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1.
Glycoconj J ; 36(5): 419-428, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31297734

RESUMO

Gangliosides altered during the pathological conditions and particularly in cancers. Here, we aimed to profile the gangliosides in breast cancer serum and propose potential biomarkers. LC-FTMS method was first used to identify all the ganglioside species in serum, then LC-MS/MS-MRM method was employed to quantitate the levels of gangliosides in serum from healthy volunteers and patients with benign breast tumor or breast cancer. 49 ganglioside species were determined, including GM1, GM2, GM3, GD1, GD3 and GT1 species. Compared to healthy volunteers, the levels of GM1, GM2, GM3, GD1 and GD3 displayed a rising trend in breast cancer patients. In particular, as the major glycosphingolipid component, GM3 showed excellent diagnostic accuracy in cancer serum (AUC > 0.9). PCA profile of the GM3 species showed clear distinction between normal and cancer serum. What's more, ROC curve proved great diagnostic accuracy of GM3 between cancer and benign serum. In addition, GM3 was discovered as a diagnostic marker to differentiate luminal B subtype from other subtypes. Furthermore, a positive correlation between GM3 and Ki-67 status of patients was identified. In conclusion, our results introduced the alteration patterns of serum gangliosides in breast cancer and suggested serum GM3 as a potential diagnostic biomarker in breast cancer diagnosis and luminal B subtype distinction.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Gangliosídeo G(M3)/sangue , Neoplasias/diagnóstico , Adulto , Idoso , Área Sob a Curva , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Cromatografia Líquida , Diagnóstico Diferencial , Feminino , Gangliosídeos/sangue , Gangliosídeos/classificação , Humanos , Antígeno Ki-67/sangue , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Análise de Componente Principal , Prognóstico , Curva ROC , Espectrometria de Massas em Tandem
3.
J Mol Endocrinol ; 59(1): 93-104, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28500248

RESUMO

Polycystic ovary syndrome (PCOS) affects up to 18% of reproductive-aged women with reproductive and metabolic complications. While lipidomics can identify associations between lipid species and metabolic diseases, no research has examined the association of lipid species with the pathophysiological features of PCOS. The aim of this study was to examine the lipidomic profile in women with and without PCOS. This study was a cross-sectional study in 156 age-matched pre-menopausal women (18-45 years, BMI >20 kg/m2; n = 92 with PCOS, n = 64 without PCOS). Outcomes included the association between the plasma lipidomic profile (325 lipid species (24 classes) using liquid chromatography mass spectrometry) and PCOS, adiposity, homeostasis assessment of insulin resistance (HOMA), sex hormone-binding globulin (SHBG) and free androgen index (FAI). There were no associations of the lipidomic profile with PCOS or testosterone. HOMA was positively associated with 2 classes (dihydroceramide and triacylglycerol), SHBG was inversely associated with 2 classes (diacylglycerol and triacylglycerol), FAI was positively associated with 8 classes (ceramide, phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylinositol, diacylglycerol and triacylglycerol) and waist circumference was associated with 8 classes (4 positively (dihydroceramide, phosphatidylglycerol, diacylglycerol and triacylglycerol) and 4 inversely (trihexosylceramide, GM3 ganglioside, alkenylphosphatidylcholine and alkylphosphatidylethanolamine)). The lipidomic profile was primarily related to central adiposity and FAI in women with or without PCOS. This supports prior findings that adiposity is a key driver of dyslipidaemia in PCOS and highlights the need for weight management through lifestyle interventions.


Assuntos
Dislipidemias/sangue , Metabolismo dos Lipídeos , Metaboloma , Obesidade/sangue , Síndrome do Ovário Policístico/sangue , Adulto , Glicemia/metabolismo , Ceramidas/sangue , Ceramidas/classificação , Estudos Transversais , Dislipidemias/diagnóstico , Dislipidemias/patologia , Feminino , Gangliosídeos/sangue , Gangliosídeos/classificação , Glicerofosfolipídeos/sangue , Glicerofosfolipídeos/classificação , Humanos , Insulina/sangue , Resistência à Insulina , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/patologia , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/patologia , Pré-Menopausa/fisiologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Triglicerídeos/sangue , Triglicerídeos/classificação
4.
Acta Neuropathol Commun ; 4: 23, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26936605

RESUMO

INTRODUCTION: Guillain-Barré syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage. RESULTS AND CONCLUSIONS: In this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy.


