauri L; Sato C; Kitajima K; Prinetti A; Sonnino S; Inokuchi JI [Ad] Endereço: From the Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan. [Ti] Título: Altered expression of ganglioside GM3 molecular species and a potential regulatory role during myoblast differentiation. [So] Source: J Biol Chem;292(17):7040-7051, 2017 Apr 28. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] 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. [Mh] Termos MeSH primário: Diferenciação Celular Gangliosídeo G(M3)/química Mioblastos/citologia [Mh] Termos MeSH secundário: Animais Proliferação Celular 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 [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ceramides); 0 (G(M3) Ganglioside); 0 (Glycosphingolipids); 0 (Lipids); GZP2782OP0 (N-Acetylneuraminic Acid) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170713 [Lr] Data última revisão: 170713 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170310 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M116.771253

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[PMID]: 28212433 [Au] Autor: Chan RB; Perotte AJ; Zhou B; Liong C; Shorr EJ; Marder KS; Kang UJ; Waters CH; Levy OA; Xu Y; Shim HB; Pe'er I; Di Paolo G; Alcalay RN [Ad] Endereço: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, United States of America. [Ti] Título: Elevated GM3 plasma concentration in idiopathic Parkinson's disease: A lipidomic analysis. [So] Source: PLoS One;12(2):e0172348, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Parkinson's disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the 'Spot' study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols. Each lipid species was analyzed using a logistic regression model. The plasma concentrations of two lipid subclasses, triglycerides and monosialodihexosylganglioside (GM3), were different between PD and control participants. GM3 ganglioside concentration had the most significant difference between PD and controls (1.531±0.037 pmol/µl versus 1.337±0.040 pmol/µl respectively; p-value = 5.96E-04; q-value = 0.048; when normalized to total lipid: p-value = 2.890E-05; q-value = 2.933E-03). Next, we used a collection of 20 GM3 and glucosylceramide (GlcCer) species concentrations normalized to total lipid to perform a ROC curve analysis, and found that these lipids compare favorably with biomarkers reported in previous studies (AUC = 0.742 for males, AUC = 0.644 for females). Our results suggest that higher plasma GM3 levels are associated with PD. GM3 lies in the same glycosphingolipid metabolic pathway as GlcCer, a substrate of the enzyme glucocerebrosidase, which has been associated with PD. These findings are consistent with previous reports implicating lower glucocerebrosidase activity with PD risk. [Mh] Termos MeSH primário: Gangliosídeo G(M3)/sangue Doença de Parkinson/sangue [Mh] Termos MeSH secundário: Idoso Idoso de 80 Anos ou mais Biomarcadores/sangue Estudos de Casos e Controles Feminino Seres Humanos Masculino Meia-Idade Doença de Parkinson/fisiopatologia Caracteres Sexuais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (G(M3) Ganglioside) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171117 [Lr] Data última revisão: 171117 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170218 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0172348

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[PMID]: 28179425 [Au] Autor: Han YB; Chen LQ; Li Z; Tan YM; Feng Y; Yang GY [Ad] Endereço: From the State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. [Ti] Título: Structural Insights into the Broad Substrate Specificity of a Novel Endoglycoceramidase I Belonging to a New Subfamily of GH5 Glycosidases. [So] Source: J Biol Chem;292(12):4789-4800, 2017 Mar 24. