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FTY720

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https://www.readbyqxmd.com/read/29774054/beta-adrenoceptor-blockade-ameliorates-impaired-glucose-tolerance-and-alterations-of-the-cerebral-ceramide-metabolism-in-an-experimental-model-of-ischemic-stroke
#1
Sebastian Luger, Annette Schwebler, Rajkumar Vutukuri, Nerea Ferreiros Bouzas, Sandra Labocha, Yannick Schreiber, Robert Brunkhorst, Helmuth Steinmetz, Josef Pfeilschifter, Waltraud Pfeilschifter
Background: Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data...
2018: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/29740911/the-sphingosine-analog-fingolimod-fty720-enhances-tone-and-contractility-of-rat-gastric-fundus-smooth-muscle
#2
M Kraft, U K Zettl, T Noack, R Patejdl
BACKGROUND: Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high-K+ solution...
May 8, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/29728804/sphk-2-promotes-the-particle-induced-inflammation-of-raw264-7-by-maintaining-consistent-expression-of-tnf-%C3%AE-and-il-6
#3
Guangpu Yang, Minghui Gu, Weishen Chen, Wenhua Liu, Yinbo Xiao, Haixing Wang, Weiming Lai, Guoyan Xian, Ziji Zhang, Ziqing Li, Puyi Sheng
Aseptic implant loosening is a devastating long-term complication of total joint arthroplasty. It is mainly initiated by the interaction of wear debris and macrophages. However, how does the chronic inflammation persist and how to stop it is poorly understood. Sphingosine kinases (SPHKs) are an essential feature of immunosuppressive M2 polarisation in macrophages and a promoter for chronic inflammation. In this study, RAW 264.7 macrophages were exposed to stimulation with titanium particles (0.1 mg/ml), and the subsequent expression of SPHKs and pro-inflammatory cytokines was evaluated...
May 4, 2018: Inflammation
https://www.readbyqxmd.com/read/29720672/fty720-decreases-tumorigenesis-in-group-3-medulloblastoma-patient-derived-xenografts
#4
Evan F Garner, Adele P Williams, Laura L Stafman, Jamie M Aye, Elizabeth Mroczek-Musulman, Blake P Moore, Jerry E Stewart, Gregory K Friedman, Elizabeth A Beierle
Group 3 tumors account for 28% of medulloblastomas and have the worst prognosis. FTY720, an immunosuppressant currently approved for treatment of multiple sclerosis, has shown antitumor effects in several human cancer cell lines. We hypothesized that treatment with FTY720 (fingolimod) would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). Three Group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Expression of PP2A and its endogenous inhibitors I2PP2A and CIP2A was detected by immunohistochemistry and immunoblotting...
May 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29703731/dysregulation-of-sphingolipid-metabolism-contributes-to-bortezomib-induced-neuropathic-pain
#5
Katherine Stockstill, Timothy M Doyle, Xisheng Yan, Zhoumou Chen, Kali Janes, Joshua W Little, Kathryn Braden, Filomena Lauro, Luigino Antonio Giancotti, Caron Mitsue Harada, Ruchi Yadav, Wen Hua Xiao, Jack M Lionberger, William L Neumann, Gary J Bennett, Han-Rong Weng, Sarah Spiegel, Daniela Salvemini
The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain...
April 27, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29700602/influence-of-sphingosine-1-phosphate-signaling-on-hcmv-replication-in-human-embryonal-lung-fibroblasts
#6
Anika Zilch, Christian Rien, Cynthia Weigel, Stefanie Huskobla, Brigitte Glück, Katrin Spengler, Andreas Sauerbrei, Regine Heller, Markus Gräler, Andreas Henke
The human cytomegalovirus (HCMV) is a common pathogen, which causes severe or even deadly diseases in immunocompromised patients. In addition, congenital HCMV infection represents a major health concern affecting especially the lung tissue of the susceptible individuals. Antivirals are a useful strategy to treat HCMV-caused diseases. However, all approved drugs target viral proteins but significant toxicity and an increasing resistance against these compounds have been observed. In infected cells, numerous host molecules have been identified to play important roles during HCMV replication...
