Revealing Metabolic Perturbation Following Heavy Methamphetamine Abuse by Human Hair Metabolomics and Network Analysis.

Methamphetamine (MA) is a highly addictive central nervous system stimulant. Drug addiction is not a static condition but rather a chronically relapsing disorder. Hair is a valuable and stable specimen for chronic toxicological monitoring as it retains toxicants and metabolites. The primary focus of this study was to discover the metabolic effects encompassing diverse pathological symptoms of MA addiction. Therefore, metabolic alterations were investigated in human hair following heavy MA abuse using both targeted and untargeted mass spectrometry and through integrated network analysis. The statistical analyses (t-test, variable importance on projection score, and receiver-operator characteristic curve) demonstrated that 32 metabolites (in targeted metabolomics) as well as 417 and 224 ion features (in positive and negative ionization modes of untargeted metabolomics, respectively) were critically dysregulated. The network analysis showed that the biosynthesis or metabolism of lipids, such as glycosphingolipids, sphingolipids, glycerophospholipids, and ether lipids, as well as the metabolism of amino acids (glycine, serine and threonine; cysteine and methionine) is affected by heavy MA abuse. These findings reveal crucial metabolic effects caused by MA addiction, with emphasis on the value of human hair as a diagnostic specimen for determining drug addiction, and will aid in identifying robust diagnostic markers and therapeutic targets.

The Role of Glycosphingolipids in Immune Cell Functions.

Glycosphingolipids (GSLs) exhibit a variety of functions in cellular differentiation and interaction. Also, they are known to play a role as receptors in pathogen invasion. A less well-explored feature is the role of GSLs in immune cell function which is the subject of this review article. Here we summarize knowledge on GSL expression patterns in different immune cells. We review the changes in GSL expression during immune cell development and differentiation, maturation, and activation. Furthermore, we review how immune cell GSLs impact membrane organization, molecular signaling, and trans-interactions in cellular cross-talk. Another aspect covered is the role of GSLs as targets of antibody-based immunity in cancer. We expect that recent advances in analytical and genome editing technologies will help in the coming years to further our knowledge on the role of GSLs as modulators of immune cell function.

Review: Glycosphingolipids in health and disease.

Glycosphingolipids are ubiquitous membrane constituents that are subdivided in neutral or acidic fractions (gangliosides and sulfatides). Their analysis requires extraction and separation by thin-layer chromatography or high-performance liquid chromatography. Ganglioside composition changes occur in response to variations in cellular morphology and function. Glycosphingolipids are implicated in the pathogenesis of various diseases, including glycosphingolipidoses, peripheral neuropathies caused by anti-ganglioside antibodies, and secretory diarrhea. Gangliosides play a role in the induction of apoptosis. For example, ceramide-induced apoptosis is associated with increased synthesis of a ganglioside, GD3. Gangliosides are also potential diagnostic markers and therapeutic targets for cancer.

Effect of differentiation and cell density on glycosphingolipid class and molecular species composition of mouse neuroblastoma NB2a cells.

The effects of cell density and retinoic acid-induced differentiation on the class and molecular species composition of mouse neuroblastoma NB2a cell glycosphingolipids were examined under conditions where the period of culture was controlled. The total amount of neutral glycosphingolipids per cell decreased both with differentiation and as the cells became confluent. The relative amount of the neutral glycosphingolipid classes was not affected by differentiation, whereas there were small but significant changes in the relative amount of the neutral glycosphingolipid classes as the cells became confluent. The total amount of the gangliosides was unaffected by either differentiation or cell density, but there were significant changes in the ganglioside class composition as a result of both cell density and differentiation, and the effects were additive. The molecular species of all the major neutral glycosphingolipid and ganglioside classes were essentially identical, and were altered only slightly by either differentiation or cell density.

Glycosphingolipids of the globo-series are associated with the monocytic lineage of human myeloid cells.

Neutral glycosphingolipids (neutral GSLs) of the human myeloid leukemia cell lines ML-2, ML-3, HL-60 and THP-1-0 were metabolically labeled with [3H]galactose and [3H]glucosamine, and analyzed by high-performance liquid chromatography. They were compared with unlabeled neutral GSLs from purified human granulocytes and monocytes. Neutral GSLs were identified by retention times and the structures were further confirmed by degradation with specific exoglycosidases. Two neutral GSLs of the globoseries, globotetraosylceramide and globotriaosylceramide were found in monocytes and the monoblastic leukemia line THP-1-0. The leukemia-derived cell-lines, ML-3 and HL-60, representing successively earlier stages of myeloid differentiation, contained respectively less neutral GSLs of the globoseries and an increasing proportion of (neo)lacto neutral GSLs. Granulocytes and the cell line ML-2 contained almost exclusively neutral GSLs of the (neo)lacto series.