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PubMed2001

Serum ganglioside patterns in multiple sclerosis.

The relative distribution of gangliosides was determined in the serum of 37 patients with multiple sclerosis (MS) and of 30 healthy subjects. There was a significant increase of GM1 and GD1a, and a decrease of GM3 proportion in the serum of relapsing-remitting MS patients (RRMS) during their first MS attack. The RRMS patients in relapse with a long duration of the disease had a significant decrease of GM1 and an increase of GD1a portion in the serum. An increase of GD1a, one of the major brain neuron ganglioside fraction, suggested the neuron injury in the early and with a long duration RRMS. The finding of an increase of GM1, the main human myelin ganglioside, during the first MS attack in RRMS patients confirms previous evidence for the possible involvement of gangliosides in the early pathological course of demyelination in MS.

G(M1) Ganglioside↗
PubMed1998

Direct immobilization of gangliosides onto gold-carboxymethyldextran sensor surfaces by hydrophobic interaction: applications to antibody characterization.

We describe a novel immobilization technique to investigate interactions between immobilized gangliosides (GD3, GM1, and GM2) and their respective antibodies, antibody fragments, or binding partners using an optical biosensor. Immobilization was performed by direct injection onto a carboxymethyldextran sensor chip and did not require derivatization of the sensor surface or the ganglioside. The ganglioside appeared to bind to the sensor surface by hydrophobic interaction, leaving the carbohydrate epitope available for antibody or, in the case of GM1, cholera toxin binding. The carboxyl group of the dextran chains on the sensor surface did not appear to be involved in the immobilization as evidenced by equivalent levels of immobilization following conversion of the carboxyl groups into acyl amino esters, but rather the dextran layer provided a hydrophilic coverage of the sensor chip which was essential to prevent nonspecific binding. This technique gave better reactivity and specificity for anti-ganglioside monoclonal antibodies (anti-GD3: KM871, KM641, R24; and anti-GM2: KM966) than immobilization by hydrophobic interaction onto a gold sensor surface or photoactivated cross-linking onto carboxymethydextran. This rapid immobilization procedure has facilitated detailed kinetic analysis of ganglioside/antibody interactions, with the surface remaining viable for a large number of cycles (>125). Kinetic constants were determined from the biosensor data using linear regression, nonlinear least squares and equilibrium analysis. The values of kd, ka, and KAobtained by nonlinear analysis (KAKM871 = 1.05, KM641 = 1.66, R24 = 0.14, and KM966 = 0.65 x 10(7) M-1) were essentially independent of concentration and showed good agreement with data obtained by other analytical methods.

Antibodies, Monoclonal↗
PubMed1977

Gangliosides of active and inactive neuroblastoma clones.

It is possible to divide neuroblastoma cells into clones able to synthesize neurotransmitters (active clones) or not (inactive clones). The analysis of gangliosides of active and inactive clones shows that their total lipid sialic acids is markedly lower than that of neuron-enriched fractions prepared from brain. The ganglioside pattern of the cultured cells also differs notably from those obtained with neuronal fractions from brain. The absence of tri- and tetrasialogangliosides and the presence of appreciable amounts of the simplest monosialogangliosides are particularly noticeable in the neuroblastoma. Morphological differentiation obtained by serum deprivation, dibutyryl cyclic AMP or bromodeoxyuridine does not restore a true neuronal pattern. Gangliosides could not therefore be used as a marker of neuronal differentiation in this type of cell. No correlations can be found between the ganglioside pattern and the ability of cells to synthesize neurotransmitters.

Bromodeoxyuridine↗
PubMed1992

Myelin gangliosides of human peripheral nervous system: an enrichment of GM1 in the motor nerve myelin isolated from cauda equina.

Myelins of the PNS were isolated from human motor and sensory nerves of cauda equina, and their ganglioside compositions were compared. The predominant ganglioside in the human PNS myelins, both from motor and sensory nerves, was LM1 (sialosylneolactotetraosylceramide). Sialosyl-nLc6Cer and disialosyl-nLc4Cer, GD3, GM3, and GD1b were detected as common components of the two nerve myelins. Furthermore, it was revealed that the motor nerve myelin contained GM1 (about 15% of total gangliosides), whereas sensory nerve myelin contained only a trace amount of GM1 (less than 5%), by TLC analyses together with TLC immunostaining using anti-GM1 antibody. As for the disialoganglioside fraction, the content of GD1a, as well as that of GM1, differed in motor and sensory nerves. Thus, the different contents of the ganglioseries gangliosides in human motor and sensory nerve myelins were demonstrated.

