-
International Immunology Aug 2019AbstractSphingosine 1-phosphate (S1P), a sphingolipid mediator, regulates various cellular functions via high-affinity G protein-coupled receptors, S1P1-5. The S1P-S1P... (Review)
Review
AbstractSphingosine 1-phosphate (S1P), a sphingolipid mediator, regulates various cellular functions via high-affinity G protein-coupled receptors, S1P1-5. The S1P-S1P receptor signaling system plays important roles in lymphocyte trafficking and maintenance of vascular integrity, thus contributing to the regulation of complex inflammatory processes. S1P is enriched in blood and lymph while maintained low in intracellular or interstitial fluids, creating a steep S1P gradient that is utilized to facilitate efficient egress of lymphocytes from lymphoid organs. Blockage of the S1P-S1P receptor signaling system results in a marked decrease in circulating lymphocytes because of a failure of lymphocyte egress from lymphoid organs. This provides a basis of immunomodulatory drugs targeting S1P1 receptor such as FTY720, an immunosuppressive drug approved in 2010 as the first oral treatment for relapsing-remitting multiple sclerosis. The S1P-S1P receptor signaling system also plays important roles in maintenance of vascular integrity since it suppresses sprouting angiogenesis and regulates vascular permeability. Dysfunction of the S1P-S1P receptor signaling system results in various vascular defects, such as exaggerated angiogenesis in developing retina and augmented inflammation due to increased permeability. Endothelial-specific deletion of S1P1 receptor in mice fed high-fat diet leads to increased formation of atherosclerotic lesions. This review highlights the importance of the S1P-S1P receptor signaling system in inflammatory processes. We also describe our recent findings regarding a specific S1P chaperone, apolipoprotein M, that anchors to high-density lipoprotein and contributes to shaping the endothelial-protective and anti-inflammatory properties of high-density lipoprotein.
Topics: Animals; Humans; Inflammation; Lysophospholipids; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 31049553
DOI: 10.1093/intimm/dxz037 -
Cells Jun 2022Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the... (Review)
Review
Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the immune system. S1P-S1PR signaling has been well characterized in immune trafficking and activation in both innate and adaptive immune systems. Despite this knowledge, the full scope in the pathogenesis of autoimmune disorders is not well characterized yet. From the discovery of fingolimod, the first S1P modulator, until siponimod, the new molecule recently approved for the treatment of secondary progressive multiple sclerosis (SPMS), there has been a great advance in understanding the S1P functions and their involvement in immune diseases, including multiple sclerosis (MS). Modulation on S1P is an interesting target for the treatment of various autoimmune disorders. Improved understanding of the mechanism of action of fingolimod has allowed the development of the more selective second-generation S1PR modulators. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are known to play a major role in MS pathogenesis. The understanding of S1PR1's role facilitated the development of pharmacological strategies directed to this target, and theoretically reduced the safety concerns derived from the use of fingolimod. A great advance in the MS treatment was achieved in March 2019 when the Food and Drug Association (FDA) approved Siponimod, for both active secondary progressive MS and relapsing-remitting MS. Siponimod became the first oral disease modifying therapy (DMT) specifically approved for active forms of secondary progressive MS. Additionally, for the treatment of relapsing forms of MS, ozanimod was approved by FDA in March 2020. Currently, there are ongoing trials focused on other new-generation S1PR1 modulators. This review approaches the fundamental aspects of the sphingosine phosphate modulators and their main similarities and differences.
Topics: Autoimmune Diseases; Fingolimod Hydrochloride; Humans; Lysophospholipids; Multiple Sclerosis; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine
PubMed: 35805142
DOI: 10.3390/cells11132058 -
Science (New York, N.Y.) Oct 2018Detection of analytes by means of field-effect transistors bearing ligand-specific receptors is fundamentally limited by the shielding created by the electrical double...
