thermozymocidin and sphingosine-1-phosphate

Spingolipids (SLs) are an important component of central nervous system (CNS) myelin sheaths and affect the viability of brain cells (oligodendrocytes, neurons and astrocytes) that is determined by signaling mediated by bioactive sphingoids (lyso-SLs). Recent studies indicate that two lipids, ceramide and sphingosine 1-phosphate (S1P), are particularly involved in many human diseases including the autoimmune inflammatory demyelination of multiple sclerosis (MS). In this review we: (1) Discuss possible sources of ceramide in CNS; (2) Summarize the features of the metabolism of S1P and its downstream signaling through G-protein-coupled receptors; (3) Link perturbations in bioactive SLs metabolism to MS neurodegeneration and (4) Compile ceramide and S1P relationships to this process. In addition, we described recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod) as well as proposed intervention to specify critical SL levels that tilt balances of apoptotic/active ceramide versus anti-apoptotic/inactive dihydroceramide that may offer a novel and important therapeutic approach to MS.

Topics: Apoptosis; Ceramides; Fatty Acids, Monounsaturated; Fingolimod Hydrochloride; Humans; Lysophospholipids; Metabolic Networks and Pathways; Multiple Sclerosis; Myelin Sheath; Propylene Glycols; Receptors, G-Protein-Coupled; Serine C-Palmitoyltransferase; Signal Transduction; Sphingolipids; Sphingosine

Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo synthesis. In the present research we evaluated the effects of myriocin application on type 2 diabetes mellitus in three different types of skeletal muscles: (1) slow-oxidative (red gastrocnemius), (2) oxidative-glycolytic (soleus), and (3) glycolytic (white gastrocnemius). For these reasons the animals were randomly divided into four groups: "control" (C), "myriocin" (M), "high fat diet" (HFD), "high fat diet" (HFD), and "high fat diet + myriocin" (HFD + M). Our in vivo study demonstrated that ceramide synthesis inhibition reduces intramuscular ceramide, its precursor sphinganine, and its derivatives sphingosine and sphingosine-1-phosphate concentrations. Moreover, FFA and TG contents were also decreased after myriocin treatment. Thus, myriocin presents potential therapeutic perspectives with respect to the treatment of insulin resistance and its serious consequences in obese patients.

Topics: Animals; Ceramides; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Monounsaturated; Glycolysis; Insulin Resistance; Lysophospholipids; Male; Muscle, Skeletal; Oxygen; Rats; Rats, Wistar; Signal Transduction; Sphingolipids; Sphingosine

Sphingosine kinase is a key enzyme in sphingolipid metabolism, catalysing the conversion of sphingosine or dihydrosphingosine into sphingosine-1-phosphate or dihydrosphingosine-1-phosphate respectively. In mammals, sphingosine-1-phosphate is a powerful signalling molecule regulating cell growth, differentiation, apoptosis and immunity. Functions of sphingosine kinase or sphingosine-1-phosphate in pathogenic protozoans are virtually unknown. While most organisms possess two closely related sphingosine kinases, only one sphingosine kinase homologue (SKa) can be identified in Leishmania, which are vector-borne protozoan parasites responsible for leishmaniasis. Leishmania SKa is a large, cytoplasmic enzyme capable of phosphorylating both sphingosine and dihydrosphingosine. Remarkably, deletion of SKa leads to catastrophic defects in both the insect stage and mammalian stage of Leishmania parasites. Genetic and biochemical analyses demonstrate that proper expression of SKa is essential for Leishmania parasites to remove toxic metabolites, to survive stressful conditions, and to cause disease in mice. Therefore, SKa is a pleiotropic enzyme with vital roles throughout the life cycle of Leishmania. The essentiality of SKa and its apparent divergence from mammalian counterparts suggests that this enzyme can be selectively targeted to reduce Leishmania infection.

Topics: Animals; Antifungal Agents; DNA Replication; DNA, Protozoan; Ethanolamine; Fatty Acids, Monounsaturated; Genes, Protozoan; Leishmania; Leishmaniasis; Lysophospholipids; Mice; Mice, Inbred BALB C; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Virulence

Melanoma is the most aggressive form of skin cancer, and it resists chemotherapy. Candidate drugs for effective anti-cancer treatment have been sought from natural resources. Here, we have investigated anti-proliferative activity of myriocin, serine palmitoyltransferase inhibitor, in the de novo sphingolipid pathway, and its mechanism in B16F10 melanoma cells.. We assessed cell population growth by measuring cell numbers, DNA synthesis, cell cycle progression, and expression of cell cycle regulatory proteins. Ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate levels were analysed by HPLC.. Myriocin inhibited proliferation of melanoma cells and induced cell cycle arrest in the G(2) /M phase. Expressions of cdc25C, cyclin B1 and cdc2 were decreased in the cells after exposure to myriocin, while expression of p53 and p21(waf1/cip1) was increased. Levels of ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate in myriocin-treated cells after 24 h were reduced by approximately 86%, 57%, 75% and 38%, respectively, compared to levels in control cells.. Our results suggest that inhibition of sphingolipid synthesis by myriocin in melanoma cells may inhibit expression of cdc25C or activate expression of p53 and p21(waf1/cip1) , followed by inhibition of cyclin B1 and cdc2, resulting in G(2) /M arrest of the cell cycle and cell population growth inhibition. Thus, modulation of sphingolipid metabolism by myriocin may be a potential target of mechanism-based therapy for this type of skin cancer.

