Gangliosides are expressed in the outer leaflet of the plasma membrane of the cells of all vertebrates and are particularly abundant in the nervous system. Ganglioside metabolism is closely associated with the pathology of

Glycosphingolipids (GSLs) and their sialic acid-containing derivatives, gangliosides, are important cellular components and are abundant in the nervous system. They are known to undergo dramatic changes during brain development. However, knowledge on the mechanisms underlying their qualitative and qualitative changes is still fragmentary. In this investigation, we have provided a detailed study on the developmental changes of the expression patterns of GSLs, GM3, GM1, GD3, GD1a, GD2, GD1b, GT1b, GQ1b, A2B5 antigens (c-series gangliosides such as GT3 and GQ1c), Chol-1a (GT1aa and GQ1ba), glucosylceramide, galactosylceramide (O1 antigen), sulfatide (O4 antigen), stage-specific embryonic antigen-1 (Lewis x) glycolipids, and human natural killer-1 glycolipid (sulfoglucuronosyl paragloboside) in developing mouse brains [embryonic day 12 (E12) to adult]. In E12-E14 brains, GD3 was a predominant ganglioside. After E16, the concentrations of GD3 and GM3 markedly decreased, and the concentrations of a-series gangliosides, such as GD1a, increased. GT3, glucosylceramide, and stagespecific embryonic antigen-1 were expressed in embryonic brains. Human natural killer-1 glycolipid was expressed transiently in embryonic brains. On the other hand, Chol-1a, galactosylceramide, and sulfatide were exclusively found after birth. To provide a better understanding of the metabolic basis for these changes, we analyzed glycogene expression patterns in the developing brains and found that GSL expression is regulated primarily by glycosyltransferases, and not by glycosidases. In parallel studies using primary neural precursor cells in culture as a tool for studying developmental events, dramatic changes in ganglioside and glycosyltransferase gene expression were also detected in neurons induced to differentiate from neural precursor cells, including the expression of GD3, followed by up-regulation of complex a-and b-series gangliosides. These changes in cell culture systems resemble that occurring in brain. We conclude that the dramatic changes in GSL pattern and content can serve as useful markers in neural development and that these changes are regulated primarily at the level of glycosyltransferase gene expression.

Allyl sulfides are characteristic flavor components obtained from garlic. These sulfides are thought to be responsible for their epidemiologically proven anticancer effect on garlic eaters. This study was aimed at clarifying the molecular basis of this anticancer effect of garlic by using human colon cancer cell lines HCT-15 and DLD-1. The growth of the cells was significantly suppressed by diallyl trisulfide (DATS, HCT-15 IC 50 ‫؍‬ 11.5 M, DLD-1 IC 50 ‫؍‬ 13.3 M); however, neither diallyl monosulfide nor diallyl disulfide showed such an effect. The proportion of HCT-15 and that of DLD-1 cells residing at the G 1 and S phases were decreased by DATS, and their populations at the G 2 /M phase were markedly increased for up to 12 h. The cells with a sub-G 1 DNA content were increased thereafter. Caspase-3 activity was also dramatically increased by DATS. Fluorescence-activated cell sorter analysis performed on the cells arrested at the G 1 /S boundary revealed cell cycle-dependent induction of apoptosis through the transition of the G 2 /M phase to the G 1 phase by DATS. DATS inhibited tubulin polymerization in an in vitro cell-free system. DATS disrupted microtubule network formation of the cells, and microtubule fragments could be seen at the interphase. Peptide mass mapping by liquid chromatography-tandem mass spectrometry analysis for DATS-treated tubulin demonstrated that there was a specific oxidative modification of cysteine residues Cys-12␤ and Cys-354␤ to form S-allylmercaptocysteine with a peptide mass increase of 72.1 Da. The potent antitumor activity of DATS was also demonstrated in nude mice bearing HCT-15 xenografts. This is the first paper describing intracellular target molecules directly modified by garlic components.Allyl sulfides, e.g. diallyl monosulfide (DAS), 4 diallyl disulfide (DADS), and diallyl trisulfide (DATS), are characteristic flavor components of the essential oil prepared from garlic (Allium sativum L.). Garlic is widely served around the world, and it has been reported that allyl sulfides inhibit both the initiation and promotion stages of tumorigenesis in experimental carcinogenesis models for various types of cancer (1-5). Recently, several lines of investigation have shown that allyl sulfides suppress cell growth and induce apoptosis in multiple cancer cell lines (6 -12). We previously reported that the sulfur-containing volatile oils prepared from garlic and onion inhibit proliferation and induce differentiation of the human promyelocytic leukemia cell line HL-60 (13). However, the molecular mechanisms underlying the antitumorigenesis of allyl sulfides are still not fully understood.Microtubules are ubiquitous proteins present in eukaryotes as components of the cytoskeleton and play pivotal roles in a variety of cellular processes involving cell division, motility, and intracellular trafficking (14). The microtubules are dynamic polymers composed of ␣␤-tubulin heterodimers, and they form the mitotic spindles, which are known to introduce the replicated DNA molecules to the res...

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Summary Gangliosides are sialic acid-containing glycosphingolipids (GSLs) that are most abundant in the nervous system. They are localized primarily in the outer leaflets of plasma membranes and participated in cell-cell recognition, adhesion, and signal transduction and are integral components of cell surface microdomains or lipid rafts along with proteins, sphingomyelin and cholesterol. Ganglioside-rich lipid rafts play an important role in signaling events affecting neural development and the pathogenesis of certain diseases. Disruption of ganglioside synthase genes in mice induces developmental defects and neural degeneration. Targeting ganglioside metabolism may represent a novel therapeutic strategy for intervention in certain diseases. In this review, we focus on recent advances on metabolic and functional studies of gangliosides in normal brain development and in certain neurological disorders.