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PubMed1978

Isolation and characterization of a novel ganglioside, monosialosyl pentahexaosyl ceramide from human brain.

A novel monosialosyl ganglioside was isolated from human brain in a yield of 2.1 nmol of the lipid-bound sialic acid per g of wet weight (0.09% of total lipid-bound sialic acid). The ganglioside was resistant to the action of Vibrio cholerae neuraminidase. By treatment with N-acetylhexosaminidase, methylation analysis, CrO3 oxidation, and partial acid hydrolysis, the structure of this ganglioside was determined to be; GalNAc(beta, 1-4)Gal(beta, 1-3)GalNAc(beta, 1-4)Gal(beta, 1-4)Glc(beta, 1-1)ceramide. (formula: see text). The treatment of the ganglioside with 1 N formic acid at 80 degrees C for 2 h produced mainly gangliotetraosyl ceramide, suggesting that the terminal N-acetylgalactosamine was more labile on formic acid treatment than galactose at nonreducing terminal.

Adult↗
PubMed1979

Ganglioside compositions of erythrocytes from various strains of inbred mice. Ocurrence of sialosylgalactosylceramide in red blood cells of inbred mice.

The gangliosides from the erythrocytes of various strains of inbred mice were analyzed. The ganglioside compositions differed in different strains and the strains could be divided into 4 types on the basis of this difference. The main ganglioside is GM4 or sialosyl galactosyl ceramide in Type 1, and unidentified ganglioside in Type 2, GM4 and GM2 in almost equal amounts in Type 3, and GM2 in Type 4.

Animals↗
PubMed1983

1,1,3,3-Tetramethylurea and triethanolamine as a new useful matrix for fast atom bombardment mass spectrometry of gangliosides and neutral glycosphingolipids.

Analysis of gangliosides from bovine brain was successfully performed by a newly developed method of fast atom bombardment mass spectrometry (FAB-MS). The use of triethanolamine with a few drops of 1,1,3,3-tetramethylurea as the matrix solution gave intense molecular ions of intact gangliosides tested, namely, GM1 and GD1a, corresponding to (M + Na)+ and (M + 2Na-H)+. Glycerol, that is usually used as a matrix solution for FAB-mass spectrometry, was not suitable for the analysis of gangliosides. Along with the molecular ion species, the ions pertaining to the carbohydrate sequence also appeared on the spectrum. The method was found to be useful for structural analysis using intact molecules of gangliosides and neutral glycosphingolipids.

Animals↗
PubMed1984

Gene-regulated expression of glycolipids: appearance of GD3 ganglioside in rat cells on transfection with transforming gene E1 of human adenovirus type 12 DNA and its transcriptional subunits.

Malignant transformation is known to be associated with characteristic changes of cell surface glycolipids, but the genetic background and underlying molecular mechanism of these changes are still unknown. Incorporation of oncogenic elements into cultured cells should provide a useful model for studies on this problem. We analyzed gangliosides of a clonal and fibroblastic rat cell line, 3Y1, and its transformed counterparts, E1Y, HY1, and CY1 cell lines. E1Y cells were established by transfection of 3Y1 cells with the transforming gene E1, minimum DNA fragment of human adenovirus type 12 (Ad 12) required for complete transformation of cells. HY1 cell line is the cells established with E1A which is a transcriptional subunit of the E1 and can transform incompletely cells. CY1 was established by co-transfection with parts of non-transforming gene E3 and E4 of Ad 12 DNA in addition to the E1. GD3 ganglioside (NeuAc alpha 2-8NeuAc alpha 2-3Gal beta 1-4Glc beta 1-1Cer) appeared in all these transfection-transformed cells but was undetectable in untransformed control cells. The appearance of GD3 was undoubtedly due to expression of E1A gene in association with oncogenic cell transformation. The expression of other gangliosides, particularly GM2 and GM1, were also influenced by transfection, but their expressions depended on the kind of oncogenic DNA fragments used. These results all suggest that ganglioside metabolism is under unexpectedly complicated gene control.

Adenoviruses, Human↗
PubMed1994

Altered ganglioside expression by SH-SY5Y cells upon retinoic acid-induced neuronal differentiation.

