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PubMed1989

Metabolism of exogenous gangliosides in cerebellar granule cells, differentiated in culture.

The metabolism of exogenous gangliosides in the CNS has been investigated using cerebellar granule cells in culture as a model. For this purpose, GM2 and GM1, both isotopically radiolabeled at the level of the terminal sugar residue or of the long chain base moiety, were administered to differentiated cells for a 15-h pulse, and their metabolic fate was followed in a time course protocol. At each time investigated (1, 2, and 4 days after the pulse), several compounds, besides the ones administered, were detected: (a) GM2 (only after GM1 was given), GM3, lactosylceramide, glucosylceramide, and ceramide, all products of ganglioside stepwise catabolism; (b) GM1 (only after GM2 was given), GD1a, GD1b, O-Ac-GT1b, and GT1b, that is, gangliosides more complex than the one administered; and (c) sphingomyelin. The compounds derived from ganglioside catabolism and sphingomyelin were detected only after administration of long chain base-labeled precursors, whereas the others were found regardless of the labeling position of the precursor. In addition, radioactivity was incorporated in the delipidized residue when sugar-labeled gangliosides were given to cells. Besides qualitative differences, quantitative ones were found after administration of the different precursors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Ganglioside composition in human meningiomas.

The ganglioside composition in meningioma specimens from 20 patients was analyzed to find potential meningioma-associated structures. The characterization was performed by immunological staining with specific monoclonal antibodies to ganglioside antigens and fast atom bombardment-mass spectrometry. The major gangliosides were GM3 and GD3, and most of the meningioma specimens could be divided into a "GM3-rich" or a "GD3-rich" group. Gangliosides of the gangliotetraose series were represented by GM1, GD1a, GD1b, and GT1b, which were found in minor amounts in all the specimens. The ratios of GM1/GD1a and GD1a/GD1b differed from that in normal brain, and therefore existence of this series could not be explained by contamination with brain material. Ganglioside 3'-isoLM1, found in human malignant glioma, could not be detected in any meningioma specimen.

Brain Chemistry↗
PubMed1999

Immunosuppressive activity of glycosphingolipids. Influence of serum factors on ganglioside inhibition of IL-4-dependent cell proliferation.

Gangliosides have been shown to inhibit proliferation of the interleukin-4 (IL-4) responsive cell line CT.4R. Kinetic analysis has revealed that ganglioside GT1b is a competitive inhibitor of proliferation, while GM and GM3 show a mixed pattern of inhibition, i.e., exhibit more than one inhibition type. Contribution of the competitive cell inhibition for GM1 and GM3 depends on serum factors added: the higher is the percentage of FCS, the larger is the contribution of competitive inhibition. The pattern of proliferation inhibition shown for GT1b does not depend on the FCS content. We have also studied the interaction of the recombinant IL-4 with fluorescent (anthrylvinyl-labelled) gangliosides GM1 and GM3 and lactosylceramide incorporated into liposomes. Dissociation constants of the IL-4-ganglioside complexes have been determined; lactosylceramide does not interact with rIL-4. The K(d) values for the lymphokine complexes with gangliosides support the conclusion based on the kinetic analysis that IL-4 has a higher affinity for GM3 (K(d) = 5 nM) than for GM1 (K(d) = 0.28 microM).

Animals↗
PubMed1988

Gangliosides GM2, IV4GalNAcGM1b, and IV4GalNAcGC1a as antigens for monoclonal immunoglobulin M in neuropathy associated with gammopathy.

It was previously reported that monoclonal IgM from two patients with gammopathy and neuropathy showed similar specificity by reacting with the same group of unidentified minor components in the ganglioside fractions of human nervous tissues (Ilyas, A. A., Quarles, R. H., Dalakas, M. C., and Brady, R. O. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 6697-6700). Enzymatic degradation, ion-exchange chromatography, and immunostaining of purified ganglioside standards on thin-layer chromatograms have now revealed that the antigenic glycolipids recognized by the IgM from these patients are gangliosides GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-4Glc beta 1-1Cer(GM2), GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-3GalNAc beta 1-4Gal beta 1-4Glc beta 1-1Cer (IV4GalNAcGM1b), and GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-3GalNAc beta 1-4 beta Gal(3-2 alpha NeuAc)beta 1-4Glc beta 1-1-Cer (IV4GalNAcGD1a). The monoclonal IgM appears to be reacting with the terminal [GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-] moiety shared by these three gangliosides and is a useful probe for detecting small amounts of GM2, IV4GalNAcGM1b, IV4GalNAcGD1a, and other gangliosides with the same terminal sugar configuration in tissues. Species distribution studies using the antibody revealed that GM2 is present in the brains and nerves of all species examined, while IV4GalNAcGM1b and IV4GalNAcGD1a exhibit some striking species specificity. GM2, but not IV4GalNAcGD1a, is enriched in purified myelin from human brain.

