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Nicolas Coant, Wataru Sakamoto, Cungui Mao, Yusuf A Hannun
Over the past three decades, extensive research has been able to determine the biologic functions for the main bioactive sphingolipids, namely ceramide, sphingosine, and sphingosine 1-phosphate (S1P) (Hannun, 1996; Hannun et al., 1986; Okazaki et al., 1989). These studies have managed to define the metabolism, regulation, and function of these bioactive sphingolipids. This emerging body of literature has also implicated bioactive sphingolipids, particularly S1P and ceramide, as key regulators of cellular homeostasis...
October 11, 2016: Advances in Biological Regulation
Wohn-Jenn Leu, Sharada Prasanna Swain, She-Hung Chan, Jui-Ling Hsu, Shih-Ping Liu, Mei-Ling Chan, Chia-Chun Yu, Lih-Ching Hsu, Yen-Lin Chou, Wei-Ling Chang, Duen-Ren Hou, Jih-Hwa Guh
A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation...
October 19, 2016: Oncotarget
Shin-Ichi Inaba, Maki Goto, Kaoru Tanaka-Takanaka, Hisako Tanaka, Wataru Tomisato, Hiroshi Yuita, Hiromi Doi-Komuro, Ryotaku Inoue, Keiko Oshima, Takashi Kagari, Takaichi Shimozato, Takashi Izumi
The pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS-0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. M1, the phosphorylated active metabolite of CS-0777, is a selective sphingosine 1-phosphate receptor-1 modulator. A linear one-and two-compartment model with reversible metabolism process characterized the time courses of CS-0777 and M1 concentrations in rats and monkeys, respectively...
October 20, 2016: Biopharmaceutics & Drug Disposition
Salim S Hayek, Yuri Klyachkin, Ahmed Asfour, Nima Ghasemzadeh, Mosaab Awad, Iraj Hesaroieh, Hina Ahmed, Brandon Gray, Jinhee Kim, Edmund K Waller, Arshed A Quyyumi, Ahmed K Abdel-Latif
: : Bone marrow-derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) were quantified using mass spectrometry...
October 14, 2016: Stem Cells Translational Medicine
Shrestha Priyadarsini, Tina B McKay, Akhee Sarker-Nag, Jeremy Allegood, Charles Chalfant, Jian-Xing Ma, Dimitrios Karamichos
Prolonged hyperglycemia during diabetes mellitus can cause severe ophthalmic complications affecting both the anterior and posterior ocular segments leading to impaired vision or blindness. Diabetes-induced corneal pathologies are associated with decreased wound healing capacity, corneal edema, and altered epithelial basement membrane. The mechanism by which diabetes modulates structure and function within the corneal stroma are unknown. In our study, we characterized the effects of diabetes on extracellular matrix, lipid transport, and cellular metabolism by defining the entire metabolome and lipidome of Type 1 and Type 2 human diabetic corneal stroma...
October 11, 2016: Experimental Eye Research
Tao Tian, Weiliang Tian, Fan Yang, Risheng Zhao, Qian Huang, Yunzhao Zhao
BACKGROUND: Sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptors (S1PRs) signaling plays a key role in inflammatory responses. Lei et al. showed that SphK1 inhibition presented a hepatoprotective effect on acute liver damage via decreasing hepatic high-mobility group box 1 (HMGB1) cytoplasmic translocation. OBJECTIVE: We aim to determine whether SphK1 or S1PRs inhibition improves lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver failure by inhibiting the mitogen-activated protein kinases (MAPKs) pathway...
October 2016: United European Gastroenterology Journal
Béatrice Breart, Philippe Bousso
T cells are sequestered for several days in lymph nodes following antigen recognition but the precise mechanism regulating their timing of egress is not fully understood. In particular, whether interactions with antigen-presenting cells (APCs) and/or strength of the TCR stimulation shape T-cell residence time is unclear. We report here that the probability of T-cell egress decreases upon stimulation with high affinity TCR ligands. In contrast, low affinity peptides favor early egress, a phenomenon that could be reversed by sustaining antigen availability...
