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FTY720

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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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 scars (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) as well as in animal HS model. Upon treating HSFs or normal dermal fibroblasts (NFs) 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 G0/G1 phase, promoting apoptosis, inhibiting migration and contraction, and suppressing the expressions of α-smooth muscle actin (α-SMA), 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
#11
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
https://www.readbyqxmd.com/read/28241801/the-protective-effects-of-propofol-against-cocl2-induced-ht22-cell-hypoxia-injury-via-pp2a-camkii%C3%AE-nnos-pathway
#12
Yan Lu, Wei Chen, Chen Lin, Jiaqiang Wang, Minmin Zhu, Jiawei Chen, Changhong Miao
BACKGROUND: Perioperative cerebral ischemia/hypoxia could induce hippocampal injury and has been reported to induce cognitive impairment. In this study, we used cobalt chloride (CoCl2) to build a hypoxia model in mouse hippocampal cell lines. Propofol, a widely used intravenous anesthetic agent, has been demonstrated to have neuroprotective effect. Here, we explored whether and how propofol attenuated CoCl2-induced mouse hippocampal HT22 cell injury. METHODS: Mouse hippocampal HT22 cells were pretreated with propofol, and then stimulated with CoCl2...
February 28, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/28240814/an-engineered-macroencapsulation-membrane-releasing-fty720-to-precondition-pancreatic-islet-transplantation
#13
Daniel T Bowers, Claire E Olingy, Preeti Chhabra, Linda Langman, Parker H Merrill, Ritu S Linhart, Michael L Tanes, Dan Lin, Kenneth L Brayman, Edward A Botchwey
Macroencapsulation is a powerful approach to increase the efficiency of extrahepatic pancreatic islet transplant. FTY720, a small molecule that activates signaling through sphingosine-1-phosphate receptors, is immunomodulatory and pro-angiogenic upon sustained delivery from biomaterials. While FTY720 (fingolimod, Gilenya) has been explored for organ transplantation, in the present work the effect of locally released FTY720 from novel nanofiber-based macroencapsulation membranes is explored for islet transplantation...
February 27, 2017: Journal of Biomedical Materials Research. Part B, Applied Biomaterials
https://www.readbyqxmd.com/read/28239381/presentation-of-autoantigen-in-peripheral-lymph-nodes-is-sufficient-for-priming-autoreactive-cd8-t-cells
#14
Nadine Honke, Namir Shaabani, John R Teijaro, Urs Christen, Cornelia Hardt, Judith Bezgovsek, Philipp A Lang, Karl S Lang
Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8(+) T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningitis virus (LCMV), a finding showing that the spleen was not necessary in generating autoimmunity...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28226242/plasmodium-falciparum-ligand-binding-to-erythrocytes-induce-alterations-in-deformability-essential-for-invasion
#15
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 the 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
#16
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
#17
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 (HCFs) and human KC cells (HKCs), we examined the SPL pathway modulation. Both cell types were stimulated by the three transforming growth factor (TGF)-β isoforms: TGF-β1 (T1), TGF-β2 (T2), and TGF-β3 (T3)...
April 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
#18
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 21, 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
#19
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
#20
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...
March 15, 2017: Life Sciences
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