Animals↗
PubMed2001

Inhibition effects of gangliosides G(M1), G(D1a) and G(T1b) on base-catalyzed isomerization of prostaglandin A(2).

Micellar inhibition effect of gangliosides on a degradation of drug was investigated, where ganglioside G(M1) (GM1), G(D1a) (GD1a) and G(T1b) (GTlb) whose sialic acid residue is one, two and three, respectively, were used. The base-catalyzed isomerization of prostaglandin A(2) (PGA(2)) to prostaglandin B(2) (PGB(2)) was chosen as a model experiment. The rate for the isomerization of PGA(2) was determined by measuring the concentration of PGA(2) (and PGB(2)) with a high-performance liquid chromatography. Gangliosides micelles inhibited the isomerization of PGA(2). The inhibition effect of GT1b micelles was larger than that of GD1a micelles. This result would be due to the larger absolute value of surface potential of GT1b micelles, which brings about a larger electrostatic repulsion between micellar surface and OH(-). The terminal sialic acid residue of ganglioside was effective to inhibit the isomerization of PGA(2). GM1 micelles without terminal sialic acid residue but with large aggregation number exhibited a superior steric shielding effect rather than an electrostatically repulsive effect. The inhibition effect of GM1 micelles was enhanced by the mixed micellization with the other ganglioside with a terminal sialic acid residue. GM1-GD1a or GM1-GT1b mixed micelles remarkably inhibited the isomerization of PGA(2). The physiological activity of PGs in the biological membranes containing gangliosides was also discussed.

Journal Article↗
PubMed2002

Immunohistochemical detection of hepatic GM1 and GM2 gangliosides in streptozotocin-induced diabetic rats.

This study was undertaken to investigate the consequences of diabetes on the expression of GM1 and GM2 gangliosides in rat liver. Experimental diabetes was induced by treatment with Streptozotocin (STZ) in adult male Sprague-Dawley rats. Two-dimensional thin-layer chromatography of total ganglioside preparations of liver tissues from STZ-induced diabetic rats showed an increased amount of GM1, while GM2 could not be detected. In order to identify ganglioside expression and corroborate possible changes after short-term diabetes (3 weeks), frozen sections of the liver were stained with two monoclonal antibodies, GMB16 (GM1 specific) and GMB28 (GM2 specific). Although both antibodies were capable of immunostaining the diabetic hepatocytes at the cell surface, strong reactivity was observed for GMB16 while GMB28 developed only a weak labeling. The hepatic ganglioside expression of insulin-stabilized diabetic rats was restored, resembling the profile of normal rats. The important alterations in the expression of GM1 and GM2 gangliosides in short-term diabetes were accompanied by certain microscopic changes in the liver, so that these gangliosides may be useful markers in the detection of early liver diabetic complications.

Journal Article↗
PubMed2004

Molecular mechanism for transcriptional activation of ganglioside GM3 synthase and its function in differentiation of HL-60 cells.

Previous studies have demonstrated that the activity of GM3 synthase and GM3 content are increased during the differentiation of human promyelocytic leukemia HL-60 cells into the monocyte/macrophage lineage after phorbol 12-myristate 13-acetate (PMA) treatment. However, the molecular mechanisms involved in transcriptional activation of GM3 synthase during differentiation of PMA-induced HL-60 cells are not well understood. As evidenced by western blot analysis, PMA induced the marked activation of protein kinase C (PKC)/extracellular regulated kinases (ERKs) signal transduction pathway during the differentiation of HL-60 cells. In addition, PKC/ERKs activation induced by PMA in HL-60 cells led to the phosphorylation of cAMP-responsive element binding protein (CREB) as a transcription factor. In PMA-stimulated HL-60 cells, the PKC/ERKs-dependent CREB activation regulated expression of GM3 synthase, inducing a synthesis of ganglioside GM3 product. On the other hand, although ganglioside GM3 was shown to be able to induce the differentiation of HL-60 cells into the monocyte/macrophage lineage, effect of ganglioside GM3 on expression of CD11b as a differentiation marker in HL-60 cells has been not reported yet. Interestingly, the increased ganglioside GM3 through PKC/ERKs/CREB-dependent pathway by PMA resulted in an increase of CD11b surface antigen expression and induction of HL-60 cells adherence. Treatment with L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), glucosylceramide synthase inhibitor, decreased induction of not only CD11b expression but also cellular adherence by reduction of PMA-induced ganglioside GM3. Furthermore, treatment of HL-60 cells with exogenous ganglioside GM3 induced CD11b expression. These results show that the enhanced expression of GM3 synthase through PKC/ERKs-dependent CREB activation by PMA is associated with the differentiation of HL-60 cells by inducing expression of CD11b known as a monocyte/macrophage differentiation maker.

