sphingosine-1-phosphate and Diabetes-Mellitus

This study aims to explore the potential biomarkers in the development of diabetes mellitus (DM) into diabetic retinopathy (DR).. Systematic review of diabetic metabolomics was used to screen the differential metabolites and related pathways during the development of DM. Non-targeted lipidomics of rat plasma was performed to explore the differential metabolites in the development of DM into DR in vivo. To verify the effects of differential metabolites in inducing retinal microvascular endothelial cells (RMECs) injury by increasing oxidative stress, high glucose medium containing differential metabolites was used to induce rat RMECs injury and cell viability, malondialdehyde (MDA) contents, superoxide dismutase (SOD) activities, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated in vitro. Network pharmacology was performed to explore the potential mechanism of differential metabolites in inducing DR.. Through the systematic review, 148 differential metabolites were obtained and the sphingolipid metabolic pathway attracted our attention. Plasma non-targeted lipidomics found that sphingolipids were accompanied by the development of DM into DR. In vitro experiments showed sphinganine and sphingosine-1-phosphate aggravated rat RMECs injury induced by high glucose, further increased MDA and ROS levels, and further decreased SOD activities and MMP. Network pharmacology revealed sphinganine and sphingosine-1-phosphate may induce DR by regulating the AGE-RAGE and HIF-1 signaling pathways.. Integrated systematic review, lipidomics and experiment verification reveal that abnormal sphingolipid metabolism facilitates DR by inducing oxidative stress on RMECs. Our study could provide the experimental basis for finding potential biomarkers for the diagnosis and treatment of DR.

Topics: Animals; Biomarkers; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Glucose; Lipidomics; Oxidative Stress; Rats; Reactive Oxygen Species; Sphingolipids; Superoxide Dismutase

Sphingosine-1-phosphate signaling is emerging as a critical regulator of cellular processes that is initiated by the intracellular production of bioactive lipid molecule, sphingosine-1-phosphate. Binding of sphingosine-1-phosphate to its extracellular receptors activates diverse downstream signaling that play a critical role in governing physiological processes. Increasing evidence suggests that this signaling pathway often gets impaired during pathophysiological and diseased conditions and hence manipulation of this signaling pathway may be beneficial in providing treatment. In this review, we summarized the recent findings of S1P signaling pathway and the versatile role of the participating candidates in context with several disease conditions. Finally, we discussed its possible role as a novel drug target in different diseases.

Topics: Arthritis, Rheumatoid; Ceramidases; Diabetes Mellitus; Humans; Lysophospholipids; Molecular Targeted Therapy; Multiple Sclerosis; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine

Sphingosine kinase (SphK) is an important signalling enzyme that catalyses the phosphorylation of sphingosine (Sph) to form sphingosine‑1‑phosphate (S1P). The multifunctional lipid, S1P binds to a family of five G protein-coupled receptors (GPCRs). As an intracellular second messenger, S1P activates key signalling cascades responsible for the maintenance of sphingolipid metabolism, and has been implicated in the progression of cancer, and the development of other inflammatory and metabolic diseases. SphK and S1P are critical molecules involved in the regulation of various cellular metabolic processes, such as cell proliferation, survival, apoptosis, adhesion and migration. There is strong evidence supporting the critical roles of SphK and S1P in the progression of diabetes mellitus, including insulin sensitivity and insulin secretion, pancreatic β‑cell apoptosis, and the development of diabetic inflammatory state. In this review, we summarise the current state of knowledge for SphK/S1P signalling effects, associated with the development of insulin resistance, pancreatic β‑cell death and the vascular complications of diabetes mellitus.

Topics: Animals; Diabetes Complications; Diabetes Mellitus; Enzyme Activation; Extracellular Space; Humans; Insulin Resistance; Insulin-Secreting Cells; Intracellular Space; Isoenzymes; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Protein Transport; Signal Transduction; Sphingolipids; Sphingosine

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

Sphingolipids have emerged as molecules whose metabolism is regulated leading to generation of bioactive products including ceramide, sphingosine, and sphingosine-1-phosphate. The balance between cellular levels of these bioactive products is increasingly recognized to be critical to cell regulation; whereby, ceramide and sphingosine cause apoptosis and growth arrest phenotypes, and sphingosine-1-phosphate mediates proliferative and angiogenic responses. Sphingosine kinase is a key enzyme in modulating the levels of these lipids and is emerging as an important and regulated enzyme. This review is geared at mechanisms of regulation of sphingosine kinase and the coming to light of its role in disease.