Cauda Equina↗
PubMed2002

Phase variation of Campylobacter jejuni 81-176 lipooligosaccharide affects ganglioside mimicry and invasiveness in vitro.

The outer cores of the lipooligosaccharides (LOS) of many strains of Campylobacter jejuni mimic human gangliosides in structure. A population of cells of C. jejuni strain 81-176 produced a mixture of LOS cores which consisted primarily of structures mimicking GM(2) and GM(3) gangliosides, with minor amounts of structures mimicking GD(1b) and GD(2). Genetic analyses of genes involved in the biosynthesis of the outer core of C. jejuni 81-176 revealed the presence of a homopolymeric tract of G residues within a gene encoding CgtA, an N-acetylgalactosaminyltransferase. Variation in the number of G residues within cgtA affected the length of the open reading frame, and these changes in cgtA corresponded to a change in LOS structure from GM(2) to GM(3) ganglioside mimicry. Site-specific mutation of cgtA in 81-176 resulted in a major LOS core structure that lacked GalNAc and resembled GM(3) ganglioside. Compared to wild-type 81-176, the cgtA mutant showed a significant increase in invasion of INT407 cells. In comparison, a site-specific mutation of the neuC1 gene resulted in the loss of sialic acid in the LOS core and reduced resistance to normal human serum but had no affect on invasion of INT407 cells.

Antigens, Bacterial↗
PubMed2001

Ganglioside G(D2) in small cell lung cancer cell lines: enhancement of cell proliferation and mediation of apoptosis.

Expression levels of gangliosides and glycosyltransferase genes responsible for their syntheses in human lung cancer cell lines and a normal bronchial epithelial cell line were analyzed. Both non-small cell lung cancers and small cell lung cancers (SCLCs) mainly expressed G(M2) and G(M1), whereas only SCLCs expressed b-series gangliosides, such as G(D2), G(D1b), and G(T1b). Accordingly, many SCLC cell lines showed up-regulation of the G(D3) synthase gene. Consequently, we introduced G(D3) synthase cDNA into a SCLC line with low expression of b-series gangliosides and analyzed the effects of newly expressed gangliosides on tumor phenotypes. The transfectant cells expressing high levels of G(D2) and G(D3) exhibited markedly increased growth rates and strongly enhanced invasion activities. Addition of anti-G(D2) monoclonal antibodies into the culture medium of these cells resulted in the marked growth suppression of G(D2)-expressing cell lines with reduced activation levels of mitogen-activated protein kinases but not of nonexpressants, suggesting that G(D2) plays important roles in cell proliferation. Moreover, G(D2)-expressing cells treated with anti-G(D2) antibodies showed features of apoptotic cell death at 30 min after addition of antibodies, i.e., shrinkage of cytoplasm, binding of Annexin V, and staining with propidium iodide, followed by DNA fragmentation. This G(D2)-mediated apoptosis was associated with caspase-3 activation and partly inhibited by a caspase inhibitor, z-Val-Ala-Asp-fluoromethyl ketone. The finding that anti-G(D2) antibodies suppressed the cell growth and induced apoptosis of SCLC cells strongly suggested the usefulness of G(D2) as a target for the therapy of disastrous cancer, although the precise mechanisms for apoptosis remain to be clarified.

Antibodies, Monoclonal↗
PubMed1985

Activator protein required for the enzymatic hydrolysis of cerebroside sulfate. Deficiency in urine of patients affected with cerebroside sulfatase activator deficiency and identity with activators for the enzymatic hydrolysis of GM1 ganglioside and globotriaosylceramide.