CD11b Antigen↗
PubMed2005

Cross-seeding of wild-type and hereditary variant-type amyloid beta-proteins in the presence of gangliosides.

We investigated the molecular mechanism underlying the ganglioside-induced initiation of the assembly of wild and hereditary variant-type amyloid beta-proteins, including Arctic-, Dutch-, and Flemish-type amyloid beta-proteins. We monitored the assembly of amyloid beta-protein by thioflavin-T assay, western blotting and electron microscopy. We also examined how externally added amyloid beta-protein assembles in a cell culture. The assembly of wild-, Arctic-, Dutch-, and Flemish-type amyloid beta-proteins were accelerated in the presence of GM1, GM1, GM3 and GD3 gangliosides. Notably, all of these amyloid beta-proteins accelerated the assembly of different type of amyloid beta-protein, following prior binding to a specific ganglioside. A specific-ganglioside-bound form of variant-type amyloid beta-protein was recognized by the antibody (4396C) specific to the GM1-ganglioside-induced altered conformation of wild-type amyloid beta-protein. Moreover, the assembly of these amyloid beta-proteins in the presence of a specific ganglioside was markedly suppressed by coincubation with 4396C. This study suggests that cross-seeding can occur between wild and hereditary variant-type amyloid beta-proteins despite differences in their amino acid sequences.

Amyloid beta-Peptides↗
PubMed2000

Participation of the GM1 ganglioside in the gastrulation of anuran amphibian Bufo arenarum.

In the present paper we established the ganglioside composition of the blastula and gastrula stages of the anuran amphibian Bufo arenarum, two relevant stages characterized by dynamic changes in morphology and cellular rearrangements. Densitometric studies evidenced that GD1a and GT1b were the more abundant gangliosides of the blastula embryos whereas GM1 and GM2 were the predominant species in gastrula embryos. Analysis of ganglioside abundance indicates that the "a" and "b" synthesis pathways perform similar biosynthetic activities in the blastula stage, in contrast to the gastrula stage in which a marked predominance of the "a" pathway occurred. The spatio-temporal expression of GM1 and of polygangliotetraosyl ceramides (pGTC) was investigated by wholemount immunocytochemistry using cholera toxin B subunit (CTB) and an affinity purified human anti-GM1 antibody. The pGTC were detected as GM1 after treatment with neuraminidase. Blastomeres from the inner surface of the blastocoelic roof (BCR) of blastula embryos were GM1 and pGTC positive. At midgastrula stage, embryos showed an increased labeling on the inner surface of BCR. To establish whether the GM1 ganglioside was involved in the gastrulation processes, CTB, anti-GM1 antibodies and anti-GM1 Fab' fragments were microinjected into the blastocoel cavity of blastula embryos. Treatment with the probes blocked gastrulation. Scanning electron microscopy analysis of blocked embryos revealed that mesodermal cell migration, radial interdigitation, and convergent extension movements were affected. The blocking of gastrulation was correlated with the absence of fibronectin and EP3/EP4 on the inner surface of blastocoelic roof of CTB- or anti-GM1 treated embryos. Results show that the GM1 ganglioside is differentially expressed by embryonic cells and participates in the morphogenetic processes of amphibian gastrulation. J. Exp. Zool. 286:457-472, 2000.

Animals↗
PubMed2000

Age-related changes in GM1, GD1a, GT1b components of gangliosides in Wistar albino rats.

In this study, age-related changes of GM1, GD1a, GT1b fractions of gangliosides were investigated in whole brain of male Wistar albino rats. Insignificant increases were detected in GM1 values from the third to the 24th month, whereas GD1a and GT1b concentrations of ganglioside in 24-month-old rats decreased significantly as compared to 6-month-old rats. Although there were no significant differences in the GD1a/GT1b ratio of any groups, GM1/GD1a and GM1/GT1b ratios were significantly increased as compared to 6-month-old rats. The increase in the ratios of gangliosides are not due to an increase of GM1 fractions; they result from a decrease of GD1a and GT1b fractions of gangliosides. In conclusion, the concentration of ganglioside decreased with ageing.

