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https://www.readbyqxmd.com/read/29351902/targeting-the-sphk1-s1p-s1pr1-axis-that-links-obesity-chronic-inflammation-and-breast-cancer-metastasis
#1
Masayuki Nagahashi, Akimitsu Yamada, Eriko Katsuta, Tomoyoshi Aoyagi, Wei-Ching Huang, Krista P Terracina, Nitai C Hait, Jeremy C Allegood, Junko Tsuchida, Kizuki Yuza, Masato Nakajima, Manabu Abe, Kenji Sakimura, Sheldon Milstien, Toshifumi Wakai, Sarah Spiegel, Kazuaki Takabe
Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) which mediates cancer pathogenesis. A high fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors...
January 19, 2018: Cancer Research
https://www.readbyqxmd.com/read/29345065/fingolimod-targets-cerebral-endothelial-activation-to-block-leukocyte-recruitment-in-the-central-nervous-system
#2
Yawei Zhao, Dongyan Shi, Kelei Cao, Fengjiao Wu, Xingxing Zhu, Shuang Wen, Qiang You, Keqi Zhang, Lixin Liu, Hong Zhou
Fingolimod (FTY720), an immunomodulator, is approved as an oral treatment for patients with relapsing forms of multiple sclerosis. Its effects are largely attributed to its mechanism of selectively retaining lymphocytes in the lymph nodes to reduce autoreactive T-cell recruitment in the CNS. In this study, we investigated the therapeutic effect of FTY720 on an animal model of CNS inflammation induced by intracerebral ventricle LPS injection. We found that FTY720 treatment significantly prevented LPS-induced neutrophil recruitment in the CNS by inhibiting leukocyte recruitment in cerebral microvessels...
January 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29336057/modification-of-lymphocyte-migration-to-peyer-s-patches-by-inhibition-of-sphingosine-1-phosphate-lyase-ameliorates-murine-colitis
#3
Kazuhiko Shirakabe, Masaaki Higashiyama, Hirotaka Furuhashi, Takeshi Takajo, Koji Maruta, Yoshikiyo Okada, Chie Kurihara, Chikako Watanabe, Shunsuke Komoto, Kengo Tomita, Shigeaki Nagao, Soichiro Miura, Masayuki Saruta, Ryota Hokari
BACKGROUND AND AIM: Sphingosine-1-phosphate (S1P) receptor 1, a therapeutic target of the S1P1 agonist FTY720, plays a crucial role in lymphocyte migration and is expressed in several cells including naïve T lymphocytes and endothelial cells. 2-acetyl-4-tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase (SPL), exhibits immunomodulatory activity through increasing the S1P concentration in the secondary lymphoid organs, but its effects on colitis remain unclear. We aimed to clarify how THI affects colitis and migration of naïve T lymphocytes in Peyer's patches (PPs)...
January 15, 2018: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29334656/activated-protein-c-suppresses-osteoclast-differentiation-via-endothelial-protein-c-receptor-protease-activated-receptor-1-sphingosine-1-phosphate-receptor-and-apolipoprotein-e-receptor-2
#4
Kakunoshin Yoshida, Nobuyuki Akita, Takayuki Okamoto, Kunihiro Asanuma, Atsumasa Uchida, Akihiro Sudo, Motomu Shimaoka, Koji Suzuki, Tatsuya Hayashi
INTRODUCTION: Bone remodeling relies on a delicate balance between formation and resorption of bone tissues, processes in which bone-forming osteoblasts and bone-resorbing osteoclasts play central roles. Recently, we reported that anticoagulant activated protein C (APC) promotes osteoblast proliferation, but the role of the blood coagulation system in bone remodeling remains unclear. In this study, to further elucidate the relationship between bone remodeling and blood coagulation, we investigated the effect of APC on osteoclast differentiation...