Detection of analytes by means of field-effect transistors bearing ligand-specific receptors is fundamentally limited by the shielding created by the electrical double layer (the "Debye length" limitation). We detected small molecules under physiological high-ionic strength conditions by modifying printed ultrathin metal-oxide field-effect transistor arrays with deoxyribonucleotide aptamers selected to bind their targets adaptively. Target-induced conformational changes of negatively charged aptamer phosphodiester backbones in close proximity to semiconductor channels gated conductance in physiological buffers, resulting in highly sensitive detection. Sensing of charged and electroneutral targets (serotonin, dopamine, glucose, and sphingosine-1-phosphate) was enabled by specifically isolated aptameric stem-loop receptors.
Topics: Aptamers, Nucleotide; Biosensing Techniques; Dopamine; Glucose; Lysophospholipids; Serotonin; Sphingosine; Transistors, Electronic
PubMed: 30190311
DOI: 10.1126/science.aao6750 -
Advances in Biological Regulation May 2018The bioactive lipid, sphingosine 1-phosphate (S1P) is produced by phosphorylation of sphingosine and this is catalysed by two sphingosine kinase isoforms (SK1 and SK2).... (Review)
Review
The bioactive lipid, sphingosine 1-phosphate (S1P) is produced by phosphorylation of sphingosine and this is catalysed by two sphingosine kinase isoforms (SK1 and SK2). Here we discuss structural functional aspects of SK1 (which is a dimeric quaternary enzyme) that relate to coordinated coupling of membrane association with phosphorylation of Ser225 in the 'so-called' R-loop, catalytic activity and protein-protein interactions (e.g. TRAF2, PP2A and G). S1P formed by SK1 at the plasma-membrane is released from cells via S1P transporters to act on S1P receptors to promote tumorigenesis. We discuss here an additional novel mechanism that can operate between cancer cells and fibroblasts and which involves the release of the S1P receptor, S1P in exosomes from breast cancer cells that regulates ERK-1/2 signalling in fibroblasts. This novel mechanism of signalling might provide an explanation for the role of S1P in promoting metastasis of cancer cells and which is dependent on the micro-environmental niche.
Topics: Animals; Humans; Lysophospholipids; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Sphingosine
PubMed: 28942351
DOI: 10.1016/j.jbior.2017.09.006 -
Aging Dec 2017
Topics: Animals; Ceramides; Energy Metabolism; Humans; Lysophospholipids; Signal Transduction; Sphingosine
PubMed: 29242408
DOI: 10.18632/aging.101347 -
Biomolecules Sep 2020Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1-3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide... (Review)
Review
Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1-3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.
Topics: Animals; Cell Membrane; Humans; Lysophospholipids; Neoplasms; Phosphatidate Phosphatase; Signal Transduction; Sphingosine; Up-Regulation
PubMed: 32887262
DOI: 10.3390/biom10091263 -
Progress in Lipid Research Apr 2016Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of... (Review)
Review
Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of five S1P-specific G protein coupled receptors but also has intracellular signalling roles. There is substantial evidence to support a role for sphingosine kinases and S1P in health and disease. This review summarises recent advances in the area in relation to receptor-mediated signalling by S1P and novel intracellular targets of this lipid. New evidence for a role of each sphingosine kinase isoform in cancer, the cardiovascular system, central nervous system, inflammation and diabetes is discussed. There is continued research to develop isoform selective SK inhibitors, summarised here. Analysis of the crystal structure of SK1 with the SK1-selective inhibitor, PF-543, is used to identify residues that could be exploited to improve selectivity in SK inhibitor development for future therapeutic application.
Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Inflammation; Lysophospholipids; Models, Molecular; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Receptors, G-Protein-Coupled; Signal Transduction; Sphingosine; Structure-Activity Relationship
PubMed: 26970273
DOI: 10.1016/j.plipres.2016.03.001 -
Journal of Neurochemistry Jul 2021Sphingolipids are a class of lipids highly enriched in the central nervous system (CNS), which shows great diversity and complexity, and has been implicated in CNS... (Review)
Review
Sphingolipids are a class of lipids highly enriched in the central nervous system (CNS), which shows great diversity and complexity, and has been implicated in CNS development and function. Alterations in sphingolipid metabolism have been described in multiple diseases, including those affecting the central nervous system (CNS). In this review, we discuss the role of sphingolipid metabolism in neurodegeneration, evaluating its direct roles in neuron development and health, and also in the induction of neurotoxic activities in CNS-resident astrocytes and microglia in the context of neurologic diseases such as multiple sclerosis and Alzheimer's disease. Finally, we focus on the metabolism of gangliosides and sphingosine-1-phosphate, its contribution to the pathogenesis of neurologic diseases, and its potential as a candidate target for the therapeutic modulation of neurodegeneration.