Urine specimens from two sibs affected with cerebroside sulfatase activator deficiency were examined to ascertain whether the deficiency of the supplementary activator protein required for the enzymatic hydrolysis of cerebroside sulfate was also evident in urine. Material from chromatographic fractionations was examined for the activator activity to avoid ambiguities resulting from protein inhibition. There were substantial deficits in all chromatographic fractions corresponding to activator-containing fractions of control urines. Since patient urines contained elevated amounts of lactosylceramide, digalactosylceramide, and globotriaosylceramide and since similarities between activators for cerebroside sulfate and GM1 ganglioside hydrolyses had been noted previously, the chromatographic fractions were also examined for activators in other glycosphingolipid hydrolase systems. There was coincidence of activators for the GM1 ganglioside/beta-galactosidase and the globotriaosylceramide/alpha-galactosidase A reactions with the cerebroside sulfatase activator in control urine fractions, and the patients' urines were deficient in activator activities for the three reactions. Identity of the three activators was suggested and antiserum to purified GM1 ganglioside activator was used to test this possibility. There were depressed levels of cross-reacting material in fractions of patient urines by Ouchterlony double diffusion and in unfractionated urine by enzyme-linked immunosorbent assay. Purified activators for the cerebroside sulfate and GM1 ganglioside systems showed lines of identity with no spurring on Ouchterlony double diffusion, identical mobility on immunoelectrophoresis, and similar stimulatory activities toward hydrolysis of the three glycosphingolipid species by their respective enzymes. Finally, the three activator activities were retained by anti-GM1-activator IgG coupled to Sepharose 4B. The results suggest strongly that the same protein entity serves as activator for the enzymatic hydrolysis of cerebroside sulfate, GM1 ganglioside, and globotriaosylceramide.

Animals↗
PubMed1996

Gangliosides GM1, GM2 and GM3 inhibit the platelet-derived growth factor-induced signalling transduction pathway in vascular smooth muscle cells by different mechanisms.

Gangliosides appear to regulate proliferation of different cell types. In the present study, we investigated the effects of gangliosides GM1, GM2 and GM3 on platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell (VSMC) growth. In addition, we examined the effects of gangliosides on the PDGF-BB-dependent signalling transduction pathway in rat aortic VSMC. GM2 and GM1 inhibit the PDGF-BB-dependent receptor tyrosine autophosphorylation, stimulation of the PLC-gamma 1, increase of inositol-1,4,5-trisphosphate (InsP3), elevation in cytosolic free Ca2+ ([Ca2+]i), expression of the immediate early growth response gene c-fos and cell proliferation with the following rank order of potency GM2 > GM1. Although GM3 did not influence the PDGF-BB-dependent receptor autophosphorylation and PLC-gamma 1 activation, it effectively inhibited the PDGF-BB-dependent InsP3 formation, [Ca2+]i and cell growth. Binding studies with 125I-PDGF-BB on VSMC in the presence and absence of 10 to 50 microM of each ganglioside revealed that GM1 and GM2 effectively inhibited the specific binding of PDGF-BB with an IC50 value of 20 microM for GM2 and 30 microM for GM1. GM3 had no significant effect on the specific 125I-PDGF-BB binding. These observations suggest that GM1 and GM2 may interact with PDGF-BB or its receptor resulting in a prevention of its binding. GM3 was able to suppress the PDGF-BB-dependent increase of InsP3 and [Ca2+]i downstream of the PDGF-BB-dependent receptor autophosphorylation and PLC-gamma 1 activity.

Animals↗
PubMed1988

A new approach to the modification of cell membrane glycosphingolipids: ganglioside composition of JTC-12 P3 cells altered by feeding with galactose as a sole carbohydrate source in protein- and lipid-free synthetic medium.