Assuntos
Complemento C1q/metabolismo , Via Clássica do Complemento/fisiologia , Gangliosídeos/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Animais , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Complemento C1q/genética , Via Clássica do Complemento/genética , Diafragma/metabolismo , Diafragma/patologia , Transportadores de Ácidos Dicarboxílicos/genética , Modelos Animais de Doenças , Gangliosídeos/classificação , Gangliosídeos/imunologia , Síndrome de Guillain-Barré/metabolismo , Síndrome de Guillain-Barré/patologia , Humanos , Infiltração Leucêmica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Receptores Nicotínicos/metabolismo , Respiração/efeitos dos fármacos , Respiração/genética , Especificidade da Espécie , Simportadores/genética , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/genética
5.
Carbohydr Res ; 400: 1-8, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25299937

RESUMO

Gangliosides and sulfated glycosphingolipids, as building and functional components of animal cell membranes, participate in cell-to-cell interactions and signaling, but also in changes of cell architecture due to different pathophysiological events. In order to enable higher throughput and to facilitate structural characterization of gangliosides/sulfo-glycosphingolipids (GSL) and their neutral GSL counterparts by negative ion mass spectrometry (MS) and tandem MS techniques, a database and data analysis application have been developed. In silico developed glycosphingolipid database considers a high diversity of ceramide compositions, several sialic acid types (N-acetylneuraminic acid, N-glycolylneuraminic acid and 2-keto-3-deoxynononic acid) as well as possible additional substitutions/modifications of glycosphingolipids, such as O-acetylation, de-N-acetylation, fucosylation, glucuronosylation, sulfation, attachment of repeating terminal hexose-N-acetylhexosamine- (Hex-HexNAc-)1-6 extension, and possible lactone forms. Data analysis application, named GSL-finder, enables correlation of negative ion MS and/or low-energy tandem MS spectra with the database structures. The GSL-database construction and the GSL-finder application searching rules are explained. Validation conducted on GD1a fraction as well as on complex mixtures of native gangliosides isolated from different mammalian brain tissues (human fetal and adult brain, and calf brain tissue) demonstrated agreement with previous studies. Plain, fast, and automated routine for structural characterization of gangliosides/sulfated glycosphingolipids and their neutral GSL counterparts described here could facilitate and improve mass spectrometric analysis of complex glycosphingolipid mixtures originating from variety of normal and pathological biomaterial, where it is known that distinctive changes in glycosphingolipid composition occur.


Assuntos
Bases de Dados de Compostos Químicos , Gangliosídeos/metabolismo , Glicoesfingolipídeos/metabolismo , Animais , Bovinos , Ceramidas/química , Ceramidas/metabolismo , Simulação por Computador , Gangliosídeos/química , Gangliosídeos/classificação , Glicoesfingolipídeos/química , Glicoesfingolipídeos/classificação , Humanos , Ácidos Siálicos/química , Ácidos Siálicos/metabolismo , Sulfatos/química , Espectrometria de Massas em Tandem
6.
Electrophoresis ; 33(12): 1778-86, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22740466

RESUMO

A strategy combining high-performance thin layer chromatography (HPTLC), laser densitometry, and fully automated chip-based nanoelectrospray (nanoESIchip) performed on a NanoMate robot coupled to QTOF-MS was developed, optimized, and for the first time applied for mapping and structural identification of gangliosides (GGs) extracted and purified from a human angioblastic meningioma specimen. While HPTLC pattern indicated only seven fractions migrating as GM3, GM2, GM1, GD3, GD1a (nLD1, LD1), GD1b, GT1b, and possibly GD2, due to the high sensitivity, mass accuracy, and ability to ionize minor species in complex mixtures, nanoESIchip-QTOF MS was able to discover significantly more GG species than ever reported in meningioma. Thirty-four distinct glycosphingolipid components of which five asialo, one GM4, nine GM3, two GM2, two GD3, nine GM1, and six GD1 differing in their ceramide compositions were identified. All structures presented long-chain bases with 18 carbon atoms, while the length of the fatty acid was found to vary from C11 to C25. MS screening results indicated also that the diversity of the expressed GM1 structures is higher than expected in view of the low proportions evidenced by densitometric quantification. Simultaneous fragmentation of meningioma-associated GM1 (d18:1/24:1) and GM1 (d18:1/24:0) by MS/MS using CID confirmed the postulated structures of the ceramide moieties and provided data on the glycan core, which document that for each of the GM1 (d18:1/24:1) and GM1 (d18:1/24:0) forms both GM1a and GM1b isomers are expressed in the investigated meningioma tissue.


