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https://www.readbyqxmd.com/read/27913115/computer-design-synthesis-and-bioactivity-analyses-of-drugs-like-fingolimod-used-in-the-treatment-of-multiple-sclerosis
#1
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...
November 18, 2016: 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
#2
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
#3
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
#4
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
#5
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
#6
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 S1P1 expression...
November 16, 2016: 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
#7
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/27829841/effects-of-fty720-fingolimod-on-proliferation-differentiation-and-migration-of-brain-derived-neural-stem-cells
#8
Botao Tan, Zeruxin Luo, Yan Yue, Yuan Liu, Li Pan, Lehua Yu, Ying Yin
Insufficient proliferation, differentiation, and migration are the main pitfalls of neural stem cells (NSCs) in reparative therapeutics for the central nervous system (CNS) diseases. The potent lipid mediator sphingosine-1-phosphate (S1P) regulates cells' biological behavior broadly in the CNS. However, the effects of activating S1P on NSCs are not quite clear. In the current study, FTY720 (Fingolimod), an analog of S1P, was employed to induce the proliferation, differentiation, and migration of cultured brain-derived NSCs...
2016: Stem Cells International
https://www.readbyqxmd.com/read/27816167/inhibition-of-sphingosine-1-phosphate-receptors-in-ischemia-reperfusion-injured-autoimmunity-prone-mice
#9
Jess Edison, Sharon Frattalone, Christopher Tracy, Geoffrey E Woodard, Melissa Butts, C M Moratz
B6.MRL/lpr mice, an autoimmune strain, have an accelerated injury time course, increased intensity of tissue damage, and increased CD4+ T cell infiltration in the mesenteric ischemia/reperfusion injury model. In this study, the mechanism by which CD4+ T cells were recruited into injured tissue was addressed. Fingolimod (FTY720) was utilized to assess the role of infiltrating CD4+ T cells. FTY720 treatment was more effective in attenuating injury in B6.MRL/lpr mice then in control mice. Reduced CD4+ cell infiltration and tissue injury correlated with decreased neutrophil infiltration and pro-inflammatory cytokine generation...
October 27, 2016: Cellular Immunology
https://www.readbyqxmd.com/read/27811359/sphingosine-kinase-1-is-a-potential-therapeutic-target-for-nasopharyngeal-carcinoma
#10
Wenhua Li, Jian Li, Yunchao Wang, Keqian Zhang, Ni Li, Zhiqiang Tian, Bing Ni, Huaizhi Wang, Zhihua Ruan
Sphingosine kinase 1 (SPHK1) has been shown to be involved in the progression of various types of human cancers. We previously demonstrated that SPHK1 is overexpressed and associated with clinical stage, locoregional recurrence, distant metastasis and poor prognosis in nasopharyngeal carcinoma (NPC). However, the biological roles involving SPHK1 and its potential usefulness as a therapeutic target in NPC remain unknown. In this study, Blocking SPHK1 using siRNA or FTY720 (a SPHK1 inhibitor) significantly reduced proliferation and migration and increased cell cycle arrest and apoptosis in NPC cells...
November 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27802432/characterization-of-the-anticoagulant-and-antithrombotic-properties-of-the-sphingosine-1-phosphate-mimetic-fty720
#11
Zhen Zhao, Ruixue Wang, Zhijun Huo, Chunlei Li, Zhiyong Wang
Sphingosine 1-phosphate (S1P) is a highly active lysophospholipid implicated in various cardiocerebrovascular events such as coagulation, myocardial infarction and stroke. However, as the functional S1P receptor antagonist, whether the S1P mimetic FTY720 can modulate coagulation and/or thrombotic formation remains largely unknown. We investigated the effects of FTY720 on adenosine diphosphate (ADP)-induced platelet aggregation, coagulation parameters and thrombus formation in rats. Pretreatment with FTY720 (2...
November 2, 2016: Acta Haematologica
https://www.readbyqxmd.com/read/27785703/the-effect-of-s1p-receptor-signaling-pathway-on-the-survival-and-drug-resistance-in-multiple-myeloma-cells
#12
Di Fu, Yingchun Li, Jia Li, Xiaoyan Shi, Ronghui Yang, Yuan Zhong, Huihan Wang, Aijun Liao
Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720)...
October 27, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27769069/non-immunosuppressive-triazole-based-small-molecule-induces-anticancer-activity-against-human-hormone-refractory-prostate-cancers-the-role-in-inhibition-of-pi3k-akt-mtor-and-c-myc-signaling-pathways
#13
Wohn-Jenn Leu, Sharada Prasanna Swain, She-Hung Chan, Jui-Ling Hsu, Shih-Ping Liu, Mei-Ling Chan, Chia-Chun Yu, Lih-Ching Hsu, Yen-Lin Chou, Wei-Ling Chang, Duen-Ren Hou, Jih-Hwa Guh
A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation...
