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https://www.readbyqxmd.com/read/28627375/modulation-of-sphingosine-1-phosphate-receptor-ameliorates-harmaline-induced-essential-tremor-in-rat
#1
Narjes Dahmardeh, Majid Asadi-Shekaari, Shokouh Arjmand, Tajpari Kalantaripour, Mohsen Basiri, Mohammad Shabani
Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n=10 in each group) weighing 40-60g were divided into vehicle control groups (saline or DMSO), saline/DMSO+harmaline (30mg/kg, i.p.)+fingolimod (FTY720) (1mg/kg, i.p, 1h before harmaline injection) groups...
June 13, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28620801/fty720-attenuates-infection-induced-enhancement-of-a%C3%AE-accumulation-in-app-ps1-mice-by-modulating-astrocytic-activation
#2
Róisín M McManus, Orla M Finucane, Mieszko M Wilk, Kingston H G Mills, Marina A Lynch
It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD...
June 15, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28619847/targeted-activation-of-the-shp-1-pp2a-signalling-axis-elicits-apoptosis-of-chronic-lymphocytic-leukemia-cells
#3
Elena Tibaldi, Mario Angelo Pagano, Federica Frezzato, Valentina Trimarco, Monica Facco, Giuseppe Zagotto, Giovanni Ribaudo, Valeria Pavan, Luciana Bordin, Andrea Visentin, Francesca Zonta, Gianpietro Semenzato, Anna Maria Brunati, Livio Trentin
The Src Family Kinase (SFK) Lyn is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is the spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and the serine/threonine phosphatase 2A, eventually triggering apoptosis...
June 15, 2017: Haematologica
https://www.readbyqxmd.com/read/28619430/effect-of-fingolimod-fty720-on-choroidal-thickness-in-patients-with-multiple-sclerosis
#4
Ali Kal, Mahmut Oğuz Ulusoy, Bahriye Horasanlı, Şefik Cezairlioğlu, Öznur Kal
OBJECTIVE: Using spectral domain optical coherence tomography (SD-OCT), to compare the choroidal thickness in a healthy population (group 1), with newly diagnosed multiple sclerosis (MS) patients (group 2), with MS patients who underwent β-interferon monotherapy (group 3) and MS patients who underwent fingolimod therapy for 1 year (group 4) METHODS: Twenty-five control subjects (25 eyes), 24 newly diagnosed (24 eyes) MS patients, 22 MS patients who underwent fingolimod monotherapy for 1 year (22 eyes), and 24 MS patients who underwent β-interferon monotherapy for 1 year (24 eyes) were included in this study...
May 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28611472/cd11a-icam-1-blockade-combined-with-il-2-targeting-therapy-causes-a-paradoxical-acceleration-of-type-1-diabetes
#5
Ekua W Brenu, Timothy J Bartley, Casey M Wright, Emma Hamilton-Williams
Enhancement of regulatory T cell (Treg) function is the goal of many immunotherapies aimed at treating type 1 diabetes (T1D). The use of IL-2 is hindered by its effects on other populations such as effector T cells and NK cells. Combination therapies aimed at suppressing effector T cells while using IL-2 to expand Tregs could be beneficial and have been trialed in T1D patients. We have investigated a combination therapy using IL-2 and αCD11a blocking antibody to simultaneously expand Tregs and suppress the activation and migration of autoreactive T cells...
June 14, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28607130/s1pr1-sphingosine-1-phosphate-receptor-1-signaling-regulates-blood-flow-and-pressure
#6
Anna Cantalupo, Antonella Gargiulo, Elona Dautaj, Catherine Liu, Yi Zhang, Timothy Hla, Annarita Di Lorenzo
Nitric oxide is one of the major endothelial-derived vasoactive factors that regulate blood pressure (BP), and the bioactive lipid mediator S1P (sphingosine-1-phosphate) is a potent activator of endothelial nitric oxide synthase through G protein-coupled receptors. Endothelial-derived S1P and the autocrine/paracrine activation of S1PR (S1P receptors) play an important role in preserving vascular functions and BP homeostasis. Furthermore, FTY720 (fingolimod), binding to 4 out of 5 S1PRs recently approved by the Food and Drug Administration to treat autoimmune conditions, induces a modest and transient decrease in heart rate in both animals and humans, suggesting that drugs targeting sphingolipid signaling affect cardiovascular functions in vivo...
June 12, 2017: Hypertension
https://www.readbyqxmd.com/read/28577576/sphingosine-1-phosphate-receptor-3-and-rhoa-signaling-mediate-inflammatory-gene-expression-in-astrocytes
#7
Stephanie S Dusaban, Jerold Chun, Hugh Rosen, Nicole H Purcell, Joan Heller Brown
BACKGROUND: Sphingosine 1-phosphate (S1P) signals through G protein-coupled receptors to elicit a wide range of cellular responses. In CNS injury and disease, the blood-brain barrier is compromised, causing leakage of S1P from blood into the brain. S1P can also be locally generated through the enzyme sphingosine kinase-1 (Sphk1). Our previous studies demonstrated that S1P activates inflammation in murine astrocytes. The S1P1 receptor subtype has been most associated with CNS disease, particularly multiple sclerosis...