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Endoglycoceramidases (EGCases) specifically hydrolyze the glycosidic linkage between the oligosaccharide and the ceramide moieties of various glycosphingolipids, and they have received substantial attention in the emerging field of glycosphingolipidology. However, the mechanism regulating the strict substrate specificity of these GH5 glycosidases has not been identified. In this study, we report a novel EGCase I from 103S (103S_EGCase I) with remarkably broad substrate specificity. Based on phylogenetic analyses, the enzyme may represent a new subfamily of GH5 glycosidases. The X-ray crystal structures of 103S_EGCase I alone and in complex with its substrates monosialodihexosylganglioside (GM3) and monosialotetrahexosylganglioside (GM1) enabled us to identify several structural features that may account for its broad specificity. Compared with EGCase II from sp. M-777 (M777_EGCase II), which possesses strict substrate specificity, 103S_EGCase I possesses a longer α7-helix and a shorter loop 4, which forms a larger substrate-binding pocket that could accommodate more extended oligosaccharides. In addition, loop 2 and loop 8 of the enzyme adopt a more open conformation, which also enlarges the oligosaccharide-binding cavity. Based on this knowledge, a rationally designed experiment was performed to examine the substrate specificity of EGCase II. The truncation of loop 4 in M777_EGCase II increased its activity toward GM1 (163%). Remarkably, the S63G mutant of M777_EGCase II showed a broader substrate spectra and significantly increased activity toward bulky substrates (up to >1370-fold for fucosyl-GM1). Collectively, the results presented here reveal the exquisite substrate recognition mechanism of EGCases and provide an opportunity for further engineering of these enzymes. [Mh] Termos MeSH primário: Glicosídeo Hidrolases/metabolismo Rhodococcus equi/enzimologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Clonagem Molecular Cristalografia por Raios X Gangliosídeo G(M1)/metabolismo Gangliosídeo G(M3)/metabolismo Glicosídeo Hidrolases/química Glicosídeo Hidrolases/genética Modelos Moleculares Filogenia Conformação Proteica Engenharia de Proteínas Rhodococcus equi/química Rhodococcus equi/genética Rhodococcus equi/metabolismo Alinhamento de Sequência Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (G(M3) Ganglioside); 37758-47-7 (G(M1) Ganglioside); EC 3.2.1.- (Glycoside Hydrolases); EC 3.2.1.123 (endoglycoceramidase) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170613 [Lr] Data última revisão: 170613 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170210 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M116.763821

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[PMID]: 28051846 [Au] Autor: Matsubara T; Otani R; Yamashita M; Maeno H; Nodono H; Sato T [Ad] Endereço: Department of Biosciences and Informatics, Keio University , 3-14-1 Hiyoshi, Kouhoku-ku, Yokohama 223-8522, Japan. [Ti] Título: Selective Intracellular Delivery of Ganglioside GM3-Binding Peptide through Caveolae/Raft-Mediated Endocytosis. [So] Source: Biomacromolecules;18(2):355-362, 2017 Feb 13. [Is] ISSN: 1526-4602 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Glycosphingolipids are major components of the membrane raft, and several kinds of viruses and bacterial toxins are known to bind to glycosphingolipids in the membrane raft. Since the viral genes and pathogenic proteins that are taken into cells are directly delivered to their target organelles, caveolae/raft-mediated endocytosis represents a promising pathway for specific delivery. In the present study, we demonstrated the ability of an artificial pentadecapeptide, which binds to ganglioside GM3, to deliver protein into cells by caveolae/raft-mediated endocytosis. The cellular uptake of a biotinylated GM3-binding peptide (GM3BP)-avidin complex into HeLa cells was observed, and the cellular uptake of this complex was inhibited by an incubation with sialic acid or endocytic inhibitors such as methyl-ß-cyclodextrin, and also by an incubation at 4 °C. These results indicate that the GM3BP-avidin complex bind to GM3 in membrane raft, and are taken into cell through caveolae/raft-mediated endocytosis. The GM3BP-avidin complex was transported into cells and localized around the nucleus more slowly than a human immunodeficiency virus type 1 TAT peptide. Furthermore, the uptake of a green fluorescent protein (GFP) linked with GM3BP into HeLa cells was similar to that of the GM3BP-avidin complex, and the localization of the GM3BP-GFP fusion protein was