Assuntos
Gangliosídeos/análise , Meningioma/química , Espectrometria de Massas em Tandem/métodos , Sequência de Carboidratos , Cromatografia em Camada Fina/métodos , Gangliosídeos/química , Gangliosídeos/classificação , Humanos , Masculino , Procedimentos Analíticos em Microchip , Pessoa de Meia-Idade , Nanotecnologia , Sensibilidade e Especificidade
7.
J Neurol ; 259(7): 1366-74, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22218648

RESUMO

IgG anti-GQ1b antibodies are a powerful serological marker for the diagnosis of Fisher syndrome (FS), but little is known regarding serological markers in FS patients that do not have the autoantibodies. The authors analyzed IgG antibodies against gangliosides other than GQ1b, ganglioside complexes, and ganglioside-like lipo-oligosaccharide (LOS) of Campylobacter jejuni isolates from FS patients. We identified 24 (12%) patients with GQ1b-seronegative FS among 207 FS patients who had been referred to our laboratory for anti-ganglioside antibody testing. Patients with GQ1b-seronegative FS were male and had a history of antecedent gastrointestinal illness more frequently than FS patients with IgG anti-GQ1b antibodies. Other clinical features during the illness were not distinguishing for GQ1b-seronegative FS. Four (17%) of 24 patients with GQ1b-seronegative FS had IgG antibodies against single gangliosides such as GM1b, GD1a, or GT1a. Antibodies against GM1 and GT1a complex were detected in four GQ1b-seronegative FS patients, three of whom did not have antibodies against single gangliosides. Mass spectrometry analysis showed that C. jejuni isolates from FS patients had GD1c-, GalNAc-GM1b-, or GalNAc-GD1c-like LOS, and not GQ1b-like LOS, highlighting the utility of examining serum antibodies against these ganglioside mimics in GQ1b-seronegative FS patients. Seven (29%) had IgG antibodies against the LOS from C. jejuni strains expressing GD1c-, GalNAc-GM1b-, or GalNAc-GD1c-like LOS. These findings suggest that IgG antibodies against GM1b, GD1c, GalNAc-GM1b, and ganglioside complexes are serological markers for GQ1b-seronegative Fisher syndrome.


Assuntos
Anticorpos/sangue , Gangliosídeos/imunologia , Síndrome de Miller Fisher/sangue , Síndrome de Miller Fisher/imunologia , Adolescente , Adulto , Idoso , Biomarcadores , Infecções por Campylobacter/imunologia , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Gangliosídeos/classificação , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Síndrome de Miller Fisher/virologia , Testes Sorológicos , Estatísticas não Paramétricas , Adulto Jovem
8.
Neurol India ; 59(5): 727-32, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22019659

RESUMO

BACKGROUND: Guillain-Barré syndrome (GBS) has been the most common cause of flaccid paralysis in children after the decline in the incidence of poliomyelitis. There are not any published data from the Indian subcontinent documenting electrophysiological patterns and antiganglioside antibodies in pediatric GBS. MATERIALS AND METHODS: The study population included children with GBS referred for electrodiagnostic evaluation and also children with GBS admitted to our institute between August 2006 and July 2007. Nerve conduction studies were done to determine GBS subtypes and serum antiganglioside antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and electrophysiological features were correlated with antiganglioside antibody results. RESULTS: Of the 43 (male to female ratio = 2.1:1) children studied, 97.6% had motor weakness, 76.7% had cranial nerve palsies, 13.9% had autonomic disturbances and respiratory paralysis was found in 9.3% children. Antecedent illness was recorded in 69.8% children. The GBS subtype distribution was as follows: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 21 (48.8%), acute motor axonal neuropathy (AMAN) in 19 (44.2%), and 3 (6.9%) children were unclassified. The severity of illness was similar in both AMAN and AIDP subtypes and the recovery in both the subtypes was complete without any significant difference in the duration of recovery. Preceding diarrheal illness was more common in AMAN subtype as compared to AIDP subtype (57.9% vs. 4.7%, P = 0.007). Sensory symptoms were more common in AIDP subtype than in AMAN subtype (66.6% vs. 21%, P = 0.03}. The commonest ganglioside antibody was IgM GM2. Anti GM3 antibodies were exclusively seen in children with AMAN and IgG GD1b was significantly associated with (36.7 vs. 4%; P = 0.007) AMAN subtype. IgG GT1b was identified in 50% of patients with AIDP as compared to 22.7% in patients with AMAN. CONCLUSION: In this study, AMAN subtype accounted for a significant proportion of pediatric GBS. AMAN was associated with diarrhea and specific antiganglioside antibodies. Recovery in children with GBS was complete, irrespective of the subtype.