Topics: Animals; Atherosclerosis; Ceramides; Diabetes Mellitus; Enzyme Activation; Humans; Inflammation; Lysophospholipids; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Diabetic nephropathy remains a common cause of end-stage renal failure and its associated mortality around the world. Sphingosine 1-phosphate (S1P) is a multifunctional lipid mediator and binds to HDL via apolipoprotein M (ApoM). Since HDL has been reported to be epidemiologically associated with kidney disease, we attempted to investigate the involvement of the ApoM/S1P axis in the pathogenesis/progression of diabetic nephropathy. In type 2 diabetic patients, the serum ApoM levels were inversely correlated with the clinical stage of diabetic nephropathy. The decline in the eGFR over a 5-year observation period proceeded more rapidly in subjects with lower serum ApoM levels. In a mouse model of streptozotocin-induced diabetes, deletion of ApoM deteriorated the phenotypes of diabetic nephropathy: the urinary albumin and plasma creatinine levels increased, the kidneys enlarged, and renal fibrosis and thickening of the basement membrane progressed. On the other hand, overexpression of ApoM ameliorated these phenotypes. These protective effects of ApoM were partially inhibited by treatment with VPC23019, an antagonist of S1P1 and S1P3, but not by treatment with JTE013, an antagonist of S1P2. ApoM/S1P axis attenuated activation of the Smad3 pathway, while augmented eNOS phosphorylation through the S1P1 pathway. Moreover, ApoM/S1P increased the SIRT1 protein levels and enhanced mitochondrial functions by increasing the S1P content of the cell membrane, which might cause selective activation of S1P1. ApoM might be a useful biomarker for predicting the progression of diabetic nephropathy, and the ApoM/S1P-S1P1 axis might serve as a novel therapeutic target for preventing the development/progression of diabetic nephropathy.

Topics: Animals; Apolipoproteins; Apolipoproteins M; Diabetes Mellitus; Diabetic Nephropathies; Mice; Sphingosine

To determine the changes of serum copeptin and sphingosine 1-phosphate (S1P) in patients with restenosis after stent implantation of symptomatic intracranial artery stenosis.. An observational study.. Changyi people's Hospital, China, from February 2016 to November 2019.. A total of 76 patients with symptomatic intracranial artery stenosis and stent implantation were divided into the restenosis group (n = 16) and the non-restenosis group (n=60) according to the intracranial artery restenosis occurred after the follow-up of 1 year. Levels of serum copeptin and S1P were compared between the groups.. There were significant differences in diabetes mellitus and hypertension between the two groups (p<0.001 and p = 0.017, respectively). There were no significant differences in serum copeptin and S1P levels between the two groups before and 3 days after the operation (p = 0.927, 0.792, 0.776, and 0.906, respectively). Postoperative follow-up of one year, levels of serum copeptin in the restenosis group were higher than those in the non-restenosis group (p<0.001), and levels of serum S1P in the restenosis group were lower than those in the non-restenosis group (p = 0.003).. High serum copeptin level, low serum S1P level, hypertension, and diabetes mellitus are independent risk factors promoting restenosis after stent implantation in patients with symptomatic intracranial artery stenosis.. Copeptin, Sphingosine 1-phosphate (S1P), Symptomatic intracranial artery stenosis, Stent implantation, Restenosis.