Age Factors↗
PubMed1986

Gangliosides stimulate astroglial cell proliferation in the absence of serum.

Previous studies with microcultures of astroglial (AG) cells from newborn rat cerebrum had shown an ability of gangliosides to interact with AG cells cultured under defined conditions. We have now investigated the capability of gangliosides to stimulate DNA synthesis and cell number increases in similar secondary microcultures of newborn rat cerebrum AG cells. At a concentration of 6 X 10(-5)M, GM1 ganglioside stimulated DNA synthesis and increased cell numbers, with DNA synthesis leading cell increases by 12-24 hr. The ganglioside-induced AG cell proliferative response occurred with GD1a, GD1b and GT1b, GT1b being the most potent at 10(-5)M--while asialo GM1 and sialic acid were without effect. In the standard test cultures, DNA synthesis declined very steeply after the first day, with cell numbers stabilizing at the level reached after 2 days. Ganglioside was not itself responsible for the restricted proliferative response, as serum produced the same behaviors.

Animals↗
PubMed1994

Differential accumulation of gangliosides by the brains of MPTP-lesioned mice.

Although gangliosides have been reported to enhance recovery from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions of the substantia nigra, evidence as to whether the administered gangliosides actually reach this or any other site of lesion in the central nervous system (CNS) at which they putatively enhance recovery is lacking. Therefore, studies were carried out to determine the amount of 3H-labeled ganglioside that was accumulated by the brains of MPTP-treated mice as well as by brains of control mice. No significant difference in the accumulation of 3H-bovine brain gangliosides or 3H-GD1a was seen between lesioned and control brains up to 240 min after injection of the labeled lipids. However, significantly more label was associated with the brains of MPTP-treated mice compared to controls 120 and 240 min after the injection of 3H-GM1. Analysis of the lipids extracted from the brain of a 3H-GM1-treated mouse revealed that the majority of label was still associated with 3H-GM1, 240 min after its administration. Autoradiography of tissue sections from the brains of MPTP-treated mice injected with 3H-GM1 showed that label was present in the ventricular spaces of the brain. This observation suggests that the administered gangliosides are present in the cerebrospinal fluid, which indicates that they have the potential to reach the lesioned CNS site at which they putatively enhance recovery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Gangliosides GD1a and GM3 induce interleukin-10 production by human T cells.

Gangliosides are sialic acid-containing glycosphingolipids and exhibit various physiologic functions. Gangliosides GD1a and GM3 strongly induced interleukin-10 (IL-10) protein secretion and mRNA expression in T cells from normal human subjects while the other gangliosides were ineffective. IL-10 induction by both gangliosides was completely blocked by protein tyrosine kinase (PTK) inhibitors, herbimycin A, genistein, and tyrphostin AG 1288, but not by other signal transduction inhibitors. These results suggest that GD1a and GM3 may induce IL-10 production in T cells by regulating the PTK-dependent signaling pathway. These gangliosides may thus act as important immunoregulators via IL-10.

Benzoquinones↗
PubMed1984

Approaches in the study of ganglioside metabolism.

Ganglioside GM1, 3H-labeled in the sphingosine or terminal galactose moiety was injected into mice and its metabolic fate in the liver was followed. After administration of sphingosine-labeled GM1 all major liver gangliosides (GM3, GM2, GM1, GD1a-NeuAc, NeuG1) became radioactive, the radioactivity residing in all cases on the sphingosine moiety. The specific radioactivity was highest on GM1, followed by GM2, GM3 and GD1a-NeuAc, NeuG1. Several neutral glycosphingolipids and sphingomyelin were also formed. After administration of galactose-labelled GM1 the only radioactive gangliosides present in the liver were GM1 and GD1a-NeuAc, NeuG1, both carrying the radioactivity on the terminal galactose residue, with no formation of labelled neutral glycosphingolipids. Subcellular studies gave clear evidence that GM1, after being taken up by the liver, was mainly degraded to GM2, GM3 and neutral glycosphingolipids at the level of lysosomes. A part of it was sialylated to more complex gangliosides and some of its metabolic by-products were used for the biosynthesis of other sphingolipid species, likely at the level of the Golgi apparatus. All this suggests that exogenous GM1 is introduced in the metabolic routes of endogenous gangliosides and of other sphingolipids, which are operating in the liver.

Animals↗
PubMed1996

Gangliosides protect human melanoma cells from ionizing radiation-induced clonogenic cell death.