Topics: Animals; Antineoplastic Agents; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Ceramides; Cyclin B1; Fatty Acids, Monounsaturated; Gene Expression Regulation, Neoplastic; Lysophospholipids; Melanoma, Experimental; Mice; Proto-Oncogene Proteins p21(ras); Serine C-Palmitoyltransferase; Skin Neoplasms; Sphingomyelins; Sphingosine; Tumor Suppressor Protein p53

Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-alpha (TNF-alpha) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.

Topics: Adipose Tissue; Animals; Body Weight; Ceramides; Energy Metabolism; Fatty Acids, Monounsaturated; Ion Channels; Lysophospholipids; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Organ Size; Sphingolipids; Sphingosine; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Uncoupling Protein 3

Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis. We injected 8-week-old apoE-deficient mice with myriocin (0.3 mg/kg/every other day, intraperitoneal) for 60 days. On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001). Plasma total cholesterol and triglyceride levels demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (42% in root and 36% in en face assays) (p < 0.01). On a high fat diet, myriocin treatment caused marked decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (59, 66, and 81%, respectively) (p < 0.0001), and a marked increase in plasma phosphatidylcholine levels (100%) (p < 0.0001). Total cholesterol and triglyceride demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (39% in root and 37% in en face assays) (p < 0.01). These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties. Thus, inhibition of SPT activity could be an alternative treatment for atherosclerosis.

Topics: Acyltransferases; Animal Feed; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Ceramides; Cholesterol; Fatty Acids, Monounsaturated; Immunosuppressive Agents; Lipid Metabolism; Lipids; Lipoproteins; Lysophospholipids; Mass Spectrometry; Mice; Mice, Knockout; Phosphatidylcholines; Serine C-Palmitoyltransferase; Signal Transduction; Sphingolipids; Sphingosine; Time Factors; Triglycerides

Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the vascular endothelial growth factor (VEGF) receptors in both rats and mice. Emphysema was reproduced with intratracheal instillation of ceramide in naive mice. Excessive ceramide triggers a feed-forward mechanism mediated by activation of secretory acid sphingomyelinase, as suggested by experiments with neutralizing ceramide antibody in mice and with acid sphingomyelinase-deficient fibroblasts. Concomitant augmentation of signaling initiated by a prosurvival metabolite, sphingosine-1-phosphate, prevented lung apoptosis, implying that a balance between ceramide and sphingosine-1-phosphate is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies.

Topics: Acyltransferases; Animals; Apoptosis; Cells, Cultured; Ceramides; Dose-Response Relationship, Drug; Emphysema; Fatty Acids, Monounsaturated; Fumonisins; Humans; Lung; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Oxidoreductases; Rats; Rats, Sprague-Dawley; Serine C-Palmitoyltransferase; Smoking; Sphingosine; Up-Regulation; Vascular Endothelial Growth Factor A

Following the discovery of an immunosuppressive substance isolated from one of the entomopathogenic fungi 'vegetable wasps and plant worms', FTY720, whose immunosuppressive action is more potent than that of cyclosporin, was developed. In contrast to classical immunosuppressants such as cyclosporin, FTY720 does not affect the growth, maturation and activation of lymphocytes, but causes a reduction in the number of circulating lymphocytes as a result of enhanced homing of lymphocytes to the secondary lymphoid organs. It has recently been reported that FTY720 is phosphorylated in vivo by sphingosine kinase, and the phosphorylated FTY720 is a ligand of the receptors of sphingosine 1-phosphate (S1P), which are G-protein-coupled receptors. S1P has been recognized most prominently as a platelet-derived lipid mediator which regulates several functions of endothelial and smooth muscle cells. In addition, recent studies have suggested the crucial roles for S1P in immunological, and inflammatory modulation.

Topics: Cordyceps; Depression, Chemical; Fatty Acids, Monounsaturated; Fingolimod Hydrochloride; Immunosuppressive Agents; Inflammation Mediators; Ligands; Lymphocyte Count; Lymphocytes; Lysophospholipids; Phosphorylation; Propylene Glycols; Receptors, G-Protein-Coupled; Receptors, Lysophospholipid; Sphingosine