SH-SY5Y Neuroblastoma cells were used to study the effect of retinoic acid (RA)-induced differentiation on the expression of gangliosides and neuronal markers. In the presence of 10 microM RA, more than 70% of the cells differentiate to a neuronal phenotype within 8 days. They extend long neuritic processes and show an enhanced immuno-expression of neurone-specific enolase (NSE), neurofilament protein (NF-M), and polysialic acid (PSA). SH-SY5Y cells were found to express at least 12 different gangliosides. RA-induced neuronal differentiation led to a decrease in the content of GM2, GD3, and GD2 and to a 3-7 fold increased concentration of the ganglio-tetraosyl gangliosides GM1, GD1a, GT1a, GD1b, and GT1b. Thus, RA-induced neuronal differentiation of SH-SY5Y cells is accompanied by ganglioside changes similar to those observed during embryonic neuronal differentiation.

Antibodies, Monoclonal↗
PubMed1991

Occurrence of lacto series gangliosides 3'-isoLM1 and 3',6'-isoLD1 in human gliomas in vitro and in vivo.

Monoclonal antibodies (MAb; DMAb, monoclonal antibodies derived at Duke Medical Center) directed against the oncofetally expressed lactotetraosyl gangliosides 3'-isoLM1 (IV3NeuAc-LcOse4Cer) and 3',6'-isoLD1 (IV3NeuAc,III6NeuAc-LcOse4Cer) were produced and their reactivity spectra compared to that of the alpha-3'-isoLM1 MAb SL-50. The IgM MAb SL-50 defines the epitope NeuAc (or NeuGc)alpha 2-3Gal beta 1-3GlcNAc, the terminal sequence of both gangliosides. SL-50 requires an unsubstituted GlcNAc residue; IgM DMAb-14 will accept the alpha 2-6 linked sialic acid to GlcNAc found in 3',6'-isoLD1. Immunohistochemical localization of 3'-isoLM1 was performed on 31 biopsy specimens of human gliomas; 15 (48%) expressed 3'-isoLM1 as defined by binding of MAb SL-50. Staining of small anaplastic cells, giant cells, and the glial component of gliosarcomas was observed. Neoplastic gemistocytes, when present, showed particularly intense staining. The 3'-isoLM1 and 3',6'-isoLD1 distribution in cultured cell lines and derived xenografts of primary tumors of the human central nervous system and of embryonal or neuroectodermal tumor derivation was determined. Six of 29 cell lines expressed 3'-isoLM1: 2/16 gliomas, 3/3 teratomas, 1/1 pancreatic adenocarcinoma. No cell line expressed detectable 3',6'-isoLD1 by immunostain analysis of ganglioside extracts. The 3'-iso-LM1-positive cell lines expressed it in xenograft form; in five xenografts, the corresponding cell lines of which were 3'-isoLM1-negative, it was a proportion of the monosialoganglioside fraction. 3',6'-isoLD1 was detected in two xenografts, D-54 MG (glioma) and PA-1 (teratoma). The demonstration of 3'-isoLM1 in gliomas in in vivo forms and the relatively infrequent expression by derived cultured cells suggest that ganglioside expression is modified by environmental forces. Expression of 3'-isoLM1 and 3',6'-isoLD1 in fetal and neonatal brain, in intense reactive astrocytosis such as polyunsaturated fatty acid lipidosis, and in primary neoplasms of the central nervous system suggests their role in cell-cell attachment during development, migration, and neoplastic transformation.

Animals↗
PubMed1996

Sialyl Lewis(a) ganglioside in pancreatic cancer tissue correlates with the serum CA 19-9 level.

CA 19-9 ganglioside antigen was extracted from the tumors of 16 patients with pancreatic cancer and the antigen was confirmed by mass spectrometry to be a sialyl Lewis(a) ganglioside. Ductal adenocarcinomas from four patients, two whose Lewis blood phenotype was Le(a- b-), one with undifferentiated carcinoma, and one with an acinar cell carcinoma, did not contain detectable amounts of sialyl Le(a) ganglioside. A significant correlation was found between serum CA 19-9 levels and the recovery of ganglioside antigen from respective tumors, but not tumor burden.

Aged↗
PubMed2001

A purified GM3 ganglioside conjugated vaccine induces specific, adjuvant-dependent and non-transient antitumour activity against B16 mouse melanoma in vitro and in vivo.