With an experimental model of spontaneous lung metastases of melanoma developed in this laboratory, a range of sublines (variants and clones) with different metastatic potential and ganglioside expression was established from a single human melanoma cell line M4Be. Using an in vitro clonogenic assay and provided that cells were cultured for no more than five passages, variations in cellular radioresistance of M4Be and seven sublines derived from M4Be were detected. This study shows a positive correlation between the cell intrinsic radioresistance of M4Be and its seven sublines and their total ganglioside content. More precisely, the proportion of radioresistant cells in M4Be and the seven sublines correlated with the number of cells determined by flow cytometry that were positively labelled with a monoclonal antibody directed to GD3 disialoganglioside. Blocking the cellular biosynthesis of gangliosides with the inhibitor Fumonisin B1 or cleaving with Vibrio cholerae neuraminidase the cell surface ganglioside-bound sialic acid in a radioresistant poorly metastatic subline increased its radiosensitivity in vitro. In contrast, enrichment of a radiosensitive metastatic subline with exogenous bovine brain GM1 increased its radioresistance in vitro. These results suggest that, in the radiation dose range important for radioprotection (0-1 Gy), membrane gangliosides radioprotect human melanoma cells in vitro.

Animals↗
PubMed1996

Ganglioside composition of the rat choriocarcinoma cell line, Rcho-1.

The Rcho-1 cell line, originally established from a rat choriocarcinoma, shows differentiation into placental trophoblastic giant cell-like cells and has been used to study the mechanism of placental function control. In the present study, we analysed the ganglioside composition of Rcho-1 cells by HPTLC orcinol/H2So4, TLC/ immunostaining and immunohistochemistry. Rcho-1 cells expressed GM3 and GD3 as the major gangliosides and CTH as major neutral glycolipid when they were cultured in growth medium (20% FCS) or transplanted beneath the kidney capsule. The expression of these gangliosides was strong in the undifferentiated small cells, whereas the completely differentiated giant cells showed poor staining with antibodies against the gangliosides. Under culture conditions to induce cell differentiation using horse serum (1-20% HS), the expression of GD3 was suppressed and re-expressed when the medium was changed to growth medium, suggesting that a change of ganglioside components may trigger and define the direction of terminal differentiation. Thus the composition of glycolipids is conserved in Rcho-1 cells and is similar to that of the rat placenta, where GM3 is dominant in mid-pregnancy and decreased in late pregnancy, whereas GD3 is low in mid-pregnancy and increased in late pregnancy.

Animals↗
PubMed2004

Lack of apparent neurological abnormalities in rabbits sensitized by gangliosides.

Two very high titer polyclonal antibodies against two ganglioside antigens, GM1 and GD1a, have been raised in New Zealand white rabbits using a homogeneous suspension of the highly purified antigens in Keyhole Limpet Hemocyanin and Freund's adjuvant. The antisera were prepared over a period of 6 months with repeated injections of the ganglioside suspension, followed by an intravenous injection of the purified ganglioside solution, and collecting the serum (approximately 50 ml) at defined time intervals. The GM1-antibody, thus prepared, showed a cross reactivity toward GDlb and asialo-GM1 (GA1), while the GDla-antibody reacted with GD1a, GM1 and GA1 and GD1b as determined by immuno-overlay and ELISA methods. The titer for GM1 antiserum, determined by'ELISA, was greater than 1/10,000 dilution while the titer for GD1a antibody was greater than 1/5000 dilution. No neurological or behavioral abnormality was observed during the period of antiserum production. To evaluate any likely pathological damage caused by such a high titer ganglioside-antibody, autopsy of CNS as well PNS tissues from the rabbits were carried out after the final bleeding. No obvious pathological changes, including demyelination, were noted in any of the four rabbits. These observations cast doubt as to the direct effect of anti-ganglioside antibody induced neurological and pathological disorders.

Animals↗
PubMed1980

A differential scanning calorimetry study of the interaction of gangliosides with peanut lectin, serotonin and daunomycin.

Thermotropic behaviour of human Tay-Sachs ganglioside and of mixed bovine brain gangliosides, before and after interaction with peanut lectin, serotonin and daunomycin, was investigated. Interaction of mixed brain gangliosides with peanut lectin or serotonin causes a decrease in the enthalpy of melting, whereas interaction of this lectin with Tay-Sachs ganglioside does not influence the enthalpy of melting. Serotonin causes a small increase in the enthalpy of melting of the Tay-Sachs ganglioside.

Arachis↗