markedly different with that of the TAT-GFP fusion protein. The uptake and trafficking of GM3BP were distinguished from conventional cell-penetrating peptides. GM3BP has potential as a novel peptide for the selective delivery of therapeutic proteins and materials into cells in addition to being a cell-penetrating peptide. [Mh] Termos MeSH primário: Cavéolas/metabolismo Peptídeos Penetradores de Células/metabolismo Sistemas de Liberação de Medicamentos Endocitose/fisiologia Gangliosídeo G(M3)/metabolismo Microdomínios da Membrana/metabolismo [Mh] Termos MeSH secundário: Animais Células COS Sobrevivência Celular Cercopithecus aethiops Citoplasma/metabolismo Células HeLa Seres Humanos Espaço Intracelular Transporte Proteico Transdução de Sinais Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cell-Penetrating Peptides); 0 (G(M3) Ganglioside); 0 (tat Gene Products, Human Immunodeficiency Virus) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171011 [Lr] Data última revisão: 171011 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170105 [St] Status: MEDLINE [do] DOI: 10.1021/acs.biomac.6b01262

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[PMID]: 27923633 [Au] Autor: Trilck M; Peter F; Zheng C; Frank M; Dobrenis K; Mascher H; Rolfs A; Frech MJ [Ad] Endereço: Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, 18147 Rostock, Germany; Institute of Neurogenetics, University of Luebeck, Maria-Goeppert-Str. 1, 23562 Luebeck, Germany. Electronic address: michaela.trilck@neuro.uni-luebeck.de. [Ti] Título: Diversity of glycosphingolipid GM2 and cholesterol accumulation in NPC1 patient-specific iPSC-derived neurons. [So] Source: Brain Res;1657:52-61, 2017 Feb 15. [Is] ISSN: 1872-6240 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. On the cellular level NPC1 mutations lead to an accumulation of cholesterol and gangliosides. As a thorough analysis of the severely affected neuronal cells is unfeasible in NPC1 patients, we recently described the cellular phenotype of neuronal cells derived from NPC1 patient iPSCs carrying the compound heterozygous mutation c.1836A>C/c.1628delC. Here we expanded the analysis to cell lines carrying the prevalent mutation c.3182T>C and the novel mutation c.1180T>C, as well as to the determination of GM2 and GM3 gangliosides in NPC1 patient-specific iPSC-derived neurons and glia cells. Immunocytochemical detection of GM2 revealed punctated staining pattern predominantly localized in neurons. Detection of cholesterol by filipin staining showed a comparable staining pattern, colocalized with GM2, indicating a deposit of GM2 and cholesterol in the same cellular compartments. Accumulations were not only restricted to cell bodies, but were also found in the neuronal extensions. A quantification of the GM2 amount by HPLC-MS/MS confirmed significantly higher amounts in neurons carrying a mutation. Additionally, these cells displayed a lowered activity of the catabolic enzyme Hex A, but not B4GALNT1. Molecular docking simulations indicated binding of cholesterol to Hex A, suggesting cholesterol influences the GM2 degradation pathway and, subsequently, leading to the accumulation of GM2. Taken together, this is the first study showing an accumulation of GM2 in neuronal derivatives of patient-specific iPSCs and thus proving further disease-specific hallmarks in this human in vitro model of NPC1. [Mh] Termos MeSH primário: Colesterol/metabolismo Gangliosídeo G(M2)/metabolismo Células-Tronco Pluripotentes Induzidas/metabolismo Doença de Niemann-Pick Tipo C/metabolismo [Mh] Termos MeSH secundário: Proteínas de Transporte/genética Proteínas de Transporte/metabolismo Células Cultivadas Gangliosídeo G(M3)/metabolismo Hexosaminidase A/metabolismo Seres Humanos Células-Tronco Pluripotentes Induzidas/patologia Glicoproteínas de Membrana/genética Glicoproteínas de Membrana/metabolismo Simulação de Acoplamento Molecular Mutação Células-Tronco Neurais/metabolismo Células-Tronco Neurais/patologia Neuroglia/metabolismo Neuroglia/patologia Neurônios/metabolismo Neurônios/patologia Doença de Niemann-Pick Tipo C/genética Doença de Niemann-Pick Tipo C/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carrier Proteins); 0 (G(M3) Ganglioside); 0 (Membrane Glycoproteins); 0 (NPC1 protein, human); 19600-01-2 (G(M2) Ganglioside); 97C5T2UQ7J (Cholesterol); EC 3.2.1.52 (Hexosaminidase A) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170731 [Lr] Data última revisão: 170731 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161208 [St] Status: MEDLINE