April 26, 2018: Medical Microbiology and Immunology
https://www.readbyqxmd.com/read/29694854/s-nitrosoglutathione-reductase-gsnor-inhibitor-as-an-immune-modulator-in-experimental-autoimmune-encephalomyelitis
#7
Nishant Saxena, Jeseong Won, Seungho Choi, Avtar K Singh, Inderjit Singh
We previously reported that S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, attenuated TH 17-mediated immune responses in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Cellular GSNO homeostasis is regulated via its synthesis by reaction between nitric oxide and glutathione and its enzymatic catabolism by GSNO reductase (GSNOR). In this study, we evaluated potential of reversible inhibitor of GSNOR (N6022) in comparison with exogenous GSNO in immunopathogenesis of EAE...
April 22, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29687345/modulatory-effects-of-fingolimod-fty720-on-the-expression-of-sphingolipid-metabolism-related-genes-in-an-animal-model-of-alzheimer-s-disease
#8
Henryk Jęśko, Przemysław L Wencel, Walter J Lukiw, Robert P Strosznajder
Sphingolipid signaling disturbances correlate with Alzheimer's disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice...
April 23, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29682605/dual-affinity-heparin-based-hydrogels-achieve-pro-regenerative-immunomodulation-and-microvascular-remodeling
#9
Molly E Ogle, Jack R Krieger, Liane E Tellier, Jennifer McFaline-Figueroa, Johnna S Temenoff, Edward A Botchwey
The immune response to biomaterial implants critically regulates functional outcomes such as vascularization, transplant integration/survival, and fibrosis. To create "immunologically smart" materials, the host-material response may be engineered to optimize the recruitment of pro-regenerative leukocyte subsets which mature into corresponding wound-healing macrophages. We have recently identified a unique feature of pro-regenerative Ly6Clow monocytes that is a higher expression of both the bioactive lipid receptor sphingosine-1-phosphate receptor 3 (S1PR3) and the stromal derived factor-1α (SDF-1α) receptor CXCR4...
April 9, 2018: ACS Biomaterials Science & Engineering
https://www.readbyqxmd.com/read/29625277/the-loss-of-p21-activated-kinase-pak1-promotes-atrial-arrhythmic-activity-the-role-of-pak1-in-atrial-arrhythmia
#10
Jaime DeSantiago, Dan J Bare, Disha Varma, R John Solaro, Rishi Arora, Kathrin Banach
BACKGROUND: Atrial fibrillation (AF) is initiated through arrhythmic atrial excitation from outside the sinus node or remodeling of atrial tissue that allows reentry of excitation. Angiotensin II (AngII) has been implicated in initiation and maintenance of AF through changes in Ca2+ handling and production of reactive oxygen species (ROS). OBJECTIVE: We aimed to determine the role of Pak1, a downstream target in the AngII signaling cascade, in atrial electrophysiology and arrhythmia...
April 3, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29606369/various-signaling-pathways-in-multiple-myeloma-cells-and-effects-of-treatment-on-these-pathways
#11
REVIEW
Ali Dehghanifard, Saeid Kaviani, Saeid Abroun, Mahshad Mehdizadeh, Sajedeh Saiedi, Amirhosein Maali, Sasan Ghaffari, Mehdi Azad
Multiple myeloma (MM) results from malignancy in plasma cells and occurs at ages > 50 years. MM is the second most common hematologic malignancy after non-Hodgkin lymphoma, which constitutes 1% of all malignancies. Despite the great advances in the discovery of useful drugs for this disease such as dexamethasone and bortezomib, it is still an incurable malignancy owing to the development of drug resistance. The tumor cells develop resistance to apoptosis, resulting in greater cell survival, and, ultimately, develop drug resistance by changing the various signaling pathways involved in cell proliferation, survival, differentiation, and apoptosis...