The presence of substantial amounts of GM3 ganglioside on human melanomas and other tumours, together with its peculiar biological properties, makes this glycolipid a unique target for cancer immunotherapy. B16 mouse melanoma expresses GM3 and constitutes an appropriate model for the development of novel GM3-based vaccines. Recently, we hydrophobically incorporated purified GM3 into the outer membrane protein complex from Neisseria meningitidis to form very small size proteoliposomes (GM3/VSSP). We have examined the antitumour properties of GM3/VSSP vaccine and compared it with GM3 incorporated in very low density serum lipoproteins (GM3/VLDL). Immunization with four doses of GM3/VSSP vaccine (120 microg of ganglioside) plus Freund's adjuvant or Montanide ISA 51 significantly increased the overall survival of mice inoculated in the subcutis with 103 B16-F1 cells, whereas the GM3/VLDL immunogen was ineffective. The non-transient character of tumour protection was confirmed in animals surviving the first challenge and re-inoculated with 5 x 103 cells. GM3/VSSP vaccine also reduced the subcutaneous growth of highly aggressive B16-F10 cells. The importance of ganglioside structure in the tumour-protective effect of GM3/VSSP vaccine was confirmed using GM3 containing N-glycolylneuraminic acid, a ganglioside absent in melanoma cells. Immunostaining and enzyme-linked immunosorbent assay (ELISA) experiments showed a high specificity of immune sera against GM3 and the presence of all four IgG subclasses, with a preponderance of IgG2b and IgG3. In addition, a strong anti-B16 complement-mediated cytotoxicity was induced by vaccination with GM3/VSSP. The present data indicate the molecular specificity of GM3/VSSP vaccine as well as the adjuvant-dependent and non-transient character of tumour protection in the B16 mouse model. These findings suggest that an appropriate GM3 vaccine may be capable of inducing prolonged tumour protection in melanoma patients.

Animals↗
PubMed2006

Further evidence of local ganglioside-dependent amyloid beta-protein assembly in brain.

We investigated the molecular mechanism underlying the region-specific deposition of amyloid beta-protein in brains affected with Alzheimer's disease or cerebral amyloid angiopathy. Here, we show that a hereditary variant-type ('Iowa') amyloid beta-protein, which predominantly deposits in the cerebral vessel wall similar to Dutch and Italian-type amyloid beta-proteins, preferably assembles in the presence of GM3 ganglioside. On the basis of our previous findings that first, cerebrovascular smooth muscle cells that provide favorable sites for these variant-type amyloid beta-proteins exclusively express GM3 ganglioside, and second, Dutch and Italian-type amyloid beta-proteins also require GM3 ganglioside for their assembly, our results provide further evidence that local gangliosides play a crucial role in the region-specific amyloid beta-protein deposition in the brain.

Amyloid beta-Peptides↗
PubMed1993

Ganglioside GM3 inhibits the proliferation of cultured keratinocytes.

Ganglioside GM3 is the predominant ganglioside of keratinocyte membranes. It has been proposed in other cell types that GM3 may participate in the regulation of cell proliferation. To examine the role of GM3 in keratinocyte proliferation, purified GM3 was added to cultured keratinocytes from normal foreskin, from lesional skin of patients with psoriasis and ichthyosis, and to cutaneous squamous carcinoma cell lines. Supplemental GM3 inhibited the growth of all cultured keratinocytes in a dose-dependent manner at concentrations of 10-100 microM. Keratinocytes from patients with psoriasis and ichthyosis were most sensitive to the inhibitory effects of GM3, and confluent undifferentiated keratinocytes were least sensitive. No change in differentiation was noted after addition of GM3. GD3, 9-0-acetyl-GD3, and GD1b also inhibited keratinocyte proliferation. Gangliosides GM1 and GD1a and sialic acid had little effect. Addition of 50 microM 3H-GM3 to cultured keratinocytes resulted in 1.7 times the amount of cellular GM3. These data suggest that hematoside (GM3) and "b" pathway gangliosides (GD3, GD1b), generated by the preferential activation of sialyltransferase II versus N-acetylgalactosaminyltransferase, may be involved in control of keratinocyte growth but not of differentiation.

Cell Differentiation↗
PubMed1990

Antigen dynamics in melanocytic and nevocytic melanoma oncogenesis: anti-ganglioside and anti-ras p21 antibodies as markers of tumor progression.

Based on melanoma pathogenesis, phenotypic dynamics in pigment cell tumor progression detected with 11 MoAb have been defined. Anti-melanosomal A4F11 antibody reacts with every type of pigment cell tumor tested except for a few specimens. TNKH1 and anti-K.1.2 antibodies recognize nevocytic benign to premalignant tumors. HLA-DR, A.1.43, and A.10.33 antigens are expressed in advanced melanomas. Staining with anti-ganglioside GM3 and GD3 antibodies, M2590 and 4.2, respectively, reveals that most pigment cell tumors express gangliosides GM3 and GD3. But A2B5 antibody, which detects some polysialogangliosides such as GQ1C, reacts with highly progressed melanoma cells. Anti-ras p21 antibodies, RASK-3 and RASK-4, react with malignant melanomas and their premalignant lesions. These findings suggest the following: A4F11 is a universal marker of pigment cell tumors. TNKH1 and anti-K.1.2 antibodies might not be markers of melanocytic tumors but of nevocytic benign to premalignant tumors. Melanoma cells express gangliosides GM3 and GD3 as common pigment cell antigens and synthesize aberrant polysialogangliosides. Anti-ganglioside MoAb, including A2B5, are possible markers of the level of malignancy in melanoma cells like anti-A.1.43 and anti-A.10.33 antibodies. Enhanced ras p21 expression already appears on premalignant pigment cells.