Topics: Arteries; Constriction, Pathologic; Diabetes Mellitus; Follow-Up Studies; Glycopeptides; Humans; Hypertension; Lysophospholipids; Sphingosine; Stents

Recently, it has been established that most of the pleiotropic effects of high-density lipoprotein (HDL) are attributed to sphingosine 1-phosphate (S1P), which rides on HDL via apolipoprotein M (ApoM). In subjects with diabetes mellitus, both the pleiotropic effects of HDL and its role in reverse cholesterol transport are reported to be impaired. To elucidate the mechanisms underlying the impaired pleiotropic effects of HDL in subjects with diabetes, from the aspects of S1P and ApoM.. The incubation of HDL in a high-glucose condition resulted in the dimerization of ApoM. Moreover, the treatment of HDL with methylglyoxal resulted in the modulation of the ApoM structure, as suggested by the results of western blot analysis, isoelectric focusing electrophoresis, and two-dimensional gel electrophoresis, which was reversed by treatment with anti-glycation reagents.. The glycation of HDL resulted in impaired binding of the glycated HDL to S1P, and the S1P on glycated HDL degraded faster. In the case of human subjects, on the other hand, although both the serum ApoM levels and the ApoM content in HDL were lower in subjects with diabetes, we did not observe the polymerization of ApoM.. Modulation of the quantity and quality of ApoM might explain, at least in part, the impaired functions of HDL in subjects with diabetes mellitus. ApoM might be a useful target for laboratory testing and/or the treatment of diabetes mellitus.

Topics: Apolipoproteins M; Biological Transport; Diabetes Mellitus; Drug Discovery; Electrophoresis, Gel, Two-Dimensional; Humans; Isoelectric Focusing; Lipoproteins, HDL; Lysophospholipids; Sphingosine

Population-wide reductions in cardiovascular disease (CVD) have not been equally shared in the African American community due to a higher burden of CVD risk factors such as metabolic disorders and obesity. Differential concentrations of sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) has been associated with the development of CVD, metabolic disorders (MetD), and obesity. Whether African Americans have disparate expression levels of sphingolipids that explain higher burdens of CVD remains unknown.. A cross sectional analysis of plasma concentrations of ceramides, sphingosine, and S1P were measured from 8 whites and 7 African Americans without metabolic disorders and 7 whites and 8 African Americans with metabolic disorders using high performance liquid chromatography/tandem mass spectrometry methodology (HPLC/MS-MS). Subjects were stratified by both race and metabolic status. Subjects with one or more of the following physician confirmed diagnosis: diabetes, hypertension, hypercholesterolemia, or dyslipidemia were classified as having metabolic disease (MetD). Data was analyzed using a Two-Way ANOVA and Tukey's post hoc test.. Total ceramide levels were increased in African Americans compared to African Americans with MetD. Ceramide C16 levels were higher in whites with MetD compared to African Americans with MetD (p<0.05). Ceramide C20 levels were higher in whites with MetD compared to whites. Ceramide C20 levels were higher in African Americans compared to African Americans with MetD. Furthermore, whites with MetD had higher levels of C20 compared to African Americans with MetD (p<0.0001). Ceramide C24:0 and C24:1 in African Americans was higher compared to African Americans with MetD (p<0.05). The plasma concentration of Sph-1P ceramide was higher in African Americans vs whites (p = 0.01). Lastly, ceramide C20 negatively correlated with hemoglobin A1c (HbA1c) levels in our study cohort.. Plasma ceramide concentration patterns are distinct in African Americans with MetD. Further research with larger samples sizes are needed to confirm these findings and to understand whether racial disparities in sphingolipid concentrations have potential therapeutic implications for CVD-related health outcomes.

Topics: Adult; Aged; Black or African American; Ceramides; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Diabetes Mellitus; Dyslipidemias; Female; Gas Chromatography-Mass Spectrometry; Humans; Hypercholesterolemia; Hypertension; Lysophospholipids; Male; Middle Aged; Risk Factors; Sphingosine; White People

High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS).. We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.

Topics: Adult; Aged; Case-Control Studies; Cells, Cultured; Diabetes Mellitus; Disease Progression; Enzyme Activation; Female; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins, HDL; Lysophospholipids; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide Synthase Type III; Phosphorylation; Proto-Oncogene Proteins c-akt; Sphingosine

Researchers usually query the large biomedical literature in PubMed via keywords, logical operators and filters, none of which is very intuitive. Question answering systems are an alternative to keyword searches. They allow questions in natural language as input and results reflect the given type of question, such as short answers and summaries. Few of those systems are available online but they experience drawbacks in terms of long response times and they support a limited amount of question and result types. Additionally, user interfaces are usually restricted to only displaying the retrieved information. For our Olelo web application, we combined biomedical literature and terminologies in a fast in-memory database to enable real-time responses to researchers' queries. Further, we extended the built-in natural language processing features of the database with question answering and summarization procedures. Combined with a new explorative approach of document filtering and a clean user interface, Olelo enables a fast and intelligent search through the ever-growing biomedical literature. Olelo is available at http://www.hpi.de/plattner/olelo.