March 17, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29568889/treatment-of-experimental-autoimmune-myasthenia-gravis-rats-with-fty720-and-its-effect-on-th1-th2-cells
#12
Jiankang Huang, Ting Zhang, Hongmei Wang, Yuwu Zhao
Myasthenia gravis (MG) is an autoimmune neurological disease that is characterized by the expression of anti-acetylcholine receptor (AChR) antibodies. The immune response at AChRs of neuromuscular junction is disrupted in patients with MG, which manifests as skeletal muscle fatigue and is aggravated following periods of activity and alleviated following rest. Although a novel immune suppressant FTY720 drug, which exhibits strong immune suppression efficacy and minor adverse effects, is available, its role and mechanism in MG have not been elucidated...
March 16, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29551896/targeted-co-delivery-of-beclin-1-sirna-and-fty720-to-hepatocellular-carcinoma-by-calcium-phosphate-nanoparticles-for-enhanced-anticancer-efficacy
#13
Jun-Yi Wu, Zhong-Xia Wang, Guang Zhang, Xian Lu, Guang-Hui Qiang, Wei Hu, An-Lai Ji, Jun-Hua Wu, Chun-Ping Jiang
Purpose: FTY720, known as fingolimod, is a new immunosuppressive agent with effective anticancer properties. Although it was recently confirmed that FTY720 inhibits cancer cell proliferation, FTY720 can also induce protective autophagy and reduce cytotoxicity. Blocking autophagy with Beclin 1 siRNA after treatment with FTY720 promotes apoptosis. The objective of this study was to enhance the anticancer effect of FTY720 in hepatocellular carcinoma (HCC) by targeted co-delivery of FTY720 and Beclin 1 siRNA using calcium phosphate (CaP) nanoparticles (NPs)...
2018: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29548997/fty720-attenuates-behavioral-deficits-in-a-murine-model-of-systemic-lupus-erythematosus
#14
Dongyan Shi, Tongguan Tian, Shu Yao, Kelei Cao, Xingxing Zhu, Mingshun Zhang, Shuang Wen, Longjun Li, Meiqing Shi, Hong Zhou
Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) severely impacts patients' quality of life and leads to a poor prognosis. The current therapeutic protocol, corticosteroid administration, can also induce neuropsychiatric disorders. FTY720 is an immunomodulator that selectively confines lymphocytes in lymph nodes and reduces autoreactive T cell recruitment to the central nervous system (CNS). This study aimed to identify a novel therapeutic strategy for NPSLE. B6.MRL-lpr mice were treated with oral administration of FTY720 (2 mg/kg) three times per week for 12 weeks, to evaluate its efficacy in a model of NPSLE...
March 13, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29536648/s1pr3-is-essential-for-phosphorylated-fingolimod-to-protect-astrocytes-against-oxygen-glucose-deprivation-induced-neuroinflammation-via-inhibiting-tlr2-4-nf%C3%AE%C2%BAb-signalling
#15
Yin-Feng Dong, Ruo-Bing Guo, Juan Ji, Lu-Lu Cao, Ling Zhang, Zheng-Zhen Chen, Ji-Ye Huang, Jin Wu, Jun Lu, Xiu-Lan Sun
Fingolimod (FTY720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte-mediated inflammatory responses induced by oxygen-glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD-induced injury and inflammatory responses...
