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Urinary globotriaosylsphingosine-related biomarkers for Fabry disease targeted by metabolomics.

Fabry disease is a lysosomal storage disorder caused by deficiency of α-galactosidase A, resulting in glycosphingolipid accumulation in organs and tissues, including plasma and urine. Two disease-specific Fabry biomarkers have been identified and quantified in plasma and urine: globotriaosylceramide (Gb(3)) and globotriaosylsphingosine (lyso-Gb(3)). The search continues for biomarkers that might be reliable indicators of disease severity and response to treatment. The main objective of this study was to target other urinary biomarkers using a time-of-flight mass spectrometry metabolomic approa…

UDP-GlcNAc2-epimerase regulates cell surface sialylation and ceramide-induced cell death in human malignant lymphoma.

Stress signals induce ceramide (cer) through sphingomyelinase activation, and metabolites of cer such as sphingosine (Sph) and sphingosine-1-phoshate (S-1-P) play a significant role in many biological processes. This study aimed to elucidate the association between the alteration in cell surface sialylation and ceramide-induced cell death in the human Burkitt's lymphoma cell line, HBL-8. The highly sialylated 3G3 clone was less sensitive to C6-ceramide-induced cell death. On the other hand, the hyposialylated 3D2 clone was more sensitive to C6-ceramide-induced cell death. Neuraminidase treatme…

Effects of trifluoperazine on synaptically evoked potentials and membrane properties of CA1 pyramidal neurons of rat hippocampus in situ and in vitro.

The effects of trifluoperazine (TFP), a phenothiazine antipsychotic, on hippocampal activity were studied in the CA1 subfield, both in situ and in slices. In the extracellular studies in situ and in vitro, both somatic population spikes and dendritic excitatory postsynaptic potentials (EPSP) fields were depressed reversibly by TFP, applied by microiontophoresis or in the bath (50-100 microM). Similar effects were also seen during iontophoretic applications of sphingosine in situ. Like TFP (at micromolar concentrations) sphingosine is a dual Ca2+/calmodulin-dependent kinase and protein kinase C…

Janus Kinase Antagonists and Other Novel Small Molecules for the Treatment of Crohn's Disease.

There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease.

Abnormal gangliosides in Tay-Sachs disease, Niemann-Pick's disease, and gargoylism.

The molar ratios of N-acetyl neuraminic acid, hexose, hexosamine, and sphingosine have been determined for the abnormal ganglioside in Tay-Sachs disease that was previously detected as a fast-moving band in thin-layer chromatography, and in two abnormal fast-moving bands of gangliosides from the cortex and white matter of the brain in cases of gargoylism and Niemann-Pick's disease. The fastest-moving ganglioside band in these two conditions contains neither hexosamine nor glucose.

Langerhans cell migration: not necessarily always at the center of the skin sensitization universe.

Since their discovery in 1868, the role of Langerhans cells (LCs) in skin immunity has been researched extensively. Recent data deriving from transgenic animals that are deficient in LCs have begun to challenge the dogma that there is a universal requirement for these cells in the development of skin sensitization. This Commentary addresses relationships between LC mobilization, draining lymph node activation, and skin sensitization using immunomodulators agonistic for a family of sphingosine-1-phosphate (S1P) receptors.

Molecular characteristics of apolipoprotein M and its biological functions in kidney diseases.

Apolipoprotein M (apoM) is a subclass of apolipoproteins primarily found in high-density lipoprotein (HDL), it was mainly expressed and secreted in the liver and kidneys. ApoM functions as the carrier of sphingosine-1-phosphate (S1P) to form apoM-S1P complex, further mediating various physiological and pathological processes in the body. Most research has focused on cardiovascular diseases, such as anti-atherosclerosis, with very few studies in the field of nephrology. In recent years, scholars have found that it plays a crucial role in kidney disease. Thereby, this review would summarize the …

Apolipoprotein M: Structural insights, functional roles, and therapeutic approaches in vascular disease.

Apolipoprotein M (ApoM) is a lipocalin predominantly associated with high-density lipoprotein (HDL) that transports sphingosine-1-phosphate (S1P) in circulation. Through its stable binding and selective delivery of S1P to the endothelial S1P receptors (S1PRs), ApoM orchestrates a spectrum of vasoprotective effects. This review summarizes the structural characteristics of ApoM and its unique function as a sphingolipid chaperone, focusing on its role in vascular biology, specifically endothelial barrier integrity, vascular tone, and inflammation. We examine the biased signaling of ApoM-HDL-S1P t…

Avoid being trapped by your liver: ischemia-reperfusion injury in liver transplant triggers S1P-mediated NETosis.

Liver transplantation can be a life-saving treatment for end-stage hepatic disease. Unfortunately, some recipients develop ischemia-reperfusion injury (IRI) that leads to poor short- and long-term outcomes. Recent work has shown neutrophils contribute to IRI by undergoing NETosis, a form of death characterized by DNA ejection resulting in inflammatory extracellular traps. In this issue of the JCI, Hirao and Kojima et al. report that sphingosine-1-phosphate (S1P) expression induced by liver transplant-mediated IRI triggers NETosis. They also provide evidence that neutrophil expression of the ca…

Gaucher's disease and cancer: a sphingolipid perspective.