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[PMID]: 27729281 [Au] Autor: Dam DH; Wang XQ; Sheu S; Vijay M; Shipp D; Miller L; Paller AS [Ad] Endereço: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. [Ti] Título: Ganglioside GM3 Mediates Glucose-Induced Suppression of IGF-1 Receptor-Rac1 Activation to Inhibit Keratinocyte Motility. [So] Source: J Invest Dermatol;137(2):440-448, 2017 Feb. [Is] ISSN: 1523-1747 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Activation of insulin-like growth factor-1 (IGF-1) receptor (IGF1R) signaling induces keratinocyte migration, but little is known about its regulation, including in diabetic wounds. GM3, a lipid raft ganglioside synthesized by GM3 synthase (GM3S), regulates receptor signaling. In diabetic mice, knockout or topically applied nanoconstruct-mediated knockdown of GM3S promotes wound edge IGF1R phosphorylation and re-epithelialization. Through modulating GM3 expression, we explored the role of GM3 in regulating human keratinocyte IGF1R signaling. Increases in GM3 and GM3S expression, including by exposure to high glucose, inhibit keratinocyte migration and IGF-1-induced chemotaxis in association with inhibition of IGF1R phosphorylation, suppression of Rac1 signaling, and activation of RhoA signaling. In contrast, GM3 depletion accelerates cell migration; increases cell velocity, displacement, and persistence; and activates IGF1R-Rac1 signaling. These data implicate GM3 in mediating glucose-induced suppression of IGF1R-Rac1 signaling. Furthermore, our findings provide evidence of a pivotal role for GM3-induced insulin resistance in impairing keratinocyte migration and reinforce the previously published studies in diabetic mice supporting GM3-depleting strategies as an approach for accelerating the healing of human diabetic wounds. [Mh] Termos MeSH primário: Gangliosídeo G(M3)/fisiologia Glucose/farmacologia Queratinócitos/fisiologia Receptor IGF Tipo 1/fisiologia Proteínas rac1 de Ligação ao GTP/fisiologia [Mh] Termos MeSH secundário: Movimento Celular Pé Diabético/metabolismo Seres Humanos Resistência à Insulina Transdução de Sinais/fisiologia Cicatrização Proteína rhoA de Ligação ao GTP/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (G(M3) Ganglioside); 0 (RAC1 protein, human); EC 2.7.10.1 (Receptor, IGF Type 1); EC 3.6.5.2 (rac1 GTP-Binding Protein); EC 3.6.5.2 (rhoA GTP-Binding Protein); IY9XDZ35W2 (Glucose) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170720 [Lr] Data última revisão: 170720 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161013 [St] Status: MEDLINE

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[PMID]: 27351377 [Au] Autor: Delannoy CP; Rombouts Y; Groux-Degroote S; Holst S; Coddeville B; Harduin-Lepers A; Wuhrer M; Elass-Rochard E; Guérardel Y [Ad] Endereço: Univ. Lille , CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F 59000 Lille, France. [Ti] Título: Glycosylation Changes Triggered by the Differentiation of Monocytic THP-1 Cell Line into Macrophages. [So] Source: J Proteome Res;16(1):156-169, 2017 Jan 06. [Is] ISSN: 1535-3907 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The human acute monocytic leukemia cell line THP-1 is widely used as an in vitro phagocytic cell model because it exhibits several immune properties similar to native monocyte-derived macrophages. In this study, we investigated the alteration of N- and O-linked glycans as well as glycosphingolipids, during THP-1 differentiation, combining mass spectrometry, flow cytometry, and quantitative real-time PCR. Mass spectrometry revealed that macrophage differentiation led to a marked upregulation of expression of GM3 ganglioside as well as an increase in complex-type structures, particularly triantennary glycans, occurring at the expense of high-mannose N-glycans. Moreover, we observed a slight decrease in the