A significant difference in the glycosphingolipid composition of JTC-12 P3 cells established from monkey kidney tissue was observed when cells cultured in a protein- and lipid-free synthetic medium containing glucose (DM-160) as a sole carbohydrate source were transferred and cultured in the same medium containing galactose and pyruvic acid (DM-170) in place of glucose. In particular, the amounts of gangliosides GM3, GM2, and GD3 in the cells cultured in DM-170 were 5.3-, 17.8-, and more than 8-fold those in the cells cultured in DM-160, respectively, indicating that anabolism of gangliosides is greatly enhanced in cells cultured in the presence of galactose and pyruvic acid, as compared with cells cultured in the presence of glucose. In fact, after cultivation of cells in the medium with N-acetyl-D-[14C]mannosamine for 96 h, the radioactivity incorporated into the gangliosides of the cells in DM-170 was 10-fold that of the cells in DM-160. Among the gangliosides of the cells in DM-170, highly sialylated molecules such as GD3, GD1a, GD1b, and GT1b were preferentially labeled, indicating that the sialyltransferases responsible for the synthesis of gangliosides are significantly more activated in cells cultured in DM-170 than in DM-160. These observations reveal that the glycosphingolipid composition of the plasma membrane can be modified epigenetically under well-defined conditions and provide important clues for clarifying the roles of glycosphingolipids associated with particular cell functions.

Animals↗
PubMed2000

Molecular cloning of mouse ganglioside sialidase and its increased expression in Neuro2a cell differentiation.

Ganglioside sialidases have been implicated in neuronal differentiation processes, including neurite outgrowth. To understand further the roles and regulation mechanisms of the sialidase in neuronal systems, we have cloned mouse ganglioside sialidase cDNA and observed its expression in Neuro2a cell differentiation. A 3339-base pair cDNA, cloned based on the sequence information of previously cloned enzymes, encodes 418 amino acids containing three Asp boxes characteristic of sialidases. Northern blot analysis revealed a 3.4-kilobase transcript expressed highly in heart but also in several other tissues including brain. In situ hybridization of mouse brain demonstrated the mRNA to be present in the cerebral cortex, as well as in the granule cell layer, Purkinje cells, and deep cerebellar nucleus of the cerebellum. Transient expression of the cDNA in COS-1 cells resulted in over 300-fold increase in sialidase activity toward gangliosides compared with the control level, with a preference for ganglioside substrate. During 5-bromodeoxyuridine-induced Neuro2a cell differentiation, the expression of the sialidase was increased as assessed by activity assays and quantitative reverse transcription-polymerase chain reaction analyses. Stable transfection of the sialidase in Neuro2a cells resulted in accelerated neurite arborization following 5-bromodeoxyuridine treatment, indicating the direct participation of this ganglioside sialidase in neuronal cell differentiation.

Amino Acid Sequence↗
PubMed2003

Effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury.

OBJECTIVE: To observe the effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury (TBI). METHODS: An acute experimental closed TBI model in rats was induced by a fluid-percussion brain injury model. At five and sixty minutes after TBI, the animals were intraperitoneally injected by ganglioside GM1 (30 mg/kg) or the same volume of saline. At the 6th hour after TBI, effects of ganglioside GM1 or saline on changes of mean arterial pressure (MAP), contents of water, lactic acid (LA) and lipid peroxidation (LPO) in the injured cerebral tissues were observed. RESULTS: After TBI, MAP decreased and contents of water, LA and LPO increased in brain injury group; however, MAP was back to normal levels and contents of water, LA and LPO decreased in ganglioside GM1 treated group, compared with those in brain injury group (P < 0.05). No significant difference between the saline treated group and the brain injury group (P > 0.05) was observed. CONCLUSIONS: Ganglioside GM1 does have obvious neuroprotective effect on early TBI.

Animals↗
PubMed1991

Ganglioside GM3:GD3 ratio as an index for the management of melanoma.

This report evaluates the relevance of the ratio of the melanoma-associated ganglioside, GD3, and its precursor, GM3, to prognosis and management of Stage II disease. Tumor biopsy specimens from 42 melanoma patients were examined for the ratio and found that GD3 and GM3 constitute 80% of the total lipid bound sialic acids (LBSA) of melanoma. Although the ratio of GM3:GD3 in melanocytes, the progenitors of melanoma, is 19:1 (based on %LBSA), it ranged from 15:1 to 1:5 in tumor biopsy specimens. Patients are categorized into three groups based on their GM3:GD3 ratio (%LBSA) of tumor tissues as Group I (ratio ranged from 15:1 to 1.5:1) (10 of 42), Group II (1.4:1 to 1:1.4) (13 of 42), and Group III (1:1.5 to 1:5) (19 of 42). When the overall survival of patients from the onset of Stage II disease was evaluated among different groups, patients belonging to Group I survived significantly longer than patients of Group II (P = 0.02) and Group III (P = 0.01). Interestingly, Group III expressed immunogenic gangliosides (GD2, GM2, and O-AcGD3) better than the other groups and may benefit more from therapies targeted against these gangliosides antigens. The results of this study indicate that GM3:GD3 ratio is an unusual but well-defined biochemical criteria that may be useful for prognosis and therapeutic management of the disease. Therefore, we propose a routine analysis of the GM3:GD3 ratio of tumors excised after surgery. Screening the ratio is feasible since melanoma expresses a simple profile of gangliosides unlike other forms of cancer.

