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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
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
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
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
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
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
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
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-synthesizingenzyme 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
Jan Korbecki, Izabela Gutowska, Ireneusz Kojder, Dariusz Jeżewski, Marta Goschorska, Agnieszka Łukomska, Anna Lubkowska, Dariusz Chlubek, Irena Baranowska-Bosiacka
Recent years have seen considerable progress in understanding the biochemistry of cancer. For example, more significance is now assigned to the tumor microenvironment, especially with regard to intercellular signaling in the tumor niche which depends on many factors secreted by tumor cells. In addition, great progress has been made in understanding the influence of factors such as neurotensin, growth differentiation factor-15 (GDF-15), sphingosine-1-phosphate (S1P), and infection with cytomegalovirus (CMV) on the 'hallmarks of cancer' in glioblastoma multiforme...
January 23, 2018: Oncotarget
Shushan Zhao, Morayo G Adebiyi, Yujin Zhang, Jacob P Couturier, Xuegong Fan, Hongqi Zhang, Rodney E Kellems, Dorothy E Lewis, Yang Xia
Sphingosine-1-phosphate (S1P) is a biolipid involved in chronic inflammation in several inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic, genetic disorder associated with severe chronic inflammation and tissue damage. We evaluated the effect of elevated S1P in chronic inflammation and tissue damage in SCD and underlying mechanisms. First, we demonstrated that interfering with S1P receptor signaling by FTY720, a U...
January 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Fei Gao, Ying Gao, Fangling Meng, Chunmei Yang, Jiangfeng Fu, Yajun Li
Over-expression of P-glycoprotein (P-gp) in the brain is an important factor leading to drug-resistant epilepsy. Clinical use of P-gp inhibitors is limited by their systemic toxicity. In the present study, we tested the hypothesis that FTY720, a sphingosine 1-phosphate (S1P) analogue used for treating multiple sclerosis, modulates the up-regulation of P-gp and improves brain delivery of phenytoin (PHT) through S1P receptor 1 in the hippocampus of a pilocarpine-induced rat model of status epilepticus (SE). We administered vehicle, FTY720 or FTY720 + W146 (an S1P receptor 1 antagonist) to SE rats...
January 30, 2018: Basic & Clinical Pharmacology & Toxicology
Lan Xiao, Yinghong Zhou, Lingxin Zhu, Shasha Yang, Rong Huang, Wei Shi, Bin Peng, Yin Xiao
Accumulating evidence indicates that the immune and skeletal systems interact with each other through various regulators during the osteoclastogenic process. Among these regulators, the bioactive lipid sphingosine-1-phosphate (S1P), which is synthesized by sphingosine kinase 1/2 (SPHK1/2), has recently been recognized to play a role in immunity and bone remodeling through its receptor sphingosine-1-phosphate receptor 1 (S1PR1). However, little is known regarding the potential role of S1PR1 signaling in inflammatory bone loss...
January 26, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Sinead A O'Sullivan, Catherine O'Sullivan, Luke M Healy, Kumlesh K Dev, Graham K Sheridan
Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R - S1P5R. The drug Gilenya® (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS...
January 27, 2018: Journal of Neurochemistry
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
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
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
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
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
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...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
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
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