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https://www.readbyqxmd.com/read/27921320/cardiac-effects-of-amiselimod-compared-with-fingolimod-and-placebo-results-of-a-randomised-parallel-group-phase-i-study-in-healthy-subjects
#1
Tomohiko Harada, Darren Wilbraham, Guillemette de La Borderie, Shinsuke Inoue, Jim Bush, A John Camm
AIM: Amiselimod (MT-1303) is a selective sphingosine 1-phosphate 1 (S1P1 ) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in pre-clinical, phase I and II studies. The aim of this study was to characterise the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo. METHODS: Eighty-one (81) healthy subjects aged 18-55 years were equally randomised to receive amiselimod 0...
December 6, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27920219/the-proprotein-convertases-in-hypercholesterolemia-and-cardiovascular-diseases-emphasis-on-proprotein-convertase-subtilisin-kexin-9
#2
REVIEW
Nabil G Seidah, Marianne Abifadel, Stefan Prost, Catherine Boileau, Annik Prat
The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development and/or in adulthood. The essential SKI-1/S1P cleaves membrane-bound transcription factors at nonbasic residues...
January 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/27914035/mobilization-of-peripheral-blood-stem-cells-and-changes-in-the-concentration-of-plasma-factors-influencing-their-movement-in-patients-with-panic-disorder
#3
Marcin Jabłoński, Jolanta Kucharska Mazur, Maciej Tarnowski, Barbara Dołęgowska, Daniel Pędziwiatr, Ewa Kubiś, Marta Budkowska, Daria Sałata, Justyna Pełka Wysiecka, Arkadiusz Kazimierczak, Artur Reginia, Mariusz Z Ratajczak, Jerzy Samochowiec
In this paper we examined whether stem cells and factors responsible for their movement may serve as new biological markers of anxiety disorders. The study was carried out on a group of 30 patients diagnosed with panic disorder (examined before and after treatment), compared to 30 healthy individuals forming the control group. We examined the number of circulating HSCs (hematopoetic stem cells) (Lin-/CD45 +/CD34 +) and HSCs (Lin-/CD45 +/AC133 +), the number of circulating VSELs (very small embryonic-like stem cells) (Lin-/CD45-/CD34 +) and VSELs (Lin-/CD45-/AC133 +), as well as the concentration of complement components: C3a, C5a and C5b-9, SDF-1 (stromal derived factor) and S1P (sphingosine-1-phosphate)...
December 2, 2016: Stem Cell Reviews
https://www.readbyqxmd.com/read/27904998/alginate-chitosan-hydrogels-provide-a-sustained-gradient-of-sphingosine-1-phosphate-for-therapeutic-angiogenesis
#4
Priscilla A Williams, Kevin T Campbell, Hessam Gharaviram, Justin L Madrigal, Eduardo A Silva
Sphingosine-1-phosphate (S1P), a bioactive lipid, is a potent candidate for treatment of ischemic vascular disease. However, designing biomaterial systems for the controlled release of S1P to achieve therapeutic angiogenesis presents both biological and engineering challenges. Thus, the objective of this study was to design a hydrogel system that provides controlled and sustained release of S1P to establish local concentration gradients that promote neovascularization. Alginate hydrogels have been extensively studied and characterized for delivery of proangiogenic factors...
November 30, 2016: Annals of Biomedical Engineering
https://www.readbyqxmd.com/read/27894870/a-benzo-b-thiophene-based-selective-type-4-s1p-receptor-agonist
#5
Wooyoung Hur, Hugh Rosen, Nathanael S Gray
S1P receptors (S1PR1-5) are a group of GPCRs activated by a high affinity binding with S1P that have important roles in the regulation of the immune system. A potent S1PR agonist FTY720 is an immunomodulator used to treat multiple sclerosis and several 'second generation' drugs are under clinical development. Subtype-selective agonists have been reported for each S1PR isotype, some of which are used as pharmacological tools for functional studies. Here we report the discovery and initial characterization of compound 5c, a benzo[b]thiophene amino carboxylate which exhibits potent and selective agonist activity for S1PR4...