January 3, 2018: Thrombosis Research
https://www.readbyqxmd.com/read/29249870/effects-of-fty720-on-lung-injury-induced-by-hindlimb-ischemia-reperfusion-in-rats
#5
Liangrong Wang, Feifei Chen, Yafei Pan, Lina Lin, Xiangqing Xiong
Background: Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. Methods: Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/29237776/human-naive-and-memory-t-cells-display-opposite-migratory-responses-to-sphingosine-1-phosphate
#6
Annabelle Drouillard, Antoinette Neyra, Anne-Laure Mathieu, Antoine Marçais, Mélanie Wencker, Jacqueline Marvel, Alexandre Belot, Thierry Walzer
The role of sphingosine-1 phosphate (S1P) in leukocyte trafficking has been well deciphered in mice but remains largely unaddressed in humans. In this study, we assessed the ex vivo response to S1P of primary human T cell subsets. We found that tonsil but not blood leukocytes were responsive to S1P gradients, suggesting that T cell responsiveness is regulated during their recirculation in vivo. Tonsil naive T cells were readily chemoattracted by S1P in an FTY720-sensitive, S1PR1-dependent manner. Surprisingly, S1P had the opposite effect on effector memory T cells, resident memory T cells, and recently activated T cells, inhibiting their spontaneous or chemokine-induced migration...
December 13, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29234668/a-genome-wide-screen-for-fty720-sensitive-mutants-reveals-genes-required-for-ros-homeostasis
#7
Kanako Hagihara, Kanako Kinoshita, Kouki Ishida, Shihomi Hojo, Yoshinori Kameoka, Ryosuke Satoh, Teruaki Takasaki, Reiko Sugiura
Fingolimod hydrochloride (FTY720), a sphingosine-1-phosphate (S1P) analogue, is an approved immune modulator for the treatment of multiple sclerosis (MS). Notably, in addition to its well-known mode of action as an S1P modulator, accumulating evidence suggests that FTY720 induces apoptosis in various cancer cells via reactive oxygen species (ROS) generation. Although the involvement of multiple signaling molecules, such as JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase) and Sphk has been reported, the exact mechanisms how FTY720 induces cell growth inhibition and the functional relationship between FTY720 and these signaling pathways remain elusive...
November 27, 2017: Microbial Cell
https://www.readbyqxmd.com/read/29226621/cenerimod-a-novel-selective-s1p1-receptor-modulator-with-unique-signaling-properties
#8
Luca Piali, Magdalena Birker-Robaczewska, Cyrille Lescop, Sylvie Froidevaux, Nicole Schmitz, Keith Morrison, Christopher Kohl, Markus Rey, Rolf Studer, Enrico Vezzali, Patrick Hess, Martine Clozel, Beat Steiner, Martin H Bolli, Oliver Nayler
Sphingosine-1-phosphate receptor 1 (S1P1 ) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1-5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side-effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29208234/vitamin-d-attenuates-sphingosine-1-phosphate-s1p-mediated-inhibition-of-extravillous-trophoblast-migration
#9
Melissa Westwood, Khiria Al-Saghir, Sarah Finn-Sell, Cherlyn Tan, Elizabeth Cowley, Stéphane Berneau, Daman Adlam, Edward D Johnstone
INTRODUCTION: Failure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE). In other systems, the sphingolipid, sphingosine-1-phosphate (S1P), controls cell migration therefore this study determined its effect on extravillous trophoblast (EVT) function. METHODS: A transwell migration system was used to assess the behaviour of three trophoblast cell lines, Swan-71, SGHPL-4, and JEG3, and primary human trophoblasts in the presence or absence of S1P, S1P pathway inhibitors and 1,25(OH)2D3...