Topics: Databases, Factual; Diabetes Mellitus; Disease Outbreaks; Internet; Lysophospholipids; Publications; PubMed; Software; Sphingosine; User-Computer Interface; Zika Virus Infection

The use of nondepleting Abs specific for CD4 and CD8 is an effective strategy to tolerize CD4

Topics: Animals; Antibodies, Monoclonal; CD4 Antigens; CD8 Antigens; Cell Movement; Cells, Cultured; Chemokine CXCL12; Diabetes Mellitus; Female; Humans; Immune Tolerance; Lymphocyte Activation; Lysophospholipids; Mice; Mice, Inbred NOD; Mice, Knockout; Neuropeptides; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; RAC2 GTP-Binding Protein; Signal Transduction; Sphingosine; T-Lymphocytes

Our previous studies have confirmed that the sphingosine kinase 1 (SphK1)-sphingosine 1-phosphate (S1P) signaling pathway in the kidney under diabetic conditions is closely correlated with the pathogenesis of diabetic nephropathy (DN). The activation of SphK1-S1P pathway by high glucose (HG) can increase the expression of fibronectin (FN), an important fibrotic component, in glomerular mesangial cells (GMCs) by promoting the DNA-binding activity of transcription factor AP-1. However, the mechanism responsible for the sustained activation of SphK1-S1P pathway remains unclear. Given the binding motifs for AP-1 within the first intron of the SphK1 gene, we speculated that the activated AP-1 in the kidney under HG condition possibly regulates SphK1 expression in a positive feedback manner, thereby promoting the sustained activation of SphK1-S1P pathway and mediating the pathological progression of DN. Here, we observed the effect of AP-1 on SphK1 expression in GMCs and explored the molecular mechanism involved in the sustained activation of SphK1-S1P pathway. We found two consensus binding motifs for AP-1 in the promoter sequences and non-coding region downstream of the transcriptional initiation of the rat SphK1 gene by chromatin immunoprecipitation assay. The treatment of GMCs with both HG and S1P significantly increased the protein expression of c-Jun and c-Fos, and obviously enhanced the phosphorylation of c-Jun at Ser63 and Ser73, and c-Fos at Ser32. Knockdown of c-Jun and c-Fos with siRNAs substantially inhibited the expression of SphK1 and FN, whereas overexpression of c-Jun and c-Fos significantly increased the expression of SphK1 and FN. Curcumin treatment greatly decreased the levels of c-Jun, c-Fos, SphK1, and FN in the kidney tissues of diabetic rats. SiRNAs targeting SphK1 and S1P2 receptor respectively inhibited the phosphorylation of c-Jun (ser63 and ser73) and c-Fos (ser32), as well as FN expression under both normal and HG conditions. Our data demonstrated that the activated SphK1-S1P signaling pathway in GMCs under diabetic conditions is closely associated with AP-1 to form a positive feedback loop. This positive feedback loop functions as an important molecular basis for the sustained activation of SphK1-S1P pathway and increased FN expression that lead to the initiation and progression of DN.

Topics: Animals; Binding Sites; Cells, Cultured; Curcumin; Diabetes Mellitus; Diabetic Nephropathies; DNA-Binding Proteins; Enzyme Inhibitors; Fibronectins; Glucose; JNK Mitogen-Activated Protein Kinases; Lysophospholipids; Male; Mesangial Cells; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-fos; Rats; Receptors, Lysosphingolipid; RNA Interference; RNA, Small Interfering; Signal Transduction; Sphingosine; Sweetening Agents; Transcription Factor AP-1