November 18, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27890706/the-sphingosine-1-phosphate-receptor-a-novel-therapeutic-target-for-multiple-sclerosis-and-other-autoimmune-diseases
#6
REVIEW
Yang Mao-Draayer, Jeffrey Sarazin, David Fox, Elena Schiopu
Multiple sclerosis (MS) is a prototype autoimmune disease of the central nervous system (CNS). Currently, there is no drug that provides a cure for MS. To date, all immunotherapeutic drugs target relapsing remitting MS (RR-MS); it remains a daunting medical challenge in MS to develop therapy for secondary progressive MS (SP-MS). Since the approval of the non-selective sphingosine-1-phosphate (S1P) receptor modulator FTY720 (fingolimod [Gilenya®]) for RR-MS in 2010, there have been many emerging studies with various selective S1P receptor modulators in other autoimmune conditions...
November 23, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27883090/sphingosine-1-phosphate-lyase-ablation-disrupts-presynaptic-architecture-and-function-via-an-ubiquitin-proteasome-mediated-mechanism
#7
Daniel N Mitroi, André U Deutschmann, Maren Raucamp, Indulekha Karunakaran, Konstantine Glebov, Michael Hans, Jochen Walter, Julie Saba, Markus Gräler, Dan Ehninger, Elena Sopova, Oleg Shupliakov, Dieter Swandulla, Gerhild van Echten-Deckert
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. Constitutive ablation of SPL in the brain (SPL(fl/fl/Nes)) but not postnatal neuronal forebrain-restricted SPL deletion (SPL(fl/fl/CaMK)) caused marked accumulation of S1P...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27881715/s1p-in-hdl-promotes-interaction-between-sr-bi-and-s1pr1-and-activates-s1pr1-mediated-biological-functions-calcium-flux-and-s1pr1-internalization
#8
Mi-Hye Lee, Kathryn M Appleton, Hesham M El-Shewy, Mary G Sorci-Thomas, Michael J Thomas, Maria F Lopes-Virella, Louis M Luttrell, Samar M Hammad, Richard L Klein
HDL normally transports about 50-70% of plasma S1P and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay (PCA) and confocal microscopy. In both primary rat aortic vascular smooth muscle (RVSMC) and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration that was mediated by S1PR1...
November 23, 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27879252/high-density-lipoprotein-associated-apolipoprotein-m-limits-endothelial-inflammation-by-delivering-sphingosine-1-phosphate-to-the-sphingosine-1-phosphate-receptor-1
#9
Mario Ruiz, Cecilia Frej, Andreas Holmér, Li J Guo, Sinh Tran, Björn Dahlbäck
OBJECTIVE: Plasma high-density lipoproteins (HDL) are potent antiatherogenic and anti-inflammatory particles. However, HDL particles are highly heterogenic in composition, and different HDL-mediated functions can be ascribed to different subclasses of HDL. Only a small HDL population contains apolipoprotein M (ApoM), which is the main plasma carrier of the bioactive lipid mediator sphingosine-1-phosphate (S1P). Vascular inflammation is modulated by S1P, but both pro- and anti-inflammatory roles have been ascribed to S1P...
November 22, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27877175/thymocytes-in-lyve1-cre-s1pr1-f-f-mice-accumulate-in-the-thymus-due-to-cell-intrinsic-loss-of-sphingosine-1-phosphate-receptor-expression
#10
Akira Takeda, Mohammad Shahadat Hossain, Pia Rantakari, Szandor Simmons, Naoko Sasaki, Marko Salmi, Sirpa Jalkanen, Masayuki Miyasaka
T cell emigration from the thymus is essential for immunological homeostasis. While stromal cell-produced sphingosine-1-phosphate (S1P) has been shown to promote thymocyte egress via the S1P receptor, S1PR1, the significance of S1P/S1PR1 signaling in the thymic stromal cells that surround T cells remains unclear. To address this issue, we developed conditional knockout mice (Lyve1-CRE/S1pr1(f/f) mice) in which S1pr1 was selectively targeted in cells expressing the lymphatic endothelial cell marker, Lyve1. In these mice, T cells were significantly reduced in secondary lymphoid tissues, and CD62L(+) mature CD4 and CD8 single-positive (SP) T cells accumulated in the medulla failed to undergo thymus egress...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27872583/ablation-of-sphingosine-1-phosphate-receptor-subtype-3-impairs-hippocampal-neuron-excitability-in-vitro-and-spatial-working-memory-in-vivo
#11
Daniela Weth-Malsch, Michiel Langeslag, Dimitra Beroukas, Luca Zangrandi, Iris Kastenberger, Serena Quarta, Philipp Malsch, Theodora Kalpachidou, Christoph Schwarzer, Richard L Proia, Rainer V Haberberger, Michaela Kress