December 2017: Placenta
https://www.readbyqxmd.com/read/29207165/combination-treatment-of-fty720-and-cisplatin-exhibits-enhanced-antitumour-effects-on-cisplatin-resistant-non-small-lung-cancer-cells
#10
Yang Li, Tinghua Hu, Tianjun Chen, Tian Yang, Hui Ren, Mingwei Chen
A major common medical treatment for lung carcinoma is cisplatin (DDP)-based therapy. However, the development or existence of chemoresistance frequently blocks its effectiveness. Currently, autophagy is recognised as a potential anticancer strategy, although there is controversy over its role in the development of cancer. In lung carcinoma, no studies of autophagy induced by FTY720, a sphingosine 1-phosphate analog and a novel immunosuppressant drug, have been published, while apoptosis has been shown to be induced by FTY720 in several cancer cell lines...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29194293/multiple-pathological-mechanisms-contribute-to-hippocampal-damage-in-the-experimental-autoimmune-encephalomyelitis-model-of-multiple-sclerosis
#11
Elizabeth L Kyran, Christine Robinson, Pece Kocovski, Zhenjiang Li, Phuc T Dang, Matthew W Hale, Jacqueline M Orian
Emotional and cognitive deficits and associated hippocampal damage observed in multiple sclerosis (MS) are now recognized as primary disease manifestations. However, the pathological substrate of these dysfunctions is unclear. In the experimental autoimmune encephalomyelitis (EAE) MS model, impaired hippocampal-dependent functions are concomitant with severe microglial reactivity and neurodegeneration, but reports vary with respect to evidence of lymphocytic infiltration, raising questions as to the nature of the underlying neurodegenerative mechanisms...
January 3, 2018: Neuroreport
https://www.readbyqxmd.com/read/29193293/functional-antagonism-of-sphingosine-1-phosphate-receptor-1-prevents-cuprizone-induced-demyelination
#12
SunJa Kim, Jacek Bielawski, Hyunmin Yang, Yu Kong, Beiyan Zhou, Jianrong Li
Recent evidence suggests that the oral drug Fingolimod (FTY720) for relapsing-remitting multiple sclerosis (MS) may act directly on the central nervous system (CNS) and modulate disease pathogenesis and progression in experimental models of MS. However, the specific subtype of sphingosine-1-phosphate (S1P) receptors that mediates the effect of FTY720 on the CNS cells has not been fully elucidated. Here, we report that S1P receptor 1 (S1PR1) is elevated in reactive astrocytes in an autoimmunity independent mouse model of MS and that selective S1PR1 modulation is sufficient to ameliorate the loss of oligodendrocytes and demyelination...
November 29, 2017: Glia
https://www.readbyqxmd.com/read/29186197/fingolimod-suppresses-neuronal-autophagy-through-the-mtor-p70s6k-pathway-and-alleviates-ischemic-brain-damage-in-mice
#13
Xiao Li, Ming-Huan Wang, Chuan Qin, Wen-Hui Fan, Dai-Shi Tian, Jun-Li Liu
The bioactive, signaling lipid, sphingosine-1-phosphate (S1P), and its analog, fingolimod (FTY720), have previously shown neuroprotective effects against ischemic brain injury. However, the underlying mechanisms have not yet been fully clarified. The roles of autophagy in ischemic stroke are being increasingly recognized. In the present study, we sought to determine whether the S1P pathway is involved in neuronal autophagy and investigate its possible mechanisms following stroke. Interestingly, we found that FTY720 significantly attenuates infarct volumes and reduces neuronal apoptosis on days 1 and 3 post stroke, accompanied by amelioration of functional deficits...
2017: PloS One
https://www.readbyqxmd.com/read/29185452/dhhc5-mediated-palmitoylation-of-s1p-receptor-subtype-1-determines-g-protein-coupling
#14
Shaymaa Mohamed Mohamed Badawy, Taro Okada, Taketoshi Kajimoto, Takeshi Ijuin, Shun-Ichi Nakamura
Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator involved in the regulation of immune cell trafficking and vascular permeability acting mainly through G-protein-coupled S1P receptors (S1PRs). However, mechanism underlying how S1PRs are coupled with G-proteins remains unknown. Here we have uncovered that palmitoylation of a prototypical subtype S1P1R is prerequisite for subsequent inhibitory G-protein (Gi) coupling. We have identified DHHC5 as an enzyme for palmitoylation of S1P1R. Under basal conditions, S1P1R was functionally associated with DHHC5 in the plasma membranes (PM) and was fully palmitoylated, enabling Gi coupling...
