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FTY720

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https://www.readbyqxmd.com/read/28543283/targeting-pp2a-and-proteasome-activity-ameliorates-features-of-allergic-airway-disease-in-mice
#1
Prema M Nair, Malcolm R Starkey, Tatt Jhong Haw, Gang Liu, Jay C Horvat, Jonathan C Morris, Nikki M Verrills, Andrew R Clark, Alaina J Ammit, Philip 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 if 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
#2
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
#3
Bharath Kumar 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
#4
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...
May 11, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28492873/sphingosine-1-phosphate-mediates-fibrosis-in-orbital-fibroblasts-in-graves-orbitopathy
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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...
March 31, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28363640/sphingosine-1-phosphate-prevents-egress-of-hematopoietic-stem-cells-from-liver-to-reduce-fibrosis
#11
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 anti-fibrotic 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 (HSC) to liver fibrosis in mice. METHODS: Purified (c-kit+/sca1+/lin-) hematopoietic stem cells (HSC) were repeatedly infused into mice undergoing fibrotic liver injury...
March 28, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28363412/fty720-derivatives-do-not-induce-fty720-like-lymphopenia
#12
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
https://www.readbyqxmd.com/read/28348370/non-classical-monocytes-are-biased-progenitors-of-wound-healing-macrophages-during-soft-tissue-injury
#13
Claire E Olingy, Cheryl L San Emeterio, Molly E Ogle, Jack R Krieger, Anthony C Bruce, David D Pfau, Brett T Jordan, Shayn M Peirce, Edward A Botchwey
Successful tissue repair requires the activities of myeloid cells such as monocytes and macrophages that guide the progression of inflammation and healing outcome. Immunoregenerative materials leverage the function of endogenous immune cells to orchestrate complex mechanisms of repair; however, a deeper understanding of innate immune cell function in inflamed tissues and their subsequent interactions with implanted materials is necessary to guide the design of these materials. Blood monocytes exist in two primary subpopulations, characterized as classical inflammatory or non-classical...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28343295/identification-of-sphingosine-1-phosphate-receptor-subtype-1-s1p1-as-a-pathogenic-factor-in-transient-focal-cerebral-ischemia
#14
Bhakta Prasad Gaire, Chi-Ho Lee, Arjun Sapkota, Sang Yeul Lee, Jerold Chun, Hee Jun Cho, Tae-Gyu Nam, Ji Woong Choi
Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P1. In spite of a clear link between S1P signaling and cerebral ischemia, it remains unknown whether the role of S1P1 is pathogenic or neuroprotective...
March 25, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28337201/phenotype-and-tissue-residency-of-lymphocytes-in-the-murine-oral-mucosa
#15
Joo-Young Park, Hyunsoo Chung, Youngnim Choi, Jung-Hyun Park
The oral mucosa is a critical barrier tissue that harbors a series of distinct immune cell subsets. Immune surveillance in the oral mucosa is important for both local and systemic immunity because the oral cavity is a heavily utilized route of pathogen entry and also serves as site of pathogen propagation. Nonetheless, composition and phenotype of the lymphocyte pool in the oral mucosa have remained poorly characterized. Utilizing a newly established protocol for mucosal immune cell isolation, here, we report that the oral mucosa features a unique cellular composition of immune cells, which differed not only from secondary lymphoid organs but also from mucosal tissues in the gut and lung...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28323056/fty720-promotes-pulmonary-fibrosis-when-administered-during-the-remodelling-phase-following-a-bleomycin-induced-lung-injury
#16
David R Gendron, Anne-Marie Lemay, Pascale Blais Lecours, Valérie Perreault-Vallières, Carole-Ann Huppé, Ynuk Bossé, Marie-Renée Blanchet, Geneviève Dion, David Marsolais
Fibrosis complicates numerous pathologies including interstitial lung diseases. Sphingosine analogs such as FTY720 can alleviate lung injury-induced fibrosis in murine models. Contradictorily, FTY720 also promotes in vitro processes normally leading to fibrosis and high doses in vivo foster lung fibrosis by enhancing vascular leakage into the lung. The goal of this study was to determine the effect of low doses of FTY720 on lung fibrosis triggered by an acute injury in mice. We first defined the time-boundaries delimiting the inflammatory and remodelling phases of an injury elicited by bleomycin based on neutrophil counts, total lung capacity and lung stiffness...
March 16, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28320405/urinary-collagen-degradation-products-as-early-markers-of-progressive-renal-fibrosis
#17
Ryanne S Hijmans, Daniel Guldager Kring Rasmussen, Saleh Yazdani, Gerjan Navis, Harry van Goor, Morten Asser Karsdal, Federica Genovese, Jacob van den Born
BACKGROUND: Renal fibrogenesis is associated with increased ECM remodeling and release of collagen fragments in urine in progressive renal disease. We investigated the diagnostic value of urinary collagen degradation products in a proteinuria-driven fibrosis rat model with and without anti-fibrotic S1P-receptor modulator FTY720 treatment. METHODS: Proteinuria was induced in male Wistar rats by Adriamycin (ADR) injection (n = 16). Healthy rats served as controls (n = 12)...
March 20, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28298211/fty720-inhibits-mesothelioma-growth-in-vitro-and-in-a-syngeneic-mouse-model
#18
Agata Szymiczek, Sandra Pastorino, David Larson, Mika Tanji, Laura Pellegrini, Jiaming Xue, Shuangjing Li, Carlotta Giorgi, Paolo Pinton, Yasutaka Takinishi, Harvey I Pass, Hideki Furuya, Giovanni Gaudino, Andrea Napolitano, Michele Carbone, Haining Yang
BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy...
March 15, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28288846/pleiotropic-fty720-is-a-specific-and-potent-therapy-for-hypertrophic-scars
#19
Fen Shi, Xiaoling Cao, Zhicheng Hu, Da Ma, Dong Guo, Jian Zhang, Changlin Zhang, Peng Liu, Shanqiang Qu, Jiayuan Zhu, Wuguo Deng, Bing Tang
Hypertrophic scarring (HS) is a fibrotic skin condition characterized by aberrant fibroblast phenotypes and excessive deposition of extracellular matrix components. 2-Amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), an immunomodulator approved for treating multiple sclerosis, is reported to attenuate fibrosis in multiple disease models. Here we found that FTY720 could significantly attenuate the proliferation and fibrosis in HS fibroblasts (HSFs) and in an animal HS model. Upon treating HSFs or normal dermal fibroblasts with FTY720 at different concentrations for different time periods, we found that FTY720 presented a pleiotropic effect specifically on HSFs but not NFs, including reducing cell viability, arresting cell cycle progression at the G0/G1 phase, promoting apoptosis, inhibiting migration and contraction, and suppressing the expressions of α-smooth muscle actin, collagen I, and collagen III...
March 10, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28270699/fty720-attenuates-angiotensin-ii-induced-podocyte-damage-via-inhibiting-inflammatory-cytokines
#20
Ke Su, Ping Zeng, Wei Liang, Zhengyu Luo, Yiman Wang, Xifeng Lv, Qi Han, Miao Yan, Cheng Chen
FTY720, a new chemical substance derived from the ascomycete Isaria sinclairii, is used for treating multiple sclerosis, renal cancer, and asthma. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite and exists in red blood cells. FTY720 is a synthetic S1P analog which can block S1P evoking physiological effects. Recently studies show that S1P was participating in activated inflammation cells induced renal injury. The objective of this study was to assess the protective effect of FTY720 on kidney damage and the potential mechanism of FTY720 which alleviate podocyte injury in chronic kidney disease...
2017: Mediators of Inflammation
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