Antibodies, Monoclonal↗
PubMed1992

Gangliosides of melanoma.

The relationships between the ganglioside composition of melanomas and their biologic behavior were investigated. (1) The amount of GM2 and/or GD2 in melanoma cells injected into nude mice correlated with the tumor growth rate. (2) GD2 content of melanoma cell lines correlated with sensitivity to radiation and vincristine. (3) GM2 expression of melanoma cells correlated with sensitivity to lymphokine-activated killer cells. (4) Gangliosides inhibited the proliferation of human T cells stimulated with interleukin-4 or interleukin-2. Based on these results, we proposed a hypothesis for the role of melanoma-associated gangliosides in the biologic behavior of melanomas and suggested a prospective melanoma treatment related to the gangliosides.

Animals↗
PubMed1996

Alteration of human melanoma gangliosides by IFN-gamma, IL-2, and IL-4.

In lesions of malignant melanoma, melanoma cells are exposed to various cytokines produced by inflammatory reactions. As a result, transformation of melanoma cells is expected to occur. We studied alterations in human melanoma cell line ganglioside composition after exposing melanoma cell lines to interferon (IFN)-gamma, interleukin (IL)-2, and IL-4 by biochemical methods. IFN-gamma increases the ratio of a-series gangliosides and the ratio of GM3/GD3. This suggests an alteration of immunoreactivity, a decrease in ganglioside sialyltransferase II activity, and an decrease in the malignant character of these cells. The alteration of the ganglioside profile varied among cytokines and cell lines. The progression of malignant melanoma may be influenced by reciprocal interactions between the melanoma cells and the host immune system.

Gangliosides↗
PubMed1997

Expression of globo-series gangliosides in human renal cell carcinoma.

Gangliosides have been shown to be involved in development, differentiation, oncogenesis, and cancer progression. We investigated immunohistochemical expression of globo-series gangliosides in human renal cell carcinoma (RCC) and whether their expression is related to the clinical course. The expression of globo-series gangliosides was evaluated in fresh-frozen sections of 55 primary renal tumors and 8 metastatic deposits using monoclonal antibodies RM1 and RM2, which define monosialosyl and disialosyl galactosylgloboside, respectively. The immunoreactivity of primary tumors to RM1 and/or RM2 was correlated with the clinicopathological data. Cumulative incidence of metastasis detected at initial diagnosis and during the follow-up period was significantly higher in the cases whose primary tumors were RM1/RM2-positive (RM1 and/or RM2-positive) than in the RM1/ RM2-negative (neither RM1 nor RM2-positive) cases (P < 0.05). During the follow-up period, metastasis developed in none of the RM1/RM2-negative cases which had not shown metastasis at initial diagnosis. High nuclear grade was observed only in the RM1/RM2-positive cases. The RM1/RM2-positive rate of the metastatic deposits was higher than that of the primary tumors. Furthermore, a metastatic deposit obtained from one of the cases whose primary tumors were equivocal for RM1/ RM2 was extensively stained by RM1 and RM2. These results indicate that globo-series gangliosides may be one of the biochemical indicators related to the metastatic potential of human RCC.

Adult↗
PubMed1987

Inhibition of basophil histamine release by gangliosides. Further studies on the significance of cell membrane sialic acid in the histamine release process.

Histamine release from human basophils was inhibited by preincubation of the cells with a glucolipid mixture containing sialic acid-containing gangliosides. This was true for histamine release induced by anti-IgE, Concanavalin A and the calcium ionophore A23187, whereas the release induced by S. aureus Wood 46 was not affected. It was demonstrated that the inhibitory capacity of the glucolipid mixture could be attributed to the content of gangliosides, since no inhibition was obtained with cerebrosides or with gangliosides from which sialic acid was removed. Preincubation of the cells with the glucolipid mixture increased the sialic acid content of the cells, and this increase was attributed to an insertion of gangliosides into the cell membrane. The inhibition of histamine release was abolished by increasing the calcium concentration, which substantiates our previous findings that cell membrane sialic acid in basophil leukocytes is involved in the regulation of histamine release, possibly by a modulation of the transmembraneous calcium fluxes preceding histamine release.

