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https://www.readbyqxmd.com/read/28104351/the-sphingosine-1-phosphate-receptor-1-agonist-sew2871-reduces-tau-ser262-phosphorylation-in-rat-hippocampal-slices
#1
Frédéric St-Cyr Giguère, Suzanne Attiori Essis, Laure Chagniel, Marc Germain, Michel Cyr, Guy Massicotte
Recent studies indicate that Tau phosphorylation can be modulated by the compound FTY720-P, a global sphingosine-1-phosphate receptor (S1PR) agonist. The present work compared the effects of more selective S1PR agonists on Tau properties, using rat hippocampal slices as model system. Whereas Tau phosphorylation was not modified by the S1PR3 agonist CYM5541, Tau-Ser262 phosphorylation was significantly decreased by treatment with the S1PR1 agonist SEW2871. This effect appears to be quite restricted, as no changes in phosphorylation were elicited by the agonist on Tau-Ser199/202, Tau-Ser396 and Tau-Ser404 residues...
January 16, 2017: Brain Research
https://www.readbyqxmd.com/read/28101047/acute-anterior-uveitis-in-a-patient-taking-fingolimod-fty720-for-multiple-sclerosis
#2
Heather Gwen Mack, Melissa Chih-Hui Tien, Owen Bruce White
Fingolimod is an oral sphingosine-1-phosphate (S1P) receptor modulator and the first oral therapy for relapsing-remitting multiple sclerosis. Its use has been complicated by a low rate of cystoid macular edema usually in the first 3 months after commencement of the medication. We report the case of a 34-year-old male with relapsing-remitting multiple sclerosis, who developed acute anterior uveitis on day 5 of fingolimod treatment. He responded to appropriate treatment and cessation of drug, but developed low-grade chronic anterior uveitis without cystoid macular edema...
September 2016: Case Reports in Ophthalmology
https://www.readbyqxmd.com/read/28077266/asp0028-in-combination-with-suboptimal-dose-of-tacrolimus-in-cynomolgus-monkey-renal-transplantation-model
#3
Hao Dun, Lijun Song, Anlun Ma, Yanxin Hu, Lin Zeng, Jieying Bai, Guangzhou Zhang, Liangyan Zhang, Kumi Koide, Yohei Okada, Kaori Hanaoka, Rie Yamamoto, Jun Hirose, Tatsuaki Morokata, Pierre Daloze, Huifang Chen
FTY720, a S1P-receptor modulator, has shown to be effective in several transplant and autoimmune disease models, via modulating lymphocyte homing into secondary lymphoid organs (SLOs), and thereby reducing these cells in peripheral blood. ASP0028, a newly developed S1P1/S1P5-selective agonist, presented comparable efficacy to FTY720 and wider safety margins than FTY720. In this study, we assessed the efficacy and safety of ASP0028 co-administered with suboptimal-dose of tacrolimus in the Cynomolgus monkey renal transplantation model...
January 7, 2017: Transplant Immunology
https://www.readbyqxmd.com/read/28056422/propofol-inhibits-lps-induced-apoptosis-in-lung-epithelial-cell-line-beas-2b
#4
Xiang Lv, Xuhui Zhou, Jia Yan, Jue Jiang, Hong Jiang
Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells...
January 2, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28039158/inhibition-of-sphingosine-1-phosphate-signaling-ameliorates-murine-nonalcoholic-steatohepatitis
#5
Amy S Mauer, Petra Hirsova, Jessica L Maiers, Vijay H Shah, Harmeet Malhi
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a lipotoxic disorder, wherein proinflammatory lipids, such as ceramide and its derivative sphingosine 1-phosphate (S1P), contribute to macrophage-associated liver inflammation. For example, we have previously demonstrated a role for S1P in steatotic hepatocyte-derived S1P enriched extracellular vesicles in macrophage chemotaxis in vitro. Therefore, we hypothesized that FTY720, an S1P antagonist, would ameliorate NASH by inhibiting proinflammatory monocyte chemotaxis...