October 11, 2016: European Journal of Immunology
Sumanta K Pal, Harry A Drabkin, James A Reeves, John D Hainsworth, Susan E Hazel, Dario A Paggiarino, Jon Wojciak, Gary Woodnutt, Rupal S Bhatt
BACKGROUND: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent...
October 11, 2016: Cancer
Hai-Yun Xiao, Scott H Watterson, Charles M Langevine, Anurag S Srivastava, Soo S Ko, Yanlei Zhang, Robert Joseph Cherney, Weiwei Guo, John L Gilmore, James E Sheppeck, Dauh-Rurng Wu, Peng Li, Duraisamy Ramasamy, Pirama Nayagam Arunachalam, Arvind Mathur, Tracy L Taylor, David J Shuster, Kim W McIntyre, Ding Ren Shen, Melissa Yarde, Mary Ellen Cvijic, Anthony M Marino, Praveen V Balimane, Zheng Yang, Dana M Banas, Georgia Cornelius, Celia J D Arienzo, Bethanne M Warrack, Lois D Lehman-McKeeman, Luisa M Salter-Cid, Jenny H Xie, Joel C Barrish, Percy H Carter, Alaric J Dyckman, T G Murali Dhar
Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a non-selective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes...
October 11, 2016: Journal of Medicinal Chemistry
David L Ebenezer, Panfeng Fu, Vidyani Suryadevara, Yutong Zhao, Viswanathan Natarajan
Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes...
September 29, 2016: Advances in Biological Regulation
K Sugahara, Y Maeda, K Shimano, A Mogami, H Kataoka, K Ogawa, K Hikida, H Kumagai, M Asayama, T Yamamoto, T Harada, P Ni, S Inoue, A Kawaguchi
BACKGROUND AND PURPOSE: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia effects associated with fingolimod and other S1P receptor modulators. EXPERIMENTAL APPROACH: The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of the G-protein-coupled inwardly rectifying potassium (GIRK) channel in human atrial myocytes were assessed...
October 7, 2016: British Journal of Pharmacology
Fiorentina Roviezzo, Rosalinda Sorrentino, Valentina Mattera Iacono, Vincenzo Brancaleone, Michela Terlizzi, Maria Antonietta Riemma, Antonio Bertolino, Antonietta Rossi, Maria Matteis, Giuseppe Spaziano, Aldo Pinto, Bruno D'Agostino, Giuseppe Cirino
Compelling evidence suggests the involvement of sphingosine-1-phosphate (S1P) in the pathogenesis of asthma. The systemic administration of S1P causes asthma like features in the mouse involving mast cells. In this study we investigated whether disodium cromoglycate (DSCG), administered as a preventative treatment as in human therapy, could affect S1P effects on airways. BALB/c mice, treated with DSCG, received subcutaneous administration of S1P. Bronchi and pulmonary tissues were collected and functional, molecular and cellular studies were performed...
October 3, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Xiangru Wang, Ravi Maruvada, Andrew J Morris, Jun O Liu, Michael J Wolfgang, Dong Jae Baek, Robert Bittman, Kwang Sik Kim
Central nervous system (CNS) infection continues to be an important cause of mortality and morbidity, necessitating new approaches for investigating its pathogenesis, prevention and therapy. Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, which develops following penetration of the blood-brain barrier (BBB). By chemical library screening, we identified epidermal growth factor receptor (EGFR) as a contributor to E. coli invasion of the BBB in vitro. Here, we obtained the direct evidence that CNS-infecting E...
October 2016: PLoS Pathogens
Marguerite Mrad, Caroline Imbert, Virginie Garcia, Florian Rambow, Nicole Therville, Stéphane Carpentier, Bruno Ségui, Thierry Levade, Rania Azar, Jean-Christophe Marine, Mona Diab-Assaf, Céline Colacios, Nathalie Andrieu-Abadie
The infiltration of melanoma tumors by macrophages is often correlated with poor prognosis. However, the molecular signals that regulate the dialogue between malignant cells and the inflammatory microenvironment remain poorly understood. We previously reported an increased expression of sphingosine kinase-1 (SK1), which produces the bioactive lipid sphingosine 1-phosphate (S1P), in melanoma. The present study aimed at defining the role of tumor SK1 in the recruitment and differentiation of macrophages in melanoma...