March 13, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29535596/neuroprotective-effect-of-protein-phosphatase-2a-tristetraprolin-following-subarachnoid-hemorrhage-in-rats
#16
Jian Yin, Ran Li, Wenchao Liu, Yunchang Chen, Xin Zhang, Xifeng Li, Xuying He, Chuanzhi Duan
Early brain injury (EBI) following subarachnoid hemorrhage (SAH) can lead to inflammation and neuronal dysfunction. There is a need for effective strategies to mitigate these effects and improve the outcome of patients who experience SAH. The mRNA-destabilizing protein tristetraprolin (TTP) is an anti-inflammatory factor that induces the decay of cytokine transcripts and has been implicated in diseases such as glioma. However, the mechanism of action of TTP in EBI after SAH is unclear. The present study investigated the effects of TTP regulation via phosphorylation in a rat model of SAH by protein phosphatase (PP)2A, which is a pleiotropic enzyme complex with multiple substrate phospho-proteins...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29534901/abscopal-effects-with-hypofractionated-schedules-extending-into-the-effector-phase-of-the-tumor-specific-t-cell-response
#17
Xuanwei Zhang, Gabriele Niedermann
PURPOSE: Hypofractionated radiation therapy (hRT) combined with immune checkpoint blockade can induce T-cell-mediated local and abscopal antitumor effects. We had previously observed peak levels of tumor-infiltrating lymphocytes (TILs) between days 5 and 8 after hRT. Because TILs are regarded as radiosensitive, hRT schedules extending into this period might be less immunogenic, prompting us to compare clinically relevant, short and extended schedules with equivalent biologically effective doses combined with anti-programmed cell death 1 (PD1) antibody treatment...
February 3, 2018: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/29489440/trpm7-mediates-mechanosensitivity-in-adult-rat-odontoblasts
#18
J Won, H Vang, J H Kim, P R Lee, Y Kang, S B Oh
Odontoblasts, with their strategic arrangement along the outermost compartment of the dentin-pulp complex, have been suggested to have sensory function. In addition to their primary role in dentin formation, growing evidence shows that odontoblasts are capable of sensing mechanical stimulation. Previously, we found that most odontoblasts express TRPM7, the nonselective mechanosensitive ion channel reported to be critical in Mg2+ homeostasis and dentin mineralization. In line with this finding, we sought to elucidate the functional expression of TRPM7 in odontoblasts by pharmacological approaches and mechanical stimulation...
February 1, 2018: Journal of Dental Research
https://www.readbyqxmd.com/read/29483712/anti-cd69-therapy-induces-rapid-mobilization-and-high-proliferation-of-hspcs-through-s1p-and-mtor
#19
Laura Notario, Elisenda Alari-Pahissa, Almudena Albentosa, Magdalena Leiva, Guadalupe Sabio, Pilar Lauzurica
CD69 regulates lymphocyte egress from the thymus and lymph nodes through cis-interactions and the downregulation of surface sphingosine-1-phosphate (S1P) receptor-1 (S1P1). However, its role in the regulation of cell egress from bone marrow has not been extensively studied. We show here that CD69 targeting induced rapid and massive mobilization of BM leukocytes, which was inhibited by desensitization to S1P with FTY720. This mobilization was reproduced with anti-human CD69 mAb treatment of mice expressing human CD69...
February 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29481916/pramipexole-and-fingolimod-exert-neuroprotection-in-a-mouse-model-of-parkinson-s-disease-by-activation-of-sphingosine-kinase-1-and-akt-kinase
#20
Joanna Motyl, Łukasz Przykaza, Paweł M Boguszewski, Piotr Kosson, Joanna B Strosznajder
Parkinson's disease (PD) is one of the most severe neurodegenerative diseases with unknown pathogenesis and currently unsuccessful therapies. Recently, neuroprotection via sphingosine-1-phosphate (S1P)-dependent signalling has become a promising target for the treatment of neurodegenerative disorders. Our previous study demonstrated down-regulation and inhibition of the S1P-synthesizing enzyme sphingosine kinase 1 (SPHK1) in a PD cellular model. Moreover, we have previously identified a neuroprotective effect of fingolimod (FTY720), a first S1P receptor modulator utilized in the clinic...
February 23, 2018: Neuropharmacology
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