proportion of multifucosylated N-glycans and α2,6-sialylation. The uncovered changes in glycosylation correlated with variations of gene expression of relevant glycosyltransferases and glycosidases including sialyltransferases, ß-N-acetylglucosaminyltransferases, fucosyltransferases, and neuraminidase. Furthermore, using flow cytometry and antibodies directed against glycan structures, we confirmed that the alteration of glycosylation occurs at the cell surface of THP-1 macrophage-like cells. Altogether, we established that macrophagic maturation of THP-1 induces dramatic modifications of the surface glycosylation pattern that may result in differential interaction of monocytic and macrophagic THP-1 with immune or bacterial lectins. [Mh] Termos MeSH primário: Diferenciação Celular/imunologia Glicoesfingolipídeos/química Macrófagos/química Monócitos/química Polissacarídeos/química [Mh] Termos MeSH secundário: Configuração de Carboidratos Sequência de Carboidratos Linhagem Celular Fucosiltransferases/genética Fucosiltransferases/imunologia Gangliosídeo G(M3)/química Gangliosídeo G(M3)/imunologia Regulação da Expressão Gênica Glicoesfingolipídeos/imunologia Glicosilação Glicosiltransferases/genética Glicosiltransferases/imunologia Seres Humanos Macrófagos/citologia Macrófagos/imunologia Manose/química Manose/imunologia Monócitos/citologia Monócitos/imunologia N-Acetilglucosaminiltransferases/genética N-Acetilglucosaminiltransferases/imunologia Neuraminidase/genética Neuraminidase/imunologia Polissacarídeos/imunologia Ácidos Siálicos/química Ácidos Siálicos/imunologia Sialiltransferases/genética Sialiltransferases/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (G(M3) Ganglioside); 0 (Glycosphingolipids); 0 (Polysaccharides); 0 (Sialic Acids); EC 2.4.- (Glycosyltransferases); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.99.- (Sialyltransferases); EC 3.2.1.18 (Neuraminidase); PHA4727WTP (Mannose) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160629 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jproteome.6b00161

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[PMID]: 27590073 [Au] Autor: Menichella DM; Jayaraj ND; Wilson HM; Ren D; Flood K; Wang XQ; Shum A; Miller RJ; Paller AS [Ad] Endereço: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA d-menichella@northwestern.edu apaller@northwestern.edu. [Ti] Título: Ganglioside GM3 synthase depletion reverses neuropathic pain and small fiber neuropathy in diet-induced diabetic mice. [So] Source: Mol Pain;12, 2016. [Is] ISSN: 1744-8069 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Small fiber neuropathy is a well-recognized complication of type 2 diabetes and has been shown to be responsible for both neuropathic pain and impaired wound healing. In previous studies, we have demonstrated that ganglioside GM3 depletion by knockdown of GM3 synthase fully reverses impaired wound healing in diabetic mice. However, the role of GM3 in neuropathic pain and small fiber neuropathy in diabetes is unknown. PURPOSE: Determine whether GM3 depletion is able to reverse neuropathic pain and small fibers neuropathy and the mechanism of the reversal. RESULTS: We demonstrate that GM3 synthase knockout and the resultant GM3 depletion rescues the denervation in mouse footpad skin and fully reverses the neuropathic pain in diet-induced obese diabetic mice. In cultured dorsal root ganglia from diet-induced diabetic mice, GM3 depletion protects against increased intracellular calcium influx in vitro. CONCLUSIONS: These studies establish ganglioside GM3 as a new candidate responsible for neuropathic pain and small fiber neuropathy in diabetes. Moreover, these observations indicate that systemic or topically applied interventions aimed at depleting GM3 may improve both the painful neuropathy and the wound healing impairment in diabetes by protecting against nerve end terminal degeneration, providing a disease-modifying approach to this common, currently intractable medical issue. [Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/fisiopatologia Dor/etiologia Dor/metabolismo Doenças do Sistema Nervoso Periférico/etiologia Doenças do Sistema Nervoso Periférico/metabolismo