Understanding the role of the bioactive lipid mediator sphingosine 1-phosphate (S1P) within the central nervous system has recently gained more and more attention, as it has been connected to major diseases such as multiple sclerosis and Alzheimer's disease. Even though much data about the functions of the five S1P receptors has been collected for other organ systems, we still lack a complete understanding for their specific roles, in particular within the brain. Therefore, it was the aim of this study to further elucidate the role of S1P receptor subtype 3 (S1P3) in vivo and in vitro with a special focus on the hippocampus...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27869314/runx1-orchestrates-sphingolipid-metabolism-and-glucocorticoid-resistance-in-lymphomagenesis
#12
A Kilbey, A Terry, S Wotton, G Borland, Q Zhang, N Mackay, A McDonald, M Bell, M J O Wakelam, E R Cameron, J C Neil
The three-membered RUNX gene family includes RUNX1, a major mutational target in human leukemias, and displays hallmarks of both tumour suppressors and oncogenes. In mouse models the Runx genes appear to act as conditional oncogenes, as ectopic expression is growth suppressive in normal cells but drives lymphoma development potently when combined with over-expressed Myc or loss of p53. Clues to underlying mechanisms emerged previously from murine fibroblasts where ectopic expression of any of the Runx genes promotes survival through direct and indirect regulation of key enzymes in sphingolipid metabolism associated with a shift in the 'sphingolipid rheostat' from ceramide to sphingosine-1-phosphate (S1P)...
November 21, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27868302/reduced-dna-methylation-of-sphingosine-1-phosphate-receptor-5-in-alveolar-macrophages-in-copd-a-potential-link-to-failed-efferocytosis
#13
Jameel Barnawi, Hubertus Jersmann, Rainer Haberberger, Sandra Hodge, Robyn Meech
BACKGROUND AND OBJECTIVE: We previously showed that alveolar macrophages from COPD patients are defective in their ability to phagocytose apoptotic cells ('efferocytosis') and that this defect is potentially linked to the sphingosine-1 phosphate (S1P) system, in particular the sphingosine-1 phosphate receptor 5 (S1PR5). In alveolar macrophages from COPD patients, S1PR5 mRNA expression levels increased and were correlated with both lung function and efferocytosis. However, it us unknown whether these changes are under epigenetic control via DNA methylation or whether DNA methylation directly modulates macrophage function...
November 20, 2016: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/27864331/role-of-sphingosine-kinase-1-and-s1p-transporter-spns2-in-hgf-mediated-lamellipodia-formation-in-lung-endothelium
#14
Panfeng Fu, David L Ebenezer, Evgeny V Berdyshev, Irina A Bronova, Mark Shaaya, Anantha Harijith, Viswanathan Natarajan
Hepatocyte growth factor (HGF) signaling via c-Met is known to promote endothelial cell motility and angiogenesis. We have previously reported that HGF stimulates lamellipodia formation and motility of human lung microvascular endothelial cells (HLMVECs) via PI3k/Akt signal transduction and reactive oxygen species generation. Here, we report a role for HGF-induced intracellular sphingosine-1-phosphate (S1P) generation catalyzed by sphingosine kinase 1 (SphK1), S1P transporter, spinster homolog 2 (Spns2), and S1P receptor, S1P1, in lamellipodia formation and perhaps motility of HLMVECs...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27861771/high-density-lipoprotein-associated-sphingosine-1-phosphate-activity-in-heterozygous-familial-hypercholesterolaemia
#15
Miguel A Frias, Aurélien Thomas, Marie-Claude Brulhart-Meynet, Oskar Kövamees, John Pernow, Mats Eriksson, Bo Angelin, Richard W James, Jonas W Brinck
BACKGROUND: Patients with heterozygous familial hypercholesterolaemia (FH) suffer from high plasma cholesterol and an environment of increased oxidative stress. We examined its potential effects on high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) content (HDL-S1P) and HDL-mediated protection against oxidative stress, both with and without statin treatment. MATERIALS AND METHODS: In a case-control study, HDL was isolated from 12 FH patients with and without statin treatment and from 12 healthy controls...