November 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141790/cerebral-toxoplasmosis-in-an-ms-patient-receiving-fingolimod
#15
Alejandro Enriquez-Marulanda, Jaime Valderrama-Chaparro, Laura Parrado, Juan Diego Vélez, Ana Maria Granados, Jorge Luis Orozco, Jairo Quiñones
Multiple Sclerosis (MS) is an autoimmune disease in which lymphocytes target putative myelin antigens in the CNS, causing inflammation and neurodegeneration. Fingolimod (FTY720) is an immunosuppressive drug used as a second line therapy for relapsing forms of MS due to its safety profile and good response to treatment. Despite its safety, there are still concerns about the possibility of Fingolimod being linked to the development of opportunistic infections like disseminated varicella zoster infections and herpes simplex encephalitis...
November 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/29140922/fingolimod-reduces-neuropathic-pain-behaviors-in-a-mouse-model-of-multiple-sclerosis-by-a-sphingosine-1-phosphate-receptor-1-dependent-inhibition-of-central-sensitization-in-the-dorsal-horn
#16
Suzanne Doolen, Tommaso Iannitti, Benjamin C Shaw, Carolyn M Grachen, Renee R Donahue, Bradley K Taylor
Multiple sclerosis (MS) is an autoimmune-inflammatory neurodegenerative disease that is often accompanied by a debilitating neuropathic pain. Disease-modifying agents slow the progression of MS and prevent relapses, yet it remains unclear if they yield analgesia. We explored the analgesic potential of fingolimod (FTY720), an agonist/functional antagonist at the sphingosine-1-phosphate receptor 1 (S1PR1), because it reduces hyperalgesia in models of peripheral inflammatory and neuropathic pain. We used a myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) mouse model of experimental autoimmune encephalomyelitis (EAE), modified to avoid frank paralysis and thus allow for assessment of withdrawal behaviors to somatosensory stimuli...
November 13, 2017: Pain
https://www.readbyqxmd.com/read/29137549/the-impact-of-a-long-acting-oral-sphingosine-1-phosphate-analogue-on-ovarian-aging-in-a-rat-model
#17
Sezcan Mumusoglu, Volkan Turan, Hasan Uckan, Aysegul Suzer, Lale Karakoc Sokmensuer, Gurkan Bozdag
In animal studies, intravenous continuous infusion or peritoneal injection of sphingosine-1-phosphate (S1P) has been shown to decrease chemotherapy- and radiotherapy-induced apoptosis on primordial follicles. Although a long-acting oral form of an S1P analogue (FTY720, fingolimod) has been recently developed and utilized in women with multiple sclerosis, there are no data exploring its ability to avoid spontaneous follicle apoptosis. Thirty 10-month-old female rats were randomly assigned to 3 groups to investigate whether fingolimod would be able to decrease the spontaneous ovarian follicle apoptosis ratio...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/29128799/fty720-inhibits-the-nrf2-are-pathway-in-human-glioblastoma-cell-lines-and-sensitizes-glioblastoma-cells-to-temozolomide
#18
Li Zhang, Handong Wang
BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of various cytoprotective genes. Constitutive Nrf2 activation in many cancers enhances cell survival and resistance to anti-cancer drugs. Our previous studies have shown that FTY720 induced autophagy-related apoptosis and necroptosis and inhibited invasion and migration in human glioblastoma cells. However, whether FTY720 regulated Nrf2 in glioblastoma cells remained unclear...
July 4, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/29127024/the-sphingosine-1-phosphate-receptor-modulator-fingolimod-as-a-therapeutic-agent-recent-findings-and-new-perspectives
#19
REVIEW
Andrea Huwiler, Uwe Zangemeister-Wittke
The immunomodulatory drug fingolimod (FTY720, Gilenya(R)) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P1 subtype by induction of receptor downregulation. Since S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression...
November 7, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29114096/fingolimod-protects-against-ischemic-white-matter-damage-by-modulating-microglia-toward-m2-polarization-via-stat3-pathway
#20
Chuan Qin, Wen-Hui Fan, Qian Liu, Ke Shang, Madhuvika Murugan, Long-Jun Wu, Wei Wang, Dai-Shi Tian
BACKGROUND AND PURPOSE: White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model...
November 7, 2017: Stroke; a Journal of Cerebral Circulation
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