Basophils↗
PubMed1992

Immunohistochemical localisation of monoclonal antibody R 24-recognized ganglioside Glac2 in early chick embryos.

The spatio-temporal cellular expression and biosynthesis of ganglioside Glac2 was investigated in early chick embryogenesis. For demonstration of embryonic Glac2-biosynthesis, chick embryos of stage 0 and of stages 4-5 were incubated in vitro in the presence of radioactive sugar precursors. It was found that chick embryos synthesize Glac2 as early as at the blastula stage as well as at the gastrula stage, both within the area pellucida and the area opaca. In contrast to the biosynthetical findings immunohistochemical staining of the chick embryos at various stages by aid of the mouse monoclonal antibody (mAb) R 24, specific for the immunoepitope NeuAc alpha, 8NeuAc alpha, 3Gal beta less than, as present on the ganglioside Glac2, revealed a spatio-temporal cellular pattern of expression of this ganglioside in early chick embryos. Immunohistochemical staining of the chick embryo at stage 0 shows that all cells of the embryo, the extraembryonic epiblast and the yolk endoderm included, are mAb R 24-positive. At the intermediate streak stage (stage 3), the cranial part of the deep layer, the so-called endophyll, is strongly mAb R 24-positive, whereas at the end of gastrulation (stage 5), mAb R 24-recognized epitopes appear to be restricted to a narrow band of deep-layer cells in the endophyllic crescent and to the yolk endoderm of the area opaca. At this stage, no labelling by the antibody is observed in cell layers of the future embryo. The beginning of neurulation (stage 7) is characterized by the expression of the mAb R 24-recognized epitope in the notochord, whilst the deep layer in the cranial part of the neural fold still expresses this epitope. No ecto- or mesodermal structures are stained by the antibody at this developmental stage. During further development (stage 12 and 13), mAb R 24-reactivity is restricted to the cranial part of the embryo with a preferential staining of cells of endodermal origin. At these stages, the notochord expresses mAb R 24 binding sites only in its cranial region. The spatial and temporal correlation between the presence of mAb R 24-recognized epitopes and the morphogenetic positioning of tissues may be indicative for a possible role of the ganglioside Glac2 in corresponding cellular interactions.

Animals↗
PubMed1980

The ganglioside content of the milk fat-globule membrane and the mouse mammary-tumour virus isolated from the milk of infected mice. Partial characterization of a new disialoganglioside.

The milk fat-globule membrane and the mouse mammary-tumour virus isolated from the milk of infected Swiss mice have been investigated for their content in gangliosides. When compared on the lipid phosphorus basis, viral envelope is found to contain more than twice as much lipid-bound sialic acid as fat-globule membrane. The ganglioside patterns of these two structures appear rather similar, except for the occurrence in fat-globule membrane of a low ganglioside homolog, presumably GM2, not detected in viral envelope. A common and dominant trait is the presence in both structures, as the main ganglioside, of a component which has been so far characterized as a disialoganglioside, having the same neutral glycolipid moiety as GD1a, but with both sialic acid residues displayig to Clostridium perfringens and Vibrio cholerae neuraminidase, the susceptibility typical of terminal sialic acid residues.

Animals↗
PubMed1981

Chloroquine-induced accumulation of gangliosides and phospholipids in skeletal muscles. Quantitative determination and characterization of stored lipids.

High doses of the lysosomotropic drug chloroquine result in lipid storage in many organs in animals. We used miniature pigs, type Göttingen, to study the lipid accumulation in skeletal muscle after chloroquine intoxication for more than 200 days. The lipids of the quadriceps muscle in intoxicated and in age-matched control pigs were characterized and determined. The lipid storage was larger in skeletal muscle than in any other organ of the intoxicated pigs. The concentration of phospholipids was increased threefold, acidic phospholipids relatively more than neutral ones. The lysosome-specific acidic phospholipid bis(monoacylglyceryl)phosphate content was almost 50-fold larger in the intoxicated pigs than in the controls. Cholesterol was increased slightly more than the phospholipids, but there was no particular accumulation of cholesteryl esters, which has been shown to occur in the liver. For the first time a storage of gangliosides, relatively more pronounced than of other lipids, was demonstrated in skeletal muscle in the drug-induced lipidosis. The concentration of total gangliosides was increased 10--15-fold, and the pattern of gangliosides showed some distinct changes resulting in at least a 100-fold increase in the concentration of ganglioside GM2 (II3NeuAc-GgOse4Cer).

Animals↗