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FTY720

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https://www.readbyqxmd.com/read/28226242/p-falciparum-ligand-binding-to-erythrocytes-induce-alterations-in-deformability-essential-for-invasion
#1
Xavier Sisquella, Thomas Nebl, Jennifer K Thompson, Lachlan Whitehead, Brian M Malpede, Nichole D Salinas, Kelly Rogers, Niraj H Tolia, Andrea Fleig, Joseph O'Neill, Wai-Hong Tham, F David Horgen, Alan F Cowman
The most lethal form of malaria in humans is caused by Plasmodium falciparum. These parasites invade erythrocytes, a complex process involving multiple ligand-receptor interactions. The parasite makes initial contact with the erythrocyte followed by dramatic deformations linked to the function of the Erythrocyte binding antigen family and P. falciparum reticulocyte binding-like families. We show EBA-175 mediates substantial changes in deformability of erythrocytes by binding to glycophorin A and activating a phosphorylation cascade that includes erythrocyte cytoskeletal proteins resulting in changes in the viscoelastic properties of the host cell...
February 22, 2017: ELife
https://www.readbyqxmd.com/read/28218904/the-protumorigenic-potential-of-fty720-by-promoting-extramedullary-hematopoiesis-and-mdsc-accumulation
#2
Y Li, T Zhou, Y Wang, C Ning, Z Lv, G Han, J C Morris, E N Taylor, R Wang, H Xiao, C Hou, Y Ma, B Shen, J Feng, R Guo, Y Li, G Chen
FTY720 (also called fingolimod) is recognized as an immunosuppressant and has been approved by the Food and Drug Administration to treat refractory multiple sclerosis. However, long-term administration of FTY720 potentially increases the risk for cancer in recipients. The underlying mechanisms remain poorly understood. Herein, we provided evidence that FTY720 administration potentiated tumor growth. Mechanistically, FTY720 enhanced extramedullary hematopoiesis and massive accumulation of myeloid-derived suppressor cells (MDSCs), which actively suppressed antitumor immune responses...
February 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28188148/analysis-of-sphingolipids-in-human-corneal-fibroblasts-from-normal-and-keratoconus-patients
#3
Hui Qi, Shrestha Priyadarsini, Sarah E Nicholas, Akhee Sarker-Nag, Jeremy Allegood, Charles E Chalfant, Nawajes A Mandal, Dimitrios Karamichos
The pathophysiology of human keratoconus (KC), a bilateral progressive corneal disease, leading to protrusion of the cornea, stromal thinning, and scarring is not well understood. In this study we investigated a novel Sphingolipid (SPL) signaling pathway through which KC may be regulated. Using human corneal fibroblasts (HCF) and human keratoconus cells (HKC) we examined the SPL pathway modulation. Both cell types were stimulated by the three TGF-β isoforms: TGF-B1 (T1), B2 (T2), and B3 (T3). All samples were analyzed using lipidomics, and real time-PCR...
February 10, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28167760/sphingosine-1-phosphate-receptor-modulation-suppresses-pathogenic-astrocyte-activation-and-chronic-progressive-cns-inflammation
#4
Veit Rothhammer, Jessica E Kenison, Emily Tjon, Maisa C Takenaka, Kalil Alves de Lima, Davis M Borucki, Chun-Cheih Chao, Annabel Wilz, Manon Blain, Luke Healy, Jack Antel, Francisco J Quintana
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28162947/fty720-supplementation-partially-improves-erectile-dysfunction-in-rats-with-streptozotocin-induced-type-1-diabetes-through-inhibition-of-endothelial-dysfunction-and-corporal-fibrosis
#5
Kai Cui, Yajun Ruan, Tao Wang, Ke Rao, Zhong Chen, Shaogang Wang, Jihong Liu
INTRODUCTION: Erectile dysfunction (ED) in patients with diabetes mellitus (DM) seriously affects their quality of life. However, these patients show a poor effect rate for oral phosphodiesterase type 5 inhibitors. Thus, new treatment methods are urgently needed. Fingolimod hydrochloride (FTY720) was approved in 2010 for the treatment of patients with the relapsing-remitting form of multiple sclerosis. AIM: To investigate whether FTY720 supplementation could ameliorate ED induced by DM (DMED)...