Topics: Animals; Central Nervous System Diseases; Gangliosides; Humans; Lipid Metabolism; Lysophospholipids; Neurodegenerative Diseases; Sphingolipids; Sphingosine
PubMed: 32402091
DOI: 10.1111/jnc.15044 -
Progress in Lipid Research Apr 2019The increased adipose tissue mass of obese individuals enhances the risk of metabolic syndrome, type 2 diabetes and cardiovascular diseases. During pathological... (Review)
Review
The increased adipose tissue mass of obese individuals enhances the risk of metabolic syndrome, type 2 diabetes and cardiovascular diseases. During pathological expansion of adipose tissue, multiple molecular controls of lipid storage, adipocyte turn-over and endocrine secretion are perturbed and abnormal lipid metabolism results in a distinct lipid profile. There is a role for ceramides and sphingosine 1-phosphate (S1P) in inducing adipose dysfunction. For instance, the alteration of ceramide biosynthesis, through the de-regulation of key enzymes, results in aberrant formation of ceramides (e.g. C and C) which block insulin signaling and promote adipose inflammation. Furthermore, S1P can induce defective adipose tissue phenotypes by promoting chronic inflammation and inhibiting adipogenesis. These abnormal changes are discussed in the context of possible therapeutic approaches to re-establish normal adipose function and to, thereby, increase insulin sensitivity in type 2 diabetes. Such novel approaches include blockade of ceramide biosynthesis using inhibitors of sphingomyelinase or dihydroceramide desaturase and by antagonism of S1P receptors, such as S1P.
Topics: Adipose Tissue; Animals; Ceramides; Humans; Lysophospholipids; Sphingosine
PubMed: 30951736
DOI: 10.1016/j.plipres.2019.04.001 -
Tumour Biology : the Journal of the... Apr 2017Elucidating the interaction between cancer and non-cancer cells, such as blood vessels, immune cells, and other stromal cells, in the tumor microenvironment is... (Review)
Review
Elucidating the interaction between cancer and non-cancer cells, such as blood vessels, immune cells, and other stromal cells, in the tumor microenvironment is imperative in understanding the mechanisms underlying cancer progression and metastasis, which is expected to lead to the development of new therapeutics. Sphingosine-1-phosphate is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis/lymphangiogenesis, and immune responsiveness, which are all factors involved in cancer progression. Sphingosine-1-phosphate is generated inside cancer cells by sphingosine kinases and then exported into the tumor microenvironment. Although sphingosine-1-phosphate is anticipated to play an important role in the tumor microenvironment and cancer progression, determining sphingosine-1-phosphate levels in the tumor microenvironment has been difficult due to a lack of established methods. We have recently developed a method to measure sphingosine-1-phosphate levels in the interstitial fluid that bathes cancer cells in the tumor microenvironment, and reported that high levels of sphingosine-1-phosphate exist in the tumor interstitial fluid. Importantly, sphingosine-1-phosphate can be secreted from cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment. Furthermore, sphingosine-1-phosphate affects both cancer and non-cancer cells in the tumor microenvironment promoting cancer progression. Here, we review the roles of sphingosine-1-phosphate in the interaction between cancer and non-cancer cells in tumor microenvironment, and discuss future possibilities for targeted therapies against sphingosine-1-phosphate signaling for cancer patients.
Topics: Humans; Lysophospholipids; Neoplasms; Sphingosine; Tumor Microenvironment
PubMed: 28381169
DOI: 10.1177/1010428317699133