November 11, 2016: European Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27857690/interferon-beta-increases-plasma-ceramides-of-specific-chain-length-in-multiple-sclerosis-patients-unlike-fingolimod-or-natalizumab
#16
Florian M Ottenlinger, Christoph A Mayer, Nerea Ferreirós, Yannick Schreiber, Anja Schwiebs, Katrin G Schmidt, Hanns Ackermann, Josef M Pfeilschifter, Heinfried H Radeke
Fingolimod is used for the treatment of multiple sclerosis (MS) and targets receptors for the bioactive sphingolipid sphingosine-1-phosphate (S1P). Whether fingolimod or other MS therapies conversely affect plasma concentrations of sphingolipids has, however, not yet been analyzed. Herein, we quantified 15 representative sphingolipid species by mass spectrometry in plasma from relapsing-remitting MS patients currently under fingolimod (n = 24), natalizumab (n = 16), or IFN-β (n = 18) treatment. Healthy controls (n = 21) and untreated MS patients (n = 11) served as control groups...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27851911/autoimmune-renal-disease-is-exacerbated-by-s1p-receptor-1-dependent-intestinal-th17-cell-migration-to-the-kidney
#17
Christian F Krebs, Hans-Joachim Paust, Sonja Krohn, Tobias Koyro, Silke R Brix, Jan-Hendrik Riedel, Patricia Bartsch, Thorsten Wiech, Catherine Meyer-Schwesinger, Jiabin Huang, Nicole Fischer, Philipp Busch, Hans-Willi Mittrücker, Ulrich Steinhoff, Brigitta Stockinger, Laura Garcia Perez, Ulrich O Wenzel, Matthias Janneck, Oliver M Steinmetz, Nicola Gagliani, Rolf A K Stahl, Samuel Huber, Jan-Eric Turner, Ulf Panzer
Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis...
November 15, 2016: Immunity
https://www.readbyqxmd.com/read/27849062/the-phosphorylated-form-of-fty720-activates-pp2a-represses-inflammation-and-is-devoid-of-s1p-agonism-in-a549-lung-epithelial-cells
#18
Md Mostafizur Rahman, Laura Prünte, Leonard F Lebender, Brijeshkumar S Patel, Ingrid Gelissen, Philip M Hansbro, Jonathan C Morris, Andrew R Clark, Nicole M Verrills, Alaina J Ammit
Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27833850/baicalin-promoted-site-2-protease-and-not-site-1-protease-in-endoplasmic-reticulum-stress-induced-apoptosis-of-human-hepatocellular-carcinoma-cells
#19
Zhe Yu, Xin Luo, Chen Wang, Jianhong Ye, Shourong Liu, Lei Xie, Fei Wang, Jianfeng Bao
Baicalin (5,6-dihydroxy-7-o-glucuronide flavone) is an extract from the roots of Chinese herb Huang Qin (Scutellaria baicalensis Georgi) and is reported to have antioxidative, antiproliferative, anti-inflammatory, and anticancer activities. This study aimed to investigate the inhibitory effect of baicalin on human hepatocellular carcinoma (HCC) cells and the involvement of endoplasmic reticulum stress-induced cell apoptosis. Two human HCC cell lines, HepG2 and SMMC7221, were used in this study. The cells were incubated with baicalin solutions at various concentrations...
November 2016: FEBS Open Bio
https://www.readbyqxmd.com/read/27830727/exploration-of-the-sphingolipid-metabolite-sphingosine-1-phosphate-and-sphingosine-as-novel-biomarkers-for-aspirin-exacerbated-respiratory-disease
#20
Hoang Kim Tu Trinh, Su-Chin Kim, Kumsun Cho, Su-Jung Kim, Ga-Young Ban, Hyun-Ju Yoo, Joo-Youn Cho, Hae-Sim Park, Seung-Hyun Kim
Sphingolipid (SL) metabolites have been suggested to be important inflammatory mediators in airway inflammation and asthma. However, little is known about SL metabolites in aspirin-exacerbated respiratory disease (AERD). We aimed to explore the potential AERD biomarkers by conducting lipidomics targeting SL metabolites. The levels of SL metabolites in serum and urine samples from 45 AERD patients and 45 aspirin-tolerant asthma (ATA) patients were quantified through mass spectrometry. During the lysine-aspirin bronchoprovocation test (ASA-BPT), the levels of serum sphingomyelin (SM) were significantly decreased in AERD (P < 0...
November 10, 2016: Scientific Reports
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