June 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28570482/targeting-the-s1p-s1pr1-axis-mitigates-cancer-induced-bone-pain-and-neuroinflammation
#8
Shaness A Grenald, Timothy M Doyle, Hong Zhang, Lauren M Slosky, Zhoumou Chen, Tally M Largent-Milnes, Sarah Spiegel, Todd W Vanderah, Daniela Salvemini
Metastatic bone pain is the single most common form of cancer pain, and persists as a result of peripheral and central inflammatory, as well as, neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P)...
May 31, 2017: Pain
https://www.readbyqxmd.com/read/28543283/targeting-pp2a-and-proteasome-activity-ameliorates-features-of-allergic-airway-disease-in-mice
#9
P M Nair, M R Starkey, T J Haw, G Liu, J C Horvat, J C Morris, N M Verrills, A R Clark, A J Ammit, P M Hansbro
BACKGROUND: Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase-2A (PP2A) is an abundant serine/threonine phosphatase with anti-inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL(S) ), or inhibiting proteasome activity with bortezomib (BORT), could suppress experimental AAD...
May 24, 2017: Allergy
https://www.readbyqxmd.com/read/28533445/lung-cd4-tissue-resident-memory-t-cells-mediate-adaptive-immunity-induced-by-previous-infection-of-mice-with-bordetella-pertussis
#10
Mieszko M Wilk, Alicja Misiak, Róisín M McManus, Aideen C Allen, Marina A Lynch, Kingston H G Mills
Th1 and Th17 cells have an established role in protective immunity to Bordetella pertussis, but this evidence is based largely on peripheral T cells. There is emerging evidence that local tissue-resident memory T (TRM) cells that accumulate in tissue following mucosal infection may be crucial for long-term immunity. In this study, we examined the role of respiratory CD4 TRM cells in immunity to B. pertussis Natural immunity to B. pertussis induced by infection is considered long lasting and effective at preventing reinfection...
May 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28516459/pp2a-deactivation-is-a-common-event-in-oral-cancer-and-reactivation-by-fty720-shows-promising-therapeutic-potential
#11
Bharath K Velmurugan, Chien-Hung Lee, Shang-Lun Chiang, Chun-Hung Hua, Mei-Chung Chen, Shu-Hui Lin, Kun-Tu Yeh, Ying-Chin Ko
Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets...
May 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28498446/synergistic-protective-effect-of-fty720-and-vitamin-e-against-simulated-cerebral-ischemia-in-vitro
#12
Xin Pang, Xuening Hou
The purpose of the present study was to explore the combination effect of FTY720 and vitamin E on cerebral ischemia. Astrocytes were isolated from newborn Sprague‑Dawley rats and were subjected to FTY720, vitamin E, or combination of the two. The astrocyte cultures were then exposed to oxygen‑glucose deprivation (OGD) to simulate an ischemic model in vitro. Cell viability, lactate dehydrogenase (LDH) leakage and cell apoptosis were detected following 12 h of exposure to OGD. In addition, the levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6, IL‑1β, total antioxidant capacity, intercellular adhesion molecule (ICAM)‑1, vascular cell adhesion molecule (VCAM)‑1, chemokine (C‑X‑C motif) ligand (CXCL)‑10, heme oxygenase (HO)‑1 and superoxide dismutase (SOD)‑1 were measured...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28492873/sphingosine-1-phosphate-mediates-fibrosis-in-orbital-fibroblasts-in-graves-orbitopathy
#13
JaeSang Ko, Min Kyoung Chae, Joon H Lee, Eun Jig Lee, Jin Sook Yoon
Purpose: To investigate the effect of sphingosine-1-phosphate (S1P) on fibrosis in orbital fibroblasts in Graves' orbitopathy (GO). Methods: Orbital fibroblasts were cultured from orbital adipose/connective tissues of patients with GO and healthy control subjects. Effects of treatment with TGF-β and cigarette smoke extract (CSE) on S1P receptor (S1PR) messenger RNA (mRNA) and S1P expression were evaluated by real-time polymerase chain reaction and Western blotting...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28480040/fty720-elevates-smooth-muscle-contraction-of-aorta-and-blood-pressure-in-rats-via-erk-activation
#14
Zhen Zhao, Jinxin Wang, Zhijun Huo, Zhiyong Wang, Qibing Mei
Sphingosine 1-phosphate (S1P) is an important signaling sphingolipid involved in the pathogenesis of various cardio cerebral vascular diseases such as ischemic stroke. In particular, the S1P mimetic FTY720 is protective for brain against ischemic conditions. However, whether and how FTY720 can modulate vascular tone and blood pressure remains to be determined. We showed that FTY720 (1 mg/kg) enhanced the contractile response of rat thoracic aortic rings induced by high potassium and phenylephrine, respectively...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28474276/sphingosine-toxicity-in-eae-and-ms-evidence-for-ceramide-generation-via-serine-palmitoyltransferase-activation
#15
Lawrence G Miller, Jennifer A Young, Swapan K Ray, Guanghu Wang, Sharad Purohit, Naren L Banik, Somsankar Dasgupta
Multiple sclerosis (MS) is a demyelinating disorder characterized by massive neurodegeneration and profound axonal loss. Since myelin is enriched with sphingolipids and some of them display toxicity, biological function of sphingolipids in demyelination has been investigated in MS brain tissues. An elevation of sphingosine with a decrease in monoglycosylceramide and psychosine (myelin markers) was observed in MS white matter and plaque compared to normal brain tissue. This indicated that sphingosine toxicity might mediate oligodendrocyte degeneration...