Assuntos
Autoanticorpos/sangue , Gangliosídeos/imunologia , Síndrome de Guillain-Barré , Condução Nervosa/fisiologia , Adolescente , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Eletrocardiografia/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Gangliosídeos/classificação , Síndrome de Guillain-Barré/classificação , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Estações do Ano , Fatores Sexuais
9.
J Neurochem ; 116(5): 926-35, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21214571

RESUMO

Gangliosides are considered to be involved in the maintenance and repair of nervous tissues. Recently, novel roles of gangliosides in the regulation of complement system were reported by us. In this study, we compared complement activation, inflammatory reaction and disruption of glycolipid-enriched microdomain (GEM)/rafts among various mutant mice of ganglioside synthases, i.e. GM2/GD2 synthase knockout (KO), GD3 synthase KO, double KO (DKO) of these two enzymes and wild type. Up-regulation of complement-related genes, deposits of C1q, proliferation of astrocytes and infiltration of microglia also showed similar gradual severity depending on the defects in ganglioside compositions. In the expression of inflammatory cytokines such as IL-1ß and tumor necrosis factor α, only DKO showed definite up-regulation. Immunoblotting of fractions from sucrose density gradient ultracentrifugation revealed that lipid raft markers such as caveolin-1 and flotillin-1 tended to disperse from the raft fractions with intensities of DKO > GM2/GD2 synthase KO > GD3 synthase KO > wild type. Decay-accelerating factor and neural cell adhesion molecule tended to disappear from the raft fraction. Phospholipids and cholesterol also tended to decrease in GEM/rafts in GM2/GD2 synthase KO and DKO, although total amounts were almost equivalent. These results indicate that destruction of GEM/rafts is caused by ganglioside deficiency with gradual intensity depending on the degree of defects of their compositions.


Assuntos
Cerebelo/patologia , Gangliosídeos/metabolismo , Inflamação/metabolismo , Microdomínios da Membrana/metabolismo , Doenças Neurodegenerativas/patologia , Regulação para Cima/genética , Fatores Etários , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Proliferação de Células , Cerebelo/metabolismo , Colesterol/metabolismo , Cromatografia em Camada Fina/métodos , Modelos Animais de Doenças , Gangliosídeos/classificação , Inflamação/genética , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Microdomínios da Membrana/genética , Camundongos , Camundongos Knockout , N-Acetilgalactosaminiltransferases/deficiência , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , RNA Mensageiro/metabolismo , Sialiltransferases/deficiência , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
J Neuroimmunol ; 219(1-2): 119-22, 2010 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-20006388

RESUMO

Anti-ganglioside complexes (GSCs) IgG antibodies have been reported in patients with Guillain-Barré (GBS) or Fisher syndrome but little is known on their presence in multifocal motor neuropathy (MMN) or other chronic immune-mediated neuropathies. We examined 24 patients with MMN, 34 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 23 with neuropathy associated with IgM monoclonal gammopathy (PN+IgM), 13 with GBS, 34 with motor neuron disease (MND), 24 with other neuropathies and 20 normal subjects. Patients' sera were tested by ELISA for IgM reactivity to GM1, GM2, GD1a, GD1b and GT1b and with GSCs made by any combination of two of these gangliosides. In all GM1 positive patients with MMN (11), PN+IgM (1), CIDP (1) and POEMS (1), binding to GM1 was abolished or consistently reduced when tested in GSCs also containing GD1a or other gangliosides. This only occurred in one of the three GM1 positive MND patients. In a patient with PN-IgM and anti-GM2 and GD1a IgM, both reactivities were reduced when tested in GSCs also containing GM1. New reactivities were found in a patient with CIDP and anti-GD1b IgM who presented an additional reactivity to GT1b/GM1 and GT1b/GM2 GSCs, and in one with PN-IgM who had reactivity to GM2/GD1b but not to individual gangliosides. Testing for IgM antibodies to GSCs rarely permitted to identify new reactivities in chronic immune neuropathies. IgM binding to gangliosides was however often modified in GSCs suggesting that these reactivities may be affected by contiguous gangliosides possibly influencing their pathogenicity.


Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , Gangliosídeos/imunologia , Imunoglobulina M/imunologia , Doença dos Neurônios Motores/imunologia , Doenças Autoimunes do Sistema Nervoso/classificação , Doenças Autoimunes do Sistema Nervoso/complicações , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Gangliosídeos/classificação , Humanos , Imunoglobulina M/sangue , Masculino , Doença dos Neurônios Motores/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia
11.
J Neurochem ; 104(1): 140-6, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18173730

RESUMO

We previously observed that gangliosides GM2, GM1, and GM3 inhibit Ca2+-uptake via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in neurons and in brain microsomes. We now systematically examine the effect of various gangliosides and their analogs on Ca2+-uptake via SERCA and demonstrate that an exposed carboxyl group on the ganglioside sialic acid residue is required for inhibition. Thus, asialo-GM2 and asialo-GM1 have no inhibitory effect, and modifications of the carboxyl group of GM1 and GM2 into a hydroxymethyl residue (CH2OH), a methyl ester (COOCH3) or a taurine-conjugated amide (CONHCH2CH2SO3H) drastically diminish their inhibitory activities. We also demonstrate that the saccharides must be attached to a ceramide backbone in order to inhibit SERCA as the ceramide-free ganglioside saccharides only inhibit SERCA to a minimal extent. Finally, we attempted to use the ceramide-free ganglioside saccharides to antagonize the effects of the gangliosides on SERCA; although some reversal was observed, the inhibitory effects of the gangliosides were not completely abolished.


Assuntos
Cálcio/metabolismo , Gangliosídeos/química , Gangliosídeos/metabolismo , Ácido N-Acetilneuramínico/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/fisiologia , Animais , Encéfalo/ultraestrutura , Relação Dose-Resposta a Droga , Gangliosídeos/classificação , Microssomos/ultraestrutura , Naftalenossulfonatos , Ratos , Espectrofotometria/métodos
12.
J Child Neurol ; 22(4): 432-4, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17621523

RESUMO

This article presents a 6-year-old girl who developed acute unilateral third cranial nerve palsy in the absence of any other sign of central nervous system involvement. Raised titers of immunoglobulin M antibodies against GM1, GD1a, and GD1b ganglioside components were demonstrated. Ten days earlier, the girl had experienced acute gastroenteritis with positive specific immunoglobulin M antibodies against enterovirus. The results of all other laboratory tests usually performed for infectious diseases were negative, and neuroradiologic findings were also normal. Oral prednisone was administered for a few days, and the ophthalmoparesis fully resolved within 1 month. Two months later, a second episode of isolated ophthalmoparesis occurred, again associated with a positive immunoglobulin M reaction against GM1, GD1a, and GD1b antigens. This report discusses the relationship between acute isolated ophthalmoparesis and antiganglioside antibodies.


Assuntos
Anticorpos/sangue , Anticorpos/imunologia , Infecções por Enterovirus/complicações , Gangliosídeos/imunologia , Oftalmoplegia/imunologia , Criança , Feminino , Gangliosídeo G(M1)/imunologia , Gangliosídeos/classificação , Humanos , Oftalmoplegia/etiologia , Oftalmoplegia/virologia
13.
Chem Pharm Bull (Tokyo) ; 54(7): 982-7, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16819216

RESUMO

Three new monosialo-gangliosides, CEG-3 (3), CEG-4 (4), and CEG-5 (5), were obtained, together with two known gangliosides, SJG-1 (1) and CG-1 (2), from the lipid fraction of the chloroform/methanol extract of the sea cucumber Cucumaria echinata. The structures of the new gangliosides were determined on the basis of chemical and spectroscopic evidence to be 1-O-[4-O-acetyl-alpha-L-fucopyranosyl-(1-->11)-(N-glycolyl-alpha-D-neuraminosyl)-(2-->6)-beta-D-glucopyranosyl]-ceramide (3) and 1-O-[alpha-L-fucopyranosyl-(1-->11)-(N-glycolyl-alpha-D-neuraminosyl)-(2-->6)-beta-D-glucopyranosyl]-ceramide (4, 5). The ceramide moieties of each compound were composed of heterogeneous sphingosine or phytosphingosine bases, and 2-hydroxy or nonhydroxylated fatty acid units. These gangliosides showed neuritogenic activity toward the rat pheochromocytoma cell line PC-12 in the presence of nerve growth factor.