December 30, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28035084/sphingosine-1-phosphate-receptor-modulators-and-drug-discovery
#6
REVIEW
Soo-Jin Park, Dong-Soon Im
Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P₁₋₅. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28011471/histone-deacetylase-inhibitors-an-attractive-therapeutic-strategy-against-breast-cancer
#7
REVIEW
Christos Damaskos, Serena Valsami, Michael Kontos, Eleftherios Spartalis, Theodoros Kalampokas, Emmanouil Kalampokas, Antonios Athanasiou, Demetrios Moris, Afrodite Daskalopoulou, Spyridon Davakis, Gerasimos Tsourouflis, Konstantinos Kontzoglou, Despina Perrea, Nikolaos Nikiteas, Dimitrios Dimitroulis
: With a lifetime risk estimated to be one in eight in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide. Patients are often treated with anti-estrogens, but it is common that some tumors develop resistance to therapy. The causation and progression of cancer is controlled by epigenetic processes, so there is an ongoing interest in research into mechanisms, genes and signaling pathways associating carcinogenesis with epigenetic modulation of gene expression...
January 2017: Anticancer Research
https://www.readbyqxmd.com/read/28002964/asymmetric-hydroboration-approach-to-the-scalable-synthesis-of-1r-3s-1-amino-3-r-6-hexyl-5-6-7-8-tetrahydronaphthalen-2-yl-cyclopentyl-methanol-bms-986104-as-a-potent-s1p1-receptor-modulator
#8
Michael G Yang, Zili Xiao, T G Murali Dhar, Hai-Yun Xiao, John L Gilmore, David Marcoux, Jenny H Xie, Kim W McIntyre, Tracy L Taylor, Virna Borowski, Elizabeth Heimrich, Yu-Wen Li, Jianlin Feng, Alda Fernandes, Zheng Yang, Praveen Balimane, Anthony M Marino, Georgia Cornelius, Bethanne M Warrack, Arvind Mathur, Dauh-Rurng Wu, Peng Li, Anuradha Gupta, Bala Pragalathan, Ding Ren Shen, Mary Ellen Cvijic, Lois D Lehman-McKeeman, Luisa Salter-Cid, Joel C Barrish, Percy H Carter, Alaric J Dyckman
We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27976451/arteriogenesis-in-murine-adipose-tissue-is-contingent-on-cd68-cd206-macrophages
#9
Scott A Seaman, Yiqi Cao, Chris A Campbell, Shayn M Peirce
OBJECTIVE: The surgical transfer of skin, fat, and/or muscle from a donor site to a recipient site within the same patient, is a widely performed procedure in reconstructive surgeries. A surgical pre-treatment strategy that is intended to increase perfusion in the flap, termed "flap delay", is a commonly employed technique by plastic surgeons prior to flap transplantation. Here, we explored whether CD68(+) /CD206(+) macrophages are required for arteriogenesis within the flap by performing gain-of-function and loss-of-function studies in a previously published flap delay murine model...
December 15, 2016: Microcirculation: the Official Journal of the Microcirculatory Society, Inc
https://www.readbyqxmd.com/read/27966000/the-differential-effects-of-fty720-on-functional-recovery-and-infarct-size-following-myocardial-ischaemia-reperfusion
#10
Derick van Vuuren, Erna Marais, Sonia Genade, Amanda Lochner
AIM: The aim of this study was to evaluate the effects of the sphingosine analogue, FTY720 (Fingolimod), on the outcomes of myocardial ischaemia/reperfusion (I/R) injury. METHODS: Two concentrations of FTY720 (1 or 2.5 µM were administered either prior to (PreFTY), or following (PostFTY) 20 minutes' global (GI) or 35 minutes' regional ischaemia (RI) in the isolated, perfused, working rat heart. Functional recovery during reperfusion was assessed following both models of ischaemia, while infarct size (IFS) was determined following RI...
November 2016: Cardiovascular Journal of Africa
https://www.readbyqxmd.com/read/27943027/fty720-attenuates-6-ohda-associated-dopaminergic-degeneration-in-cellular-and-mouse-parkinsonian-models
#11
Manru Ren, Minxing Han, Xinbing Wei, Ying Guo, Huanying Shi, Xiumei Zhang, Ruth G Perez, Haiyan Lou
FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice...
