The fate of intracellular S1P regulates lipid droplet turnover and lipotoxicity in pancreatic beta-cells.

Lipotoxicity has been considered the main cause of pancreatic beta-cell failure during type 2 diabetes development. Lipid droplets (LD) are believed to regulate the beta-cell sensitivity to free fatty acids (FFA), but the underlying molecular mechanisms are largely unclear. Accumulating evidence points, however, to an important role of intracellular sphingosine-1-phosphate (S1P) metabolism in lipotoxicity-mediated disturbances of beta-cell function.

Synthesis and biological evaluation of simplified ajudazol derivatives reveal potent 5-lipoxygenase inhibition and considerable apoptotic activity in neuroblastoma cells.

Simplified analogues of the myxobacterial polyketide ajudazol were obtained by synthesis and evaluated for their biological activities. Potent simplified 5-lipoxygenase inhibitors were identified. Moreover, strong antiproliferative and apoptotic activities were observed in brain cancer cell lines at low nano- to micromolar concentrations.

S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling.

Astrocytes are critical players in brain health and disease. Brain pathologies and lesions are usually accompanied by astroglial alterations known as reactive astrogliosis. Sphingosine 1-phosphate lyase (SGPL1) catalysis, the final step in sphingolipid catabolism, irreversibly cleaves its substrate sphingosine 1-phosphate (S1P).

The role of sphingosine 1-phosphate metabolism in brain health and disease.

Lipids are essential structural and functional components of the central nervous system (CNS). Sphingolipids are ubiquitous membrane components which were discovered in the brain in the late 19 century. In mammals, the brain contains the highest concentration of sphingolipids in the body.

S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health.

Astrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development.

Sphingosine-1-phosphate-lyase deficiency affects glucose metabolism in a way that abets oncogenesis.

Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival and migration, as well as neovascularization and inflammation. Its critical role in the development and progression of cancer is well documented. The metabolism of S1P, which exerts its effect mainly via five G protein-coupled receptors (S1PR ), is tightly regulated.

CEST-2.2 overexpression alters lipid metabolism and extends longevity of mitochondrial mutants.

Mitochondrial dysfunction can either extend or decrease Caenorhabditis elegans lifespan, depending on whether transcriptionally regulated responses can elicit durable stress adaptation to otherwise detrimental lesions. Here, we test the hypothesis that enhanced metabolic flexibility is sufficient to circumvent bioenergetic abnormalities associated with the phenotypic threshold effect, thereby transforming short-lived mitochondrial mutants into long-lived ones. We find that CEST-2.

Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance.

Cancer development is a multistep process in which cells must overcome a series of obstacles before they can become fully developed tumors. First, cells must develop the ability to proliferate unchecked. Once this is accomplished, they must be able to invade the neighboring tissue, as well as provide themselves with oxygen and nutrients.

Development of an On-Tissue Derivatization Method for MALDI Mass Spectrometry Imaging of Bioactive Lipids Containing Phosphate Monoester Using Phos-tag.

Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) is an emerging label-free method for mapping the distribution of diverse molecular species in tissue sections. Despite recent progress in MALDI-MSI analyses of lipids, it is still difficult to visualize minor bioactive lipids including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). Here, we have developed a novel on-tissue derivatization method using Phos-tag, a zinc complex that specifically binds to a phosphate monoester group.

Ectoines as novel anti-inflammatory and tissue protective lead compounds with special focus on inflammatory bowel disease and lung inflammation.

The compatible solute ectoine is one of the most abundant and powerful cytoprotectant in the microbial world. Due to its unique ability to stabilize biological membranes and macromolecules it has been successfully commercialized as ingredient of various over-the-counter drugs, achieving primarily epithelial protection. While trying to elucidate the mechanism of its cell protective properties in in-vitro studies, a significant anti-inflammatory effect was documented for the small molecule.

Special Issue on "Sphingolipids: From Pathology to Therapeutic Perspectives".

It is an honor for us to dedicate this Special Issue to our dearest friend Lina Obeid, who was not only a pioneer in the field of sphingolipids, but also a remarkable personality [...

Neurodegeneration Caused by S1P-Lyase Deficiency Involves Calcium-Dependent Tau Pathology and Abnormal Histone Acetylation.

We have shown that sphingosine 1-phosphate (S1P) generated by sphingosine kinase 2 (SK2) is toxic in neurons lacking S1P-lyase (SGPL1), the enzyme that catalyzes its irreversible cleavage. Interestingly, patients harboring mutations in the gene encoding this enzyme () often present with neurological pathologies. Studies in a mouse model with a developmental neural-specific ablation of SGPL1 (SGPL1) confirmed the importance of S1P metabolism for the presynaptic architecture and neuronal autophagy, known to be essential for brain health.

Detection of endogenous lipids in chicken feathers distinct from preen gland constituents.

Bird feather lipids are usually attributed to the oily secretion product of the uropygial (preen) gland. We have observed, however, that feathers exhibit a strong reaction with osmium tetroxide (OsO), even after treatment with detergents. This leads us to postulate the existence of endogenous feather lipids distinct from preen gland lipids.