Assuntos
Cucumaria/química , Gangliosídeos/química , Gangliosídeos/classificação , Holothuria/química , Animais , Clorofórmio/química , Gangliosídeos/análise , Gangliosídeos/isolamento & purificação , Gangliosídeos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Metanol/química , Estrutura Molecular , Neuritos/efeitos dos fármacos , Células PC12 , Ratos , Solventes/química
14.
J Neurochem ; 97(3): 641-51, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16515539

RESUMO

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a dually functional protein, acting both as a PGD2-synthesizing enzyme and as an extracellular transporter of various lipophilic small molecules. L-PGDS is expressed in oligodendrocytes (OLs) in the central nervous system and is up-regulated in OLs of the twitcher mouse, a model of globoid cell leukodystrophy (Krabbe's disease). We investigated whether up-regulation of L-PGDS is either unique to Krabbe's disease or is a more generalized phenomenon in lysosomal storage disorders (LSDs), using LSD mouse models of Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis and Niemann-Pick type C1 disease. Quantitative RT-PCR revealed that L-PGDS mRNA was up-regulated in the brains of all these mouse models. In addition, strong L-PGDS immunoreactivity was observed in OLs, but not in either astrocytes or microglia in these models. Thus, up-regulation of L-PGDS appears to be a common response of OLs in LSDs. Moreover, surface plasmon resonance analyses revealed that L-PGDS binds GM1 and GM2 gangliosides, accumulated in neurons in the course of LSD, with high affinities (KD = 65 and 210 nm, respectively). This suggests that L-PGDS may play a role in scavenging harmful lipophilic substrates in LSD.


Assuntos
Gangliosídeos/metabolismo , Oxirredutases Intramoleculares/metabolismo , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/patologia , Oligodendroglia/metabolismo , Regulação para Cima/fisiologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gangliosídeos/classificação , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Peptídeos e Proteínas de Sinalização Intracelular , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/farmacocinética , Lectinas , Lipocalinas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Proteína C1 de Niemann-Pick , Oligodendroglia/efeitos dos fármacos , Proteínas/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Ressonância de Plasmônio de Superfície/métodos , Fatores de Tempo , beta-Galactosidase/deficiência , beta-N-Acetil-Hexosaminidases/classificação , beta-N-Acetil-Hexosaminidases/deficiência
15.
J Clin Neurosci ; 12(4): 409-15, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15925771

RESUMO

This study was performed to determine whether increased ganglioside-specific T cell reactivity can be detected in the peripheral blood of patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). T cell responsiveness to the gangliosides GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed in peripheral blood mononuclear cells from untreated GBS patients (57), CIDP patients (43), patients with other peripheral neuropathies (55) and healthy control subjects (74) in a standard 6-day proliferation assay. Increased T cell reactivity to GM1 occurred in GBS patients compared to healthy controls and patients with other neuropathies. There was increased reactivity to GM3 in GBS patients compared to patients with other neuropathies but not compared to healthy controls. The frequencies of increased T cell reactivity to GM1 and GM3 in CIDP patients were intermediate between those of GBS patients and controls. We suggest that T cell reactivity to gangliosides might play a contributory role in the pathogenesis of GBS and perhaps CIDP.


Assuntos
Gangliosídeo G(M1)/farmacologia , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/patologia , Linfócitos T/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/efeitos dos fármacos , Distribuição de Qui-Quadrado , Feminino , Gangliosídeos/classificação , Gangliosídeos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/metabolismo , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/patologia , Toxoide Tetânico/farmacologia
16.
J Peripher Nerv Syst ; 10(2): 94-112, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15958123