February 2, 2017: Journal of Sexual Medicine
https://www.readbyqxmd.com/read/28161158/fingolimod-fty720-attenuates-social-deficits-learning-and-memory-impairments-neuronal-loss-and-neuroinflammation-in-the-rat-model-of-autism
#6
Hongmei Wu, Xuelai Wang, Jingquan Gao, Shuang Liang, Yanqiu Hao, Caihong Sun, Wei Xia, Yonggang Cao, Lijie Wu
AIMS: To investigate the effect of FTY720 on the valproic acid (VPA) rat model of autism. MAIN METHODS: As an animal model of autism, we used intraperitoneal injection of VPA on embryonic day 12.5 in Wistar rats. The pups were given FTY720 orally at doses of 0.25, 0.5 and 1mg/kg daily from postnatal day 15 to 35. Social behavior, spatial learning and memory were assessed at the end of FTY720 treatment. The histological change, oxidative stress, neuroinflammatory responses, and apoptosis-related proteins in the hippocampus were evaluated...
February 1, 2017: Life Sciences
https://www.readbyqxmd.com/read/28153532/fty720-fingolimod-reverses-%C3%AE-synuclein-induced-downregulation-of-brain-derived-neurotrophic-factor-mrna-in-oln-93-oligodendroglial-cells
#7
Ismael Segura-Ulate, Barbara Yang, Javier Vargas-Medrano, Ruth G Perez
Multiple system atrophy (MSA) is a demyelinating neurodegenerative disorder characterized by accumulation of aggregated α-synuclein (aSyn) inside oligodendrocyte precursors, mature oligodendroglia, and neurons. MSA dysfunction is associated with loss of trophic factor production by glial and neuronal cells. Here, we report that recombinant wild type human aSyn uptake by OLN-93, an oligodendroglia cell-line, reduced brain-derived neurotrophic factor (BDNF) expression. Furthermore, OLN-93 cells stably transfected with human wild type or an MSA-associated mutant aSyn, A53E that produces neuronal and glial inclusions, reduced BDNF mRNA to nearly unmeasurable qPCR levels...
January 31, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28153091/effect-of-fingolimod-on-neural-stem-cells-a-novel-mechanism-and-broadened-application-for-neural-repair
#8
Yuan Zhang, Xing Li, Bogoljub Ciric, Cun-Gen Ma, Bruno Gran, Abdolmohamad Rostami, Guang-Xian Zhang
Inflammatory demyelination and axonal damage of the CNS are hallmarks of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Fingolimod (FTY720), the first FDA-approved oral medication for MS, suppresses acute disease but is less effective at the chronic stage, and whether it has a direct effect on neuroregeneration in MS and EAE remains unclear. Here we show that FTY720, at nanomolar concentrations, effectively protected survival of neural stem cells (NSCs) and enhanced their development into mature oligodendrocytes (OLGs) in vitro, primarily through the S1P3 and S1P5 receptors...
February 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28134307/fingolimod-limits-acute-a%C3%AE-neurotoxicity-and-promotes-synaptic-versus-extrasynaptic-nmda-receptor-functionality-in-hippocampal-neurons
#9
Pooja Joshi, Martina Gabrielli, Luisa Ponzoni, Silvia Pelucchi, Matteo Stravalaci, Marten Beeg, Sonia Mazzitelli, Daniela Braida, Mariaelvina Sala, Enrica Boda, Annalisa Buffo, Marco Gobbi, Fabrizio Gardoni, Michela Matteoli, Elena Marcello, Claudia Verderio
Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer's disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons...
January 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28104351/the-sphingosine-1-phosphate-receptor-1-agonist-sew2871-reduces-tau-ser262-phosphorylation-in-rat-hippocampal-slices
#10
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
#11
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
#12
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
#13
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...
March 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28039158/inhibition-of-sphingosine-1-phosphate-signaling-ameliorates-murine-nonalcoholic-steatohepatitis
#14
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
#15
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
#16
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...
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
#17
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
#18
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
#19
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
#20
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
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