Sphingolipids as prognostic biomarkers of neurodegeneration, neuroinflammation, and psychiatric diseases and their emerging role in lipidomic investigation methods.

Lipids play an important role in neurodegeneration, neuroinflammation, and psychiatric disorders and an imbalance in sphingolipid levels is associated with disease. Although early diagnosis and intervention of these disorders would clearly have favorable long-term outcomes, no diagnostic tests currently exist that can accurately identify people at risk. Reliable prognostic biomarkers that are easily accessible would be beneficial to determine therapy and treatment response in clinical trials.

S1P-lyase deficiency uncouples ganglioside formation - Potential contribution to tumorigenic capacity.

Sphingosine-1-phosphate (S1P) is not only a catabolic intermediate of all sphingolipids but also an evolutionary conserved bioactive lipid with critical functions in cell survival, differentiation, and migration as well as in immunity and angiogenesis. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism. As sphingoid bases and their 1-phosphates are not only metabolic intermediates but also highly bioactive lipids that modulate a wide range of physiological processes, it would be predicted that their elevation might induce adjustments in other facets of sphingolipid metabolism and/or alter cell behavior.

Neural sphingosine 1-phosphate accumulation activates microglia and links impaired autophagy and inflammation.

Microglia mediated responses to neuronal damage in the form of neuroinflammation is a common thread propagating neuropathology. In this study, we investigated the microglial alterations occurring as a result of sphingosine 1-phosphate (S1P) accumulation in neural cells. We evidenced increased microglial activation in the brains of neural S1P-lyase (SGPL1) ablated mice (SGPL1 ) as shown by an activated and deramified morphology and increased activation markers on microglia.

Sphingolipid metabolism - an ambiguous regulator of autophagy in the brain.

In mammals, the brain exhibits the highest lipid content in the body next to adipose tissue. Complex sphingolipids are characteristic compounds of neuronal membranes. Vital neural functions including information flux and transduction occur along these membranes.

SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production.

Macroautophagy/autophagy defects have been identified as critical factors underlying the pathogenesis of neurodegenerative diseases. The roles of the bioactive signaling lipid sphingosine-1-phosphate (S1P) and its catabolic enzyme SGPL1/SPL (sphingosine phosphate lyase 1) in autophagy are increasingly recognized. Here we provide in vitro and in vivo evidence for a previously unidentified route through which SGPL1 modulates autophagy in neurons.

Sphingosine 1-phosphate - A double edged sword in the brain.

The physiological functions of sphingosine 1-phosphate (S1P) and its pathological roles in various diseases are increasingly being elucidated. Particularly, a growing body of literature has implicated S1P in the pathogenesis of brain related disorders. With the deciphering of more intricate aspects of S1P signalling, there is also a need to reconsider the notion of S1P only as a determinant of cell survival and proliferation.

Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca storage.

Sphingosine-1-phosphate (S1P) lyase irreversibly cleaves S1P, thereby catalysing the ultimate step of sphingolipid degradation. We show here that embryonic fibroblasts from S1P lyase-deficient mice (Sgpl1-MEFs), in which S1P and sphingosine accumulate, have features of Niemann-Pick disease type C (NPC) cells. In the presence of serum, overall cholesterol content was elevated in Sgpl1-MEFs, due to upregulation of the LDL receptor and enhanced cholesterol uptake.

Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism.

The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. We have shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, we generated brain-specific knockout mouse models in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated.

Sphingosine-1-phosphate: boon and bane for the brain.

Sphingosine-1-phosphate (S1P), an evolutionary conserved bioactive lipid, is essential for brain development, but might also exert detrimental effects in terminally differentiated post-mitotic neurons. Its concentration in the brain is tightly regulated by specific kinases and phosphatases, and mainly by the S1P degrading enzyme, S1P-lyase (S1PL). The role of S1P in neurons was initially studied in primary cultures by using structural analogues.

Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein.

Progressive accumulation of the amyloid β protein in extracellular plaques is a neuropathological hallmark of Alzheimer disease. Amyloid β is generated during sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In addition to the proteolytic processing by secretases, APP is also metabolized by lysosomal proteases.

Hydroxyectoine ameliorates preservation injury in deceased after cardiac death donors in experimental liver grafts.

Background: Due to the drastic shortage of organ donors, clinicians are increasingly considering the use of deceased after cardiac death donors (DCD). Compatible solutes like Ectoine and Hydroxyectoine are produced by extremophilic bacteria as a cell protectant to survive in harsh environments. We hypothesized that the addition of Hydroxyectoine to Histidine-Tryptophan-Ketoglutarate solution (HTK) could ameliorate cold ischemic preservation injury of DCD livers.

Cross-talk of membrane lipids and Alzheimer-related proteins.

Alzheimer's disease (AD) is neuropathologically characterized by the combined occurrence of extracellular β-amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the amyloid β-peptide (Aβ), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Aβ domain of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease complex involved in the generation of Aβ.