RESUMO

This presentation highlights aspects of the immunobiology of the Guillain-Barré syndromes (GBS), the world's leading cause of acute autoimmune neuromuscular paralysis. Understanding the key pathophysiological pathways of GBS and developing rational, specific immunotherapies are essential steps towards improving the clinical outcome of this devastating disorder. Much of the research into GBS over the last decade has focused on the forms mediated by anti-ganglioside antibodies, and we have made substantial progress in our understanding in several related areas. Particular highlights include (a) the emerging correlations between anti-ganglioside antibodies and specific clinical phenotypes, notably between anti-GM1/anti-GD1a antibodies and the acute motor axonal variant and anti-GQ1b/anti-GT1a antibodies and the Miller Fisher syndrome; (b) the identification of molecular mimicry between GBS-associated Campylobacter jejuni oligosaccharides and GM1, GD1a, and GT1a gangliosides as a mechanism for anti-ganglioside antibody induction; (c) the development of rodent models of GBS with sensory ataxic or motor phenotypes induced by immunisation with GD1b or GM1 gangliosides, respectively. Our work has particularly studied the motor nerve terminal as a model site of injury, and through combined active and passive immunisation paradigms, we have developed murine neuropathy phenotypes mediated by anti-ganglioside antibodies. This has been achieved through use of glycosyltransferase and complement regulator knock-out mice, both for cloning anti-ganglioside antibodies and inducing disease. Through such studies, we have proven a neuropathogenic role for murine anti-ganglioside antibodies and human GBS-associated antisera and identified several determinants that influence disease expression including (a) the level of immunological tolerance to microbial glycans that mimic self-gangliosides; (b) the ganglioside density in target tissue; (c) the level of complement activation and the neuroprotective effects of endogenous complement regulators; and (d) the role of calcium influx through complement pores in mediating axonal injury. Such studies provide us with clear information on an antibody-mediated pathogenesis model for GBS and should lead to rational therapeutic testing of agents that are potentially suitable for use in humans.


Assuntos
Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Neurobiologia , Animais , Anticorpos Anti-Idiotípicos/metabolismo , Antígenos CD/imunologia , Antígenos CD/metabolismo , Modelos Animais de Doenças , Gangliosídeos/classificação , Gangliosídeos/imunologia , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/patologia , Humanos , Modelos Biológicos , Proteínas de Neurofilamentos/imunologia , Proteínas de Neurofilamentos/metabolismo , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Junção Neuromuscular/fisiopatologia , Nervos Periféricos/imunologia , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Nervos Periféricos/ultraestrutura
17.
Ann Neurol ; 57(3): 396-407, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15732093

RESUMO

In this study, we used a monoclonal IgM antibody from a patient with a pure motor chronic demyelinating polyneuropathy, which binds specifically to the complex gangliosides GM(2), GalNAc-GD(1a), and GalNAc-GM(1b), which appear to have a common epitope of -[GalNAcbeta1-4Gal(3-2alphaNeuAc)beta1]. This was done for the following reasons: (1) to localize these gangliosides in specific cellular components of the neuromuscular junction (NMJ), and (2) to describe the anti-ganglioside antibody-induced structural and functional changes in the NMJs to gain insight into the role of gangliosides in the synaptic function. Using immunofluorescence techniques, we found that these gangliosides are located only in the presynaptic component of the motor end-plates, both in nerve terminals and in Schwann cells. After 2 weeks of continued passive transfer of the IgM monoclonal antibody over the mouse levator auris longus muscle, electromyography showed an axonal or NMJ disorder. Morphology showed important nerve terminal growth and retraction changes. Using intracellular recording electrophysiology, we found neurotransmitter release alterations, including quantal content reduction and an immature expression of voltage-dependent calcium channels similar to what occurred during NMJ development and regeneration. These changes were complement independent. The results showed that these gangliosides were involved in the reciprocal Schwann cell-nerve terminal interactions, including structural stability and neurotransmission.


Assuntos
Gangliosídeos/imunologia , Imunoglobulina M/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Gangliosídeo G(M2)/metabolismo , Gangliosídeos/classificação , Humanos , Imuno-Histoquímica/métodos , Potenciais da Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Microscopia Confocal/métodos , Denervação Muscular/métodos , Proteínas de Neurofilamentos/metabolismo , Junção Neuromuscular/fisiologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Proteínas Qa-SNARE , Receptores Colinérgicos/metabolismo , Proteínas S100/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Fatores de Tempo
18.
J Peripher Nerv Syst ; 9(3): 138-43, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15363061

RESUMO

Few reports exist on the association between the humoral immune response to glycolipids and neuropathic findings in diabetes. To address this issue, we assayed serum anti-GM1, GD1b, GD1a, and sulfatides IgG and IgM in a group of 85 non-selected diabetic patients, and correlated these antibodies to clinical and electrophysiological findings. Diabetic patients had higher mean titers of anti-GM1 (IgM), GD1b, GD1a, and sulfatide (IgG) antibodies when compared to healthy controls. Patients with a positive titer of anti-ganglioside antibodies had significant alterations of motor conduction parameters. The statistical significance increased when considering those patients with both anti-ganglioside reactivity and a high value for glycosylated hemoglobin. Production of antibodies to ganglioside may follow the exposure of hidden motor nerve epitopes in damaged motor nerves and contribute to the neuropathy.