Adolescent↗
PubMed1980

Serum gangliosides in cerebral astrocytoma.

The serum concentration and composition of gangliosides were examined in 80 humans including 10 normal subjects. A significant increase was found in the total gangliosides of serum in 7 patients with cerebral astrocytomas. There was also an increased percentage of serum gangliosides with simpler structure, particularly GM3. The serum of patients with other intracranial tumors, including pituitary adenomas, ependymoma, teratoma, and metastases, did not show an increase in total ganglioside; however the pattern of simplification was found in these and in a few patients with extracranial tumors as well. The findings suggest that astrocytoma tumors shed sialoglycolipids into the circulation, and their assay may be useful in monitoring oncological therapy.

Astrocytoma↗
PubMed1984

Biological activity of preformed cholera toxin-ganglioside GM1 complex.

Synthetic and natural amphiphiles, octyl glucoside, Nonidet P40, sodium dodecyl sulfate (SDS), gangliosides GM1 and GD1a, interact with cholera toxin (CLT) and with its active region (promoter A). The formation of CLT-amphiphile complex leads to inhibition of ADP-ribosyltransferase activity, a characteristic of promoter A elicited after thiol-reagents treatment. In all cases the interaction produces the maximum inhibitory effect above the critical micellar concentration of amphiphiles, although monomers of SDS show inhibition activity as well. The gangliosides appear to be capable of altering bilayer organization of membrane, similar to synthetic detergents. When CLT-ganglioside complexes were incubated with cell culture medium containing 10% fetal calf serum (FCS) and ADP-ribosyltransferase activity was completely restored both in cholera toxin and in promoter A. Some protein of FCS, which is avid of gangliosides, seems to be responsible for reversibility of inhibition. The results indicate that the active site of promoter A may be located in a hydrophobic pocket of the toxin structure. Furthermore, CLT was bound to reconstituted Sendai virus envelopes (RSVEs), containing a small amount of GM1. The RSVEs are made of membranous vesicles, capable of binding and fusing with host cell membrane. The incubation for 1 1hr of RSVE bearing CLT with Friend's erythroleukemic cells produced the stimulation of adenylate cyclase. This stimulation appears to be due to the translocation of the active subunit of CLT in the inner half of plasma membrane.

Adenylyl Cyclases↗
PubMed1994

In vitro modulation of changes in ganglioside patterns of differentiating neurons in the presence of an anti-GM1 antibody.

Retinal cells from 7-day-old chicken embryos were cultured in the presence of a polyclonal anti-GM1 antibody, at low and high density in a "sandwich cell culture". Cells that were about 80% neurofilament positive at all times, changed their morphology and emitted processes as controls. By examining immunocytochemical expression of gangliosides, cells cultured in the presence of the antibody maintained GD3 expression longer than controls, albeit the expression of the gangliotetraosylgangliosides (GTOG) was not considerably affected. This leads to an extension of the transient period in which differentiating cells coexpressed both types of gangliosides (GD3 and GTOG). At 3-4 days in vitro the relative synthesis of GD3 was about 30% higher and that of GD1a about 40% lower than in controls, indicating a delay in the shift of the synthesis pattern. Nevertheless, the pattern of ganglioside composition resembled at 4 days in vitro. Results indicate that the anti-GM1 antibody may modulate the expression and synthesis of gangliosides without a detectable decrease in neuritogenesis. Considering that the emission of neurites occurs in coexpressing GD3 and GTOG neurons, it is suggested that neuritogenesis could be irrespective of losing the GD3 expression.