Sphingosine-1-phosphate (S-1-P) is a bioactive sphingolipid released from activated platelets that stimulates migration of vascular smooth muscle cells (VSMC) in vitro. S-1-P is associated with oxidized low-density lipoprotein (oxLDL) and is important in vessel remodeling. S-1-P will activate multiple G protein-coupled receptors (S-1-PR 1 to 5), which can regulate multiple cellular functions, including cell migration. The aim of this study is to examine the role of S-1-PR signaling during smooth muscle cell migration in response to S-1-P.. Human VSMCs were cultured in vitro. Expression of S-1-PR 1 to 5 was determined in conditions mirroring diabetes (40 mM glucose) and metabolic syndrome (25 mM glucose with 20 μM linoleic acid and 20 μM oleic acid). Linear wound and Boyden microchemotaxis assays of migration were performed in the presence of S-1-P with and without siRNA against S-1-PR 1 to 5. Assays were performed for activation of ERK1/2, p38(MAPK) and JNK.. Human VSMCs express S-1-PR1, S-1-PR2, and S-1-PR3. There was no significant expression of S-1-PR4 and S-1-PR5. The expression of S-1-PR1 and S-1-PR3 is enhanced under high glucose conditions and metabolic syndrome conditions. Migration of VSMC in response to S-1-P is enhanced 2-fold by diabetes and 4-fold by metabolic syndrome. In diabetes, S-1-PR1 expression is enhanced, while S-1-PR2 and S-1-PR3 expression are both maintained. In metabolic syndrome, S-1-PR1 and 3 expressions are enhanced and that of S-1-PR2 is reduced. siRNA to S-1-PR1 results in a 2-fold reduction in S-1-P-mediated cell migration under all conditions. siRNA to S-1-PR2 enhanced cell migration only under normal conditions, while siRNA S-1-PR3 decreased migration in metabolic syndrome only. Down-regulation of S-1-PR1 reduced ERK1/2 activation in response to S-1-P, while that of S-1-PR2 had no effect under normal conditions. In diabetes, down-regulation of S-1-PR1 reduced activation of all three MAPKs. In metabolic syndrome, down-regulation of S-1-PR1 and S-1-PR3 reduced activation of all three MAPKs.. S-1-PR 1, 2, and 3 regulate human VSMC migration and their expression level and function are modulated by conditions simulating diabetes and metabolic syndrome.

Topics: Cell Migration Assays; Cells, Cultured; Diabetes Mellitus; Humans; Lysophospholipids; MAP Kinase Signaling System; Metabolic Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, Lysosphingolipid; Sphingosine

We observed that in isolated perfused rat kidneys, sphingosine-1-phosphate produces S1P(2) receptor-mediated vasoconstriction, and this response increased in kidneys of diabetic rats. These results suggest that the antagonists of S1P(2) receptor may have potential as drugs to control diabetes-induced vascular complications.

Topics: Animals; Blotting, Western; Diabetes Mellitus; In Vitro Techniques; Kidney; Lysophospholipids; Male; Rats; Rats, Wistar; Receptors, Lysosphingolipid; Reverse Transcriptase Polymerase Chain Reaction; Sphingosine; Vasoconstriction

Berberine (BBR) was previously found to have beneficial effects on renal injury in experimental diabetic rats. However, the mechanisms underlying the effects are not fully understood. Sphingosine kinase-Sphingosine 1-phosphate (SphK-S1P) signaling pathway has been implicated in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the effects of BBR on renal injury and the activation of SphK-S1P signaling pathway in alloxan-induced diabetic mice with nephropathy. Alloxan-induced diabetic mice were treated orally with BBR (300 mg/kg/day) or vehicle for 12 weeks. BBR inhibited the increases in fasting blood glucose, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. It also prevented renal hypertrophy, TGF-beta1 synthesis, FN and Col IV accumulation. Moreover, BBR down-regulated the elevated staining, activity and levels of mRNA and protein of SphK1, and S1P production as well. These findings suggest that the inhibitory effect of BBR on the activation of SphK-S1P signaling pathway in diabetic mouse kidney is a novel mechanism by which BBR partly exerts renoprotective effects on DN.

Topics: Albuminuria; Animals; Berberine; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glucose; Kidney; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor); Random Allocation; Signal Transduction; Sphingosine; Transforming Growth Factor beta1