Gaucher's disease is a sphingolipidosis characterized by a specific deficiency in an acidic glucocerebrosidase, which results in aberrant accumulation of glucosylceramide primarily within the lysosome. Gaucher's disease has been correlated with cases of myeloma, leukemia, glioblastoma, lung cancer, and hepatocellular carcinoma, although the reasons for the correlation are currently being debated. Some suggest that the effects of Gaucher's disease may be linked to cancer, while others implicate the therapies used to treat Gaucher's disease. This debate is not entirely surprising, as the specula

CerS2/ceramide C24:1/ROCK2 signaling-mediated angiogenesis protects against ischemic brain injury in mice.

Hypoxia adaptation can partially improve and restore the composition, structure, and function of blood vessels, thereby enhancing the prognosis of related diseases such as stroke. However, the underlying molecular mechanisms of hypoxia adaptation remain elusive. In this study, multi-omics analysis was performed across yeast, zebrafish, and mouse, revealing that sphingolipid metabolism is crucial for hypoxic adaptation. We found that the expression of the key protein ceramide synthase 2 (CerS2) in mammals and its yeast ortholog very-long-chain ceramide synthase LAC1 was up-regulated. CerS2 and

S1P/S1P Receptor Signaling in Neuromuscolar Disorders.

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is…

Abnormal podocyte TRPML1 channel activity and exosome release in mice with podocyte-specific Asah1 gene deletion.

Podocytopathy and associated nephrotic syndrome (NS) have been reported in a knockout mouse strain (Asah1fl/fl/PodoCre) with a podocyte-spec … PML1 channels was substantially suppressed in podocytes with Asah1 gene deletion. As an Ac product, sphingosine was found to rescue TRPML1 channel activity and thereby recover lysosome-MVB interaction and reduce exosome release of podocytes from Asah1fl/fl/PodoCre mice. Combination of N, N-dimethylsphingosine (DMS), a potent sphingosine kinase inhibitor, and …

A practical process for the preparation of [(32)P]S1P and binding assay for S1P receptor ligands.

Sphingosine-1-phosphate receptors (S1PRs) are important regulators of vascular permeability, inflammation, angiogenesis and vascular maturation. Identifying a specific S1PR PET radioligand is imperative, but it is hindered by the complexity and variability of current for binding affinity measurement procedures. Herein, we report a streamlined protocol for radiosynthesis of [(32)P]S1P with good radiochemical yield (36-50%) and high radiochemical purity (>99%). We also report a reproducible procedure for determining the binding affinity for compounds targeting S1PRs in vitro.

Structure-function relationship of a single double bond: the difference in lamellar phase behaviors between ceramides NS and NdS.

The barrier function of mammalian skin is closely related to the unique structure of the complex lipid matrix of the stratum corneum. Within … fects of the individual ceramide. In the present work, non-hydroxylated N-acyl chain ceramides with sphingosine and dihydrosphingosine bases with acyl chain lengths of C18, each fully protiated or partially deuterated, were obtained by chemical syntheses. As sphingosine and dihydrosphingosine-based ceramides differ just in a single double bond at the C4-C5 po …

Adipocytes promote cancer stemness properties in oral squamous cell carcinoma through C3/C3AR axis and sphingolipid metabolism.

There is convincing evidence that being overweight or having obesity is associated with an increased risk of developing oral squamous cell c … erties and supports oral carcinogenesis. Intriguingly, the inhibition of functional C3/C3AR axis by sphingosine, a bioactive sphingolipid metabolite, resulted in the suppression of OSCC cells growth and adipocyte-promoted oral CSC self-renewal. In conclusion, our findings provide a novel insight into the mechanisms underlying the role of C3/C3AR axis in media …

Utilization of Flow Cytometry, Metabolomic Analyses and a Feline Infectious Peritonitis Case Study to Evaluate the Physiological Impact of Polyprenyl Immunostimulant.

Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there a … reatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mamma …

Исследование in vitro токсикологических механизмов финолимода (S)-фосфата в камерах HEPG2.

Fingolimod (FTY720) — первый модератор рецептора фингозина-1-фосфата (S1P), утвержденный Администрацией продовольствия и лекарств США для лечения множественных склерозов. Активная форма FTY720 (S)-P действует в качестве мощного агониста рецептора S1P, что ведет к его нижнему регулированию на поверхности клеток, снижению активности и прекращению внутриклеточной сигнализации, зависимой от фингозина. Повышенные уровни фермента печени, клинически значимая травма печени и острая недостаточность печени наблюдались у пациентов, прошедших курс лечения с помощью FTY720 (S)-P, что требует дополнительног

Совпадение в аннотации оригинала
Fingolimod (FTY720) was the first sphingosine-1-phosphate (S1P) receptor modulator approved by the US Food and Drug Administration for the treatment of multiple sclerosis. The active form, FTY720 (S)-P, acts as a potent agonist of the S1P receptor, leading to its downregulation on the cell surface, reduced activity, and termination of sphingosine-dependent i…

Role of vitamin D and omega 3 fatty acids in improving HDL biogenesis among multiple sclerosis patients via orchestrating CHROME/APOA1-AS/ABCA1/APOA1 milieu.

Clinical approaches that could correct the disturbed lipid profile may improve neurological disturbances in multiple sclerosis (MS) patients. However, the underlying mechanisms are still not well understood. The study aimed to characterize the performance of vitamin D (Vit.D) and omega 3 fatty acid (ω3) in adjusting the lipid profile of MS patients via modulating CHROME/APOA1-AS/ABCA1/APOA1 along with sphingosine kinase (SPHK)-1/2, and sphingosine 1-phosphate receptors (S1PR)-1/5. 72 MS patients were recruited for this study; 25 received Vit.D, 21 received ω3, and 26 didn't receive any supplem…