Animals↗
PubMed2006

A liquid chromatography/tandem mass spectrometric approach for the determination of gangliosides GD3 and GM3 in bovine milk and infant formulae.

A liquid chromatographic/tandem mass spectrometric method using pneumatically assisted electrospray ionisation (LC/ESI-MS/MS) was developed for the determination of gangliosides GD3 and GM3 in milk and infant formulae. The gangliosides were extracted in a chloroform/methanol/water environment and cleaned up by solid-phase extraction (SPE) on an end-capped C8 sorbent. The gangliosides were detected in negative ion mode after separation on a reversed-phase (RP) C5 analytical column. From the different ganglioside molecular species, product ions at m/z 290 corresponding to an N-acetylneuraminic acid fragment were produced in the collision cell and used in selected reaction monitoring. A standard addition technique was applied for quantification. The relative repeatability standard deviations were less than 5% for GD3 (level 10 mg/L) and 14% for GM3 (level 0.1-0.2 mg/L).

Animals↗
PubMed1994

Interaction between ganglioside-containing liposome and rat T-lymphocyte: confocal fluorescence microscopic study.

Interaction between rat T-lymphocytes and a ganglioside (GM3, GD3, GT1b, or GQ1b)-containing liposome was investigated in vitro. The direct stimulation of T cell by a ganglioside-containing liposome was followed by monitoring an increase in the intracellular calcium signal using a confocal laser fluorescence microscopic method. The GT1b- or GQ1b-containing liposome strongly stimulated the cell, while the GM3- or GD3-containing liposome showed much less effect. Free gangliosides did not stimulate the cell at all under the same condition. The extent of the stimulation depended on the surface density of GT1b on the liposome accompanied by a clear threshold concentration. The efficiency of this direct T cell stimulation with the ganglioside-containing liposome was closely related to the efficiency of the tumor growth suppression reported previously by ourselves.

Aniline Compounds↗
PubMed1998

Dependence of cardiac cell Ca2+ permeability on sialic acid-containing sarcolemmal gangliosides.

The specific removal of negatively-charged sialic acid by neuraminidase produces a large increase in cardiac myocyte Ca uptake (17.3 +/- 1.1 mmol Ca/kg dry weight) and marked cell contracture. Importantly, the insertion of the negatively-charged amphiphile dodecyl sulfate in the sarcolemma eliminates the increased calcium uptake and preserves contractile function. In the present study, we further examine the role of sialic acid-Ca interaction and, specifically, the role of gangliosides (sialic acid-containing glycolipids) in cardiac cells' Ca permeability. Neonatal cell culture and adult ventricular myocytes were used. The major findings of this study are: (1) while dodecyl sulfate inhibits cellular calcium uptake and contracture development induced by sialic acid removal, cationic and neutral amphiphiles are without effect. (2) Ca channel blockers (nifedipine and protamine) and the Na/Ca exchange inhibitor Ni do not modify the effect of sialic acid removal. (3) A non-classical-channel related whole-cell current appears and increases after 21 +/- 2.2 min treatment with 0.02 U/ml neuraminidase (n = 4). Incubation with neuraminidase in the presence of dodecyl sulfate greatly delays the appearance of these currents to 44.4 +/- 6.1 min (n = 4). (4) The use of a specific probe for GM1 ganglioside, the cholera toxin B subunit (3 micrograms/ml), induces a moderate but clear increase in cellular Ca (1.63 +/- 0.3 mmol Ca kg dry weight; n = 8). However, this increase was not modified by treatment with dodecyl sulfate. (5) Finally, 50 mU/ml endoglycoceramidase, an enzyme which specifically cleaves the link between the sialic acid-containing oligosaccharide and ceramide of gangliosides, induced a significant increase in Ca uptake (4.4 +/- 0.9 mmol Ca kg dry weight, n = 4). These results indicate the importance of negatively charged sialic acid-containing gangliosides in the maintenance of cardiac cell physiological Ca permeability. The increase in Ca uptake induced by the removal of sialic acid seems to be mediated by development of a Ca "leak" via other than classical cation channels.

Animals↗