Sialiltransferases/deficiência Neuropatia de Pequenas Fibras/etiologia Neuropatia de Pequenas Fibras/metabolismo [Mh] Termos MeSH secundário: Animais Glicemia/genética Glicemia/metabolismo Células Cultivadas Diabetes Mellitus Tipo 2/etiologia Diabetes Mellitus Tipo 2/patologia Dieta Hiperlipídica/efeitos adversos Modelos Animais de Doenças Gangliosídeo G(M3)/metabolismo Gânglios Espinais/metabolismo Gânglios Espinais/patologia Resistência à Insulina/fisiologia Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Neurônios/metabolismo Dor/genética Medição da Dor Doenças do Sistema Nervoso Periférico/genética Estimulação Física/efeitos adversos Nervo Isquiático/metabolismo Sialiltransferases/genética Pele/inervação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Blood Glucose); 0 (G(M3) Ganglioside); EC 2.4.99.- (Sialyltransferases); EC 2.4.99.9 (haematoside synthetase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171018 [Lr] Data última revisão: 171018 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160904 [St] Status: MEDLINE

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[PMID]: 27539856 [Au] Autor: Kawashima N; Nishimiya Y; Takahata S; Nakayama KI [Ad] Endereço: From the Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan. [Ti] Título: Induction of Glycosphingolipid GM3 Expression by Valproic Acid Suppresses Cancer Cell Growth. [So] Source: J Biol Chem;291(41):21424-21433, 2016 Oct 07. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Glycosphingolipid GM3, a known suppressor of epidermal growth factor receptor (EGFR) phosphorylation, inhibits cell proliferation. Valproic acid, conversely, is known as an up-regulator of GM3 synthase gene (ST3GAL5). To test the possibility that valproic acid could inhibit EGFR phosphorylation by increasing the level of GM3 in cells, we treated A431 epidermoid carcinoma cells with valproic acid and found that valproic acid treatment caused an about 6-fold increase in the GM3 level but only a marginal increase in the GM2 level in these cells and that the observed increase in GM3 level was valproic acid dose-dependent. Consistent with this observation, valproic acid treatment induced GM3 synthase gene expression by about 8-fold. Furthermore, phosphorylation of EGFR was reduced, and cell proliferation was inhibited following valproic acid treatment. Consistent with these results, transient expression of GM3 synthase gene in A431 cells also increased cellular level of GM3, reduced phosphorylation of EGFR, and inhibited cell proliferation. Treatment with l-phenyl-2-decanoylamino-3-morpholino-l-propanol, an inhibitor of glucosylceramide synthesis, decreased the cellular level of GM3 and reduced the inhibitory effects of valproic acid on EGFR phosphorylation and cell proliferation. These results suggested that induction of GM3 synthesis was enough to inhibit proliferation of cancer cells by suppressing EGFR activity. Valproic acid treatment similarly increased the GM3 level and reduced phosphorylation of EGFR in U87MG glioma cells and inhibited their proliferation. These results suggested that up-regulators of GM3 synthase gene, such as valproic acid, are potential suppressors of cancer cell proliferation. [Mh] Termos MeSH primário: Gangliosídeo G(M3)/biossíntese Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Neoplasias/metabolismo Sialiltransferases/biossíntese Proteínas Supressoras de Tumor/biossíntese Ácido Valproico/farmacologia [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Gangliosídeo G(M3)/genética Seres Humanos Neoplasias/genética Fosforilação/efeitos dos fármacos Fosforilação/genética Receptor do Fator de Crescimento Epidérmico/genética Receptor do Fator de Crescimento Epidérmico/metabolismo Sialiltransferases/genética Proteínas Supressoras de Tumor/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (G(M3) Ganglioside); 0 (Tumor Suppressor Proteins); 614OI1Z5WI (Valproic Acid); EC 2.4.99.- (Sialyltransferases); EC 2.4.99.9 (haematoside synthetase); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171007 [Lr] Data última revisão: 171007 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160820 [St] Status: MEDLINE

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