May 5, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28469082/ctla4-ig-in-combination-with-fty720-promotes-allograft-survival-in-sensitized-recipients
#16
Stella H Khiew, Jinghui Yang, James S Young, Jianjun Chen, Qiang Wang, Dengping Yin, Vinh Vu, Michelle L Miller, Roger Sciammas, Maria-Luisa Alegre, Anita S Chong
Despite recent evidence of improved graft outcomes and safety, the high incidence of early acute cellular rejection with belatacept, a high-affinity CTLA4-Ig, has limited its use in clinical transplantation. Here we define how the incomplete control of endogenous donor-reactive memory T cells results in belatacept-resistant rejection in an experimental model of BALB/c.2W-OVA donor heart transplantation into C57BL/6 recipients presensitized to donor splenocytes. These sensitized mice harbored modestly elevated numbers of endogenous donor-specific memory T cells and alloantibodies compared with naive recipients...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28456941/activation-of-glucagon-like-peptide-1-receptor-promotes-neuroprotection-in-experimental-autoimmune-encephalomyelitis-by-reducing-neuroinflammatory-responses
#17
Chi-Ho Lee, Se Jin Jeon, Kyu Suk Cho, Eunjung Moon, Arjun Sapkota, Hee Sook Jun, Jong Hoon Ryu, Ji Woong Choi
The signaling axis of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) has been an important component in overcoming diabetes, and recent reports have uncovered novel beneficial roles of this signaling axis in central nervous system (CNS) disorders, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia, accelerating processes for exendin-4 repositioning. Here, we studied whether multiple sclerosis (MS) could be a complement to the CNS disorders that are associated with the GLP-1/GLP-1R signaling axis...
April 29, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28373076/fty720-fingolimod-regulates-key-target-genes-essential-for-inflammation-in-microglial-cells-as-defined-by-high-resolution-mrna-sequencing
#18
Amitabh Das, Sarder Arifuzzaman, Sun Hwa Kim, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
Although microglial cells have an essential role in the host defense of the brain, the abnormal activation of microglia can lead to devastating outcomes, such as neuroinflammation and neurodegeneration. Emerging evidence indicates that FTY720 (fingolimod), an FDA-approved drug, has beneficial effects on brain cells in the central nervous system (CNS) and, more recently, immunosuppressive activities in microglia via modulation of the sphingosine 1 phosphate (S1P) 1 receptor. However, the exact molecular aspects of FTY720 contribution in microglia remain largely unaddressed...
June 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28363640/sphingosine-1-phosphate-prevents-egress-of-hematopoietic-stem-cells-from-liver-to-reduce-fibrosis
#19
Andrew King, Diarmaid D Houlihan, Dean Kavanagh, Debashis Haldar, Nguyet Luu, Andrew Owen, Shankar Suresh, Nwe Ni Than, Gary Reynolds, Jasmine Penny, Henry Sumption, Prakash Ramachandran, Neil C Henderson, Neena Kalia, Jon Frampton, David H Adams, Philip N Newsome
BACKGROUND & AIMS: There is growing interest in the use of bone marrow cells to treat liver fibrosis, however, little is known about their antifibrotic efficacy or the identity of their effector cell(s). Sphingosine-1-phosphate (S1P) mediates egress of immune cells from the lymphoid organs into the lymphatic vessels; we investigated its role in the response of hematopoietic stem cells (HSCs) to liver fibrosis in mice. METHODS: Purified (c-kit+/sca1+/lin-) HSCs were infused repeatedly into mice undergoing fibrotic liver injury...
March 28, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28363412/fty720-derivatives-do-not-induce-fty720-like-lymphopenia
#20
Ismael Segura-Ulate, Troy K Belcher, Guadalupe Vidal-Martinez, Javier Vargas-Medrano, Ruth G Perez
FTY720 is an immunosuppressive multiple sclerosis (MS) drug that stimulates the expression of neuroprotective brain-derived-neurotrophic-factor (BDNF). In vivo preclinical data suggest that FTY720 could be beneficial for treating Parkinson's patients, though its immunosuppressive effects might limit its efficacy. Two novel FTY720-derivatives, FTY720-C2 and FTY720-Mitoxy, also stimulate BDNF expression and enter brain like FTY720 but are not phosphorylated, suggesting they will not produce FTY720-like immunosuppression...
March 2017: Journal of Pharmacological Sciences
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