September 30, 2016: Oncotarget
Hsing-Chuan Tsai, Yingxiang Huang, Christopher S Garris, Monica A Moreno, Christina W Griffin, May H Han
Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models...
June 16, 2016: JCI Insight
Katia Beider, Evgenia Rosenberg, Hanna Bitner, Avichai Shimoni, Merav Leiba, Maya Koren-Michowitz, Lena Ribakovsky, Shiri Klein, Devorah Olam, Hanna Wald, Lola Weiss, Michal Abraham, Eithan Galun, Amnon Peled, Arnon Nagler
PURPOSE: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the S1P pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with FTY720 modulator as a potential anti-MM therapeutic strategy. EXPERIMENTAL DESIGN AND RESULTS: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 co-expression in both cell lines and primary MM bone marrow samples, suggesting regulative cross-talk between CXCR4/CXCL12 and SPHK1 pathways in MM cells...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
A Łukomska, I Baranowska-Bosiacka, M Budkowska, A Pilutin, M Tarnowski, K Dec, B Dołęgowska, E Metryka, D Chlubek, I Gutowska
Sphingolipids are the main components of the lipid membrane. They also perform structural functions and participate in many signal transmission processes. One of the bioactive sphingolipids is sphingosine-1-phosphate (S1P), a ligand for five G protein-coupled receptors (S1PRs1-5), which can also act as an intracellular second messenger. S1P is responsible for the stimulation of progenitor cells in the brain, but it can also induce apoptosis of mature neurons. This study is aimed at assessing the effect of pre- and neonatal exposure to permissible Pb concentrations on S1P levels and S1PR1 (EDG1) expression in the prefrontal cortex, cerebellum, and hippocampus of rats...
January 2017: Chemosphere
Yang-Hee Kim, Yasuhiko Tabata
The objective of the present study is to evaluate the effects of the release patterns of stromal derived factor (SDF)-1 and sphingosine-1 phosphate agonist (SEW2871), used as MSC and macrophage recruitment agents, on the wound closure of diabetic mouse skin defects. To achieve different release patterns, hydrogels were prepared using two types of gelatin with isoelectric points (IEP) of 5 and 9, into which SDF-1 and SEW2871 were then incorporated in various combinations. When the hydrogels incorporating SDF-1 and SEW2871 were applied into wound defects of diabetic mice, the number of MSCs and macrophages recruited to the defects and the levels of pro- and anti- inflammatory cytokines were found to be dependent on the release profiles of SDF-1 and SEW2871...
October 3, 2016: Journal of Tissue Engineering and Regenerative Medicine
Diana I Sánchez, Bárbara González-Fernández, Beatriz San-Miguel, Juan Ortiz de Urbina, Irene Crespo, Javier González-Gallego, María J Tuñón
The sphingosine kinase (SphK)/sphingosine1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma (HCC), but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer. We investigated effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks...
October 1, 2016: Journal of Pineal Research
Y Maurice Morillon, Elizabeth Chase Lessey-Morillon, Matthew Clark, Rui Zhang, Bo Wang, Keith Burridge, Roland Tisch
The use of nondepleting Abs specific for CD4 and CD8 is an effective strategy to tolerize CD4(+) and CD8(+) T cells in a tissue-specific manner. We reported that coreceptor therapy reverses diabetes in new onset NOD mice. A striking feature of coreceptor-induced remission is the purging of T cells from the pancreatic lymph nodes (PLN) and islets of NOD mice. Evidence indicates that Abs binding to the coreceptors promotes T cell egress from these tissues. The present study examined how coreceptor therapy affects the migration of CD4(+) T cells residing in the PLN of NOD mice...
September 30, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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