December 9, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27935071/severe-murine-limb-girdle-muscular-dystrophy-type-2c-pathology-is-diminished-by-fty720-treatment
#12
Ahlke Heydemann
INTRODUCTION: Limb Girdle Muscular Dystrophy Type 2C (LGMD-2C) is caused by mutations in ɤ-sarcoglycan and is a devastating, progressive, and fully lethal human muscle wasting disease that is without effective treatment. This study examined the efficacy of the sphingosine-1-phosphate receptor modulator FTY720 in treating Sgcg-/-DBA2/J, a severe mouse model of LGMD-2C. FTY720 treatment is expected to target LGMD-2C disease progression at 2 key positions by reducing chronic inflammation and fibrosis...
December 9, 2016: Muscle & Nerve
https://www.readbyqxmd.com/read/27930948/selective-recruitment-of-non-classical-monocytes-promotes-skeletal-muscle-repair
#13
Cheryl L San Emeterio, Claire E Olingy, Yihsuan Chu, Edward A Botchwey
Regeneration of traumatic defects in skeletal muscle requires the synchronized behavior of multiple cells that participate in repair. The inflammatory cascade that is rapidly initiated after injury serves as a powerful node at which to guide the progression of healing and influence tissue repair. Here, we examine the role that myeloid cells play in the healing of traumatic skeletal muscle injury, and leverage their pro-regenerative functions using local delivery of the immunomodulatory small molecule FTY720...
February 2017: Biomaterials
https://www.readbyqxmd.com/read/27913115/computer-design-synthesis-and-bioactivity-analyses-of-drugs-like-fingolimod-used-in-the-treatment-of-multiple-sclerosis
#14
Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaattin Şen
Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis...
January 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27905921/systematic-review-of-the-role-of-angiopoietin-1-and-angiopoietin-2-in-plasmodium-species-infections-biomarkers-or-therapeutic-targets
#15
Gerdie M de Jong, Jasper J Slager, Annelies Verbon, Jaap J van Hellemond, Perry J J van Genderen
BACKGROUND: Levels of both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) correlate with malaria disease severity and are proposed as biomarkers and possible therapeutic targets. To establish their role in malaria, a systematic review was performed of the literature on Ang-1 and Ang-2 with regard to their potential as biomarkers in malaria and discuss their possible place in adjuvant treatment regimens. METHODS: Ten electronic databases were systematically searched to identify studies investigating Ang-1 and Ang-2 in human and murine malaria in both clinical and experimental settings...
December 1, 2016: Malaria Journal
https://www.readbyqxmd.com/read/27901482/hyperglycemia-triggers-hipk2-protein-degradation
#16
Silvia Baldari, Alessia Garufi, Marisa Granato, Laura Cuomo, Giuseppa Pistritto, Mara Cirone, Gabriella D'Orazi
Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27894870/a-benzo-b-thiophene-based-selective-type-4-s1p-receptor-agonist
#17
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...
January 1, 2017: 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
#18
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/27864936/effect-of-sphingosine-kinase-modulators-on-interleukin-1%C3%AE-release-sphingosine-1-phosphate-receptor-1-expression-and-experimental-autoimmune-encephalomyelitis
#19
Mark Barbour, Melissa McNaughton, Stephanie D Boomkamp, Neil MacRitchie, Hui-Rong Jiang, Nigel J Pyne, Susan Pyne
BACKGROUND AND PURPOSE: The sphingosine analogue, FTY720 (Gilenya(R) ), alleviates clinical disease progression in multiple sclerosis. Here, we variously assessed the effects of an azide analogue of (S)-FTY720 vinylphosphonate (compound 5; a sphingosine kinase 1 activator), (R)-FTY720 methyl ether (ROMe, a sphingosine kinase 2 inhibitor) and RB-020 (a sphingosine kinase 1 inhibitor and sphingosine kinase 2 substrate) on IL-1β formation, sphingosine 1-phosphate levels and expression of S1P1 receptors...
January 2017: British Journal of Pharmacology
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
#20
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
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