Assuntos
Anticorpos/sangue , Complicações do Diabetes , Diabetes Mellitus/imunologia , Gangliosídeos/imunologia , Doença dos Neurônios Motores/etiologia , Doença dos Neurônios Motores/imunologia , Potenciais de Ação/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Anticorpos/classificação , Demografia , Diabetes Mellitus/classificação , Eletromiografia/métodos , Feminino , Gangliosídeos/classificação , Humanos , Imunoglobulinas/classificação , Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia
19.
J Peripher Nerv Syst ; 8(2): 82-90, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12795712

RESUMO

Many patients with variant forms of Guillain-Barré syndrome (vGBS) associated with anti-ganglioside antibodies, including Miller Fisher syndrome (MFS), sometimes exhibit miniature endplate potential (MEPP) frequency increases (MFI, described as alpha-latrotoxin-like effects in a previous report) and the factor to produce this effect is present in their sera. MFI-positive sera increase the frequency of MEPPs, then block neuromuscular transmission at the mouse neuromuscular junction. A connection between this effect at the neuromuscular junction and some vGBS symptoms is suspected. We measured MFI directly at several points during the clinical course of 8 vGBS patients who had various symptoms and courses. Six patients had confirmed MFI and this activity decreased with convalescence. In 3 clinically mild cases, we were able to elicit MFI using normal serum to supply complement after exposure to the patient's serum. The anti-GQ1b/GT1a IgG titer, the extent of ophthalmoplegia and the extent of MFI were significantly correlated. They did not correlate with the severity of limb weakness or the occurrence of respiratory failure. These results support the hypothesis that MFI caused by anti-ganglioside antibodies is the pathogenic mechanism responsible for ophthalmoplegia in vGBS; different mechanisms or antibodies may explain limb weakness and respiratory failure. Furthermore, MFI may be an important indicator of how serum injures the nerve terminals. The symptoms of vGBS may result from multiple pathogenic factors.


Assuntos
Anticorpos Anti-Idiotípicos/sangue , Gangliosídeos/imunologia , Síndrome de Guillain-Barré , Transmissão Sináptica/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Conotoxinas/farmacologia , Reações Cruzadas , Estimulação Elétrica , Eletrofisiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Gangliosídeos/classificação , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Placa Motora/fisiologia , Músculos/fisiologia , Oftalmoplegia/sangue , Oftalmoplegia/fisiopatologia , Transtornos Respiratórios/sangue , Transtornos Respiratórios/fisiopatologia , Estatística como Assunto/métodos , Transmissão Sináptica/efeitos dos fármacos
20.
J Neurol Sci ; 210(1-2): 99-103, 2003 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12736097

RESUMO

Anti-ganglioside antibodies frequently are present in sera from patients with Guillain-Barré syndrome (GBS) during the acute phase, but no patients in whom anti-ganglioside antibodies were tested before the onset of the syndrome have been reported. We describe the first case of GBS subsequent to Campylobacter jejuni infection, in which longitudinal changes in anti-ganglioside antibody titers were measured before and after the onset of limb weakness. Serum antibody titers against GM1 (IgM/IgG), GM1b (IgM/IgG), GalNAc-GD1a (IgM/IgG), and GD1b (IgG) were highest on the day of onset, but negative before onset. Anti-C. jejuni IgG and IgA antibody titers paralleled those of the anti-ganglioside antibodies, indicative that C. jejuni infection triggered anti-ganglioside antibody production. Press et al. [J. Neurol. Sci. 190 (2001) 41] reported that anti-ganglioside antibody titers peaked during the recovery phase, but our findings are counter to theirs. We speculate that anti-ganglioside antibodies are the primary effectors of nerve damage in GBS.


Assuntos
Enterite/imunologia , Gangliosídeos/imunologia , Síndrome de Guillain-Barré/imunologia , Anticorpos/imunologia , Campylobacter jejuni/imunologia , Criança , Enterite/complicações , Feminino , Gangliosídeos/classificação , Gangliosídeos/metabolismo , Síndrome de Guillain-Barré/etiologia , Humanos , Isotipos de Imunoglobulinas/metabolismo , Infecções , Síndrome de Miller Fisher/imunologia , Fatores de Tempo
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