October 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765801/targeting-pp2a-to-overcome-enzalutamide-resistance-in-ar-breast-tumors
#14
LETTER
Ion Cristóbal, Blanca Torrejón, Manuel Pedregal, Federico Rojo, Jesús García-Foncillas
No abstract text is available yet for this article.
January 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27699272/effects-of-sphingosine-1-phosphate-receptor-1-phosphorylation-in-response-to-fty720-during-neuroinflammation
#15
Hsing-Chuan Tsai, Yingxiang Huang, Christopher S Garris, Monica A Moreno, Christina W Griffin, May H Han
Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models...
June 16, 2016: JCI Insight
https://www.readbyqxmd.com/read/27697999/the-sphingosine-1-phosphate-modulator-fty720-targets-multiple-myeloma-via-the-cxcr4-cxcl12-pathway
#16
Katia Beider, Evgenia Rosenberg, Hanna Bitner, Avichai Shimoni, Merav Leiba, Maya Koren-Michowitz, Lena Ribakovsky, Shiri Klein, Devorah Olam, Hanna Wald, Lola Weiss, Michal Abraham, Eithan Galun, Amnon Peled, Arnon Nagler
PURPOSE: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the S1P pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with FTY720 modulator as a potential anti-MM therapeutic strategy. EXPERIMENTAL DESIGN AND RESULTS: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 co-expression in both cell lines and primary MM bone marrow samples, suggesting regulative cross-talk between CXCR4/CXCL12 and SPHK1 pathways in MM cells...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27683081/modulating-sphingosine-1-phosphate-signaling-with-dop-or-fty720-alleviates-vascular-and-immune-defects-in-mouse-sepsis
#17
Nasr Y A Hemdan, Cynthia Weigel, Christina-Maria Reimann, Markus H Gräler
Sepsis is a systemic inflammatory response to pathogens and a leading cause of hospital related mortality worldwide. Sphingosine 1-phosphate (S1P) regulates multiple cellular processes potentially involved in the pathogenesis of sepsis, including antigen presentation, lymphocyte egress, and maintenance of vascular integrity. We thus explored the impact of manipulating S1P signaling in experimental polymicrobial sepsis in mice. Administration of 4-deoxypyridoxine (DOP), an inhibitor of the S1P-degrading enzyme S1P-lyase, or of the sphingosine analog FTY720 that serves as an S1P receptor agonist after phosphorylation ameliorated morbidity, improved recovery from sepsis in surviving mice, and reduced sepsis-elicited hypothermia and body weight loss...
September 29, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27681411/p21-cdc42-rac-activated-kinase-1-pak1-is-associated-with-cardiotoxicity-induced-by-antihistamines
#18
Jaesuk Yun, So Young Kim, Kyung Sik Yoon, Heejung Shin, Ho-Sang Jeong, Hyejoo Chung, Young-Hoon Kim, Jisoon Shin, Hye Jin Cha, Kyoung Moon Han, Seungha Hyeon, Tac-Hyung Lee, Hye-Kyung Park, Hyung Soo Kim
Astemizole, a non-sedating histamine H1 receptor blocker, is widely known to cause cardiac arrhythmia, which prolongs the QT interval. However, the precise molecular mechanism involved in antihistamine-induced cardiovascular adverse effects other than hERG channel inhibition is still unclear. In this study, we used DNA microarray analysis to detect the mechanisms involved in life-threatening adverse effects caused by astemizole. Rat primary cardiomyocytes were treated with various concentrations of astemizole for 24 h and the corresponding cell lysates were analyzed using a DNA microarray...
September 28, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27671228/neuroprotective-effects-of-fingolimod-in-mouse-models-of-parkinson-s-disease
#19
Peng Zhao, Xiaoxia Yang, Liu Yang, Minshu Li, Kristofer Wood, Qiang Liu, Xiaodong Zhu
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons with limited treatment options. Emerging evidence shows that FTY720 protects against neural injury via modulation of the S1P1 receptor. However, it remains unclear whether FTY720 could influence neurodegeneration in PD. Therefore, the present study was designed to determine the impact of fingolimod (FTY720), a sphingosine-1-phosphate receptor (S1PR) agonist, on 2 mouse models of PD. We found that FTY720 significantly reduced the deficit of motor function, diminished the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and attenuated the decrease of striatal dopamine and metabolite levels in mice receiving 6-hydroxydopamine (6-OHDA) or rotenone to simulate PD...
September 26, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27663260/to-fingolimod-and-beyond-the-rich-pipeline-of-drug-candidates-that-target-s1p-signaling
#20
REVIEW
Wee Siong Chew, Wei Wang, Deron R Herr
Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P1)...
November 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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