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https://www.readbyqxmd.com/read/28101047/acute-anterior-uveitis-in-a-patient-taking-fingolimod-fty720-for-multiple-sclerosis
#1
Heather Gwen Mack, Melissa Chih-Hui Tien, Owen Bruce White
Fingolimod is an oral sphingosine-1-phosphate (S1P) receptor modulator and the first oral therapy for relapsing-remitting multiple sclerosis. Its use has been complicated by a low rate of cystoid macular edema usually in the first 3 months after commencement of the medication. We report the case of a 34-year-old male with relapsing-remitting multiple sclerosis, who developed acute anterior uveitis on day 5 of fingolimod treatment. He responded to appropriate treatment and cessation of drug, but developed low-grade chronic anterior uveitis without cystoid macular edema...
September 2016: Case Reports in Ophthalmology
https://www.readbyqxmd.com/read/28095439/intracranial-injection-of-dengue-virus-induces-interferon-stimulated-genes-and-cd8-t-cell-infiltration-by-sphingosine-kinase-1-independent-pathways
#2
Wisam H Al-Shujairi, Jennifer N Clarke, Lorena T Davies, Mohammed Alsharifi, Stuart M Pitson, Jillian M Carr
We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain...
2017: PloS One
https://www.readbyqxmd.com/read/28081222/at7867-inhibits-human-colorectal-cancer-cells-via-akt-dependent-and-akt-independent-mechanisms
#3
Shihu Zhang, Zhengming Deng, Chen Yao, Ping Huang, Yi Zhang, Shibing Cao, Xiangcheng Li
AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death...
2017: PloS One
https://www.readbyqxmd.com/read/28078995/sphingolipids-in-genetic-and-acquired-forms-of-chronic-kidney-diseases
#4
Norishi Ueda
Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs...
January 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28077289/vitamin-d3-protects-against-a%C3%AE-peptide-cytotoxicity-in-differentiated-human-neuroblastoma-sh-sy5y-cells-a-role-for-s1p1-p38mapk-atf4-axis
#5
Federica Pierucci, Mercedes Garcia-Gil, Alessia Frati, Francesca Bini, Maria Martinesi, Eleonora Vannini, Marco Mainardi, Federico Luzzati, Paolo Peretto, Matteo Caleo, Elisabetta Meacci
Besides its classical function of bone metabolism regulation, 1A,25-dihydroxyvitamin D3 (1,25(OH)2D3), acts on a variety of tissues including the nervous system, where the hormone plays an important role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactive lipids that play critical and complex roles in regulating cell fate. In the present paper we have investigated whether sphingolipids are involved in the protective action of 1,25(OH)2D3. We have found that 1,25(OH)2D3 prevents amyloid-β peptide (Aβ(1-42)) cytotoxicity both in differentiated SH-SY5Y human neuroblastoma cells and in vivo...
January 7, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28077266/asp0028-in-combination-with-suboptimal-dose-of-tacrolimus-in-cynomolgus-monkey-renal-transplantation-model
#6
Hao Dun, Lijun Song, Anlun Ma, Yanxin Hu, Lin Zeng, Jieying Bai, Guangzhou Zhang, Liangyan Zhang, Kumi Koide, Yohei Okada, Kaori Hanaoka, Rie Yamamoto, Jun Hirose, Tatsuaki Morokata, Pierre Daloze, Huifang Chen
FTY720, a S1P-receptor modulator, has shown to be effective in several transplant and autoimmune disease models, via modulating lymphocyte homing into secondary lymphoid organs (SLOs), and thereby reducing these cells in peripheral blood. ASP0028, a newly developed S1P1/S1P5-selective agonist, presented comparable efficacy to FTY720 and wider safety margins than FTY720. In this study, we assessed the efficacy and safety of ASP0028 co-administered with suboptimal-dose of tacrolimus in the Cynomolgus monkey renal transplantation model...
January 7, 2017: Transplant Immunology
https://www.readbyqxmd.com/read/28075451/the-role-of-sphingolipid-signalling-in-diabetes%C3%A2-associated-pathologies-review
#7
Mei Li Ng, Carol Wadham, Olga A Sukocheva
Sphingosine kinase (SphK) is an important signalling enzyme that catalyses the phosphorylation of sphingosine (Sph) to form sphingosine‑1‑phosphate (S1P). The multifunctional lipid, S1P binds to a family of five G protein-coupled receptors (GPCRs). As an intracellular second messenger, S1P activates key signalling cascades responsible for the maintenance of sphingolipid metabolism, and has been implicated in the progression of cancer, and the development of other inflammatory and metabolic diseases...
February 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28070865/sphingosine-1-phosphate-pretreatment-amends-hypoxia-induced-metabolic-dysfunction-and-impairment-of-myogenic-potential-in-differentiating-c2c12-myoblasts-by-stimulating-viability-calcium-homeostasis-and-energy-generation
#8
Babita Rahar, Sonam Chawla, Sanjay Pandey, Anant Narayan Bhatt, Shweta Saxena
Sphingosine-1-phosphate (S1P) has a role in transpiration in patho-physiological signaling in skeletal muscles. The present study evaluated the pre-conditioning efficacy of S1P in facilitating differentiation of C2C12 myoblasts under a normoxic/hypoxic cell culture environment. Under normoxia, exogenous S1P significantly promoted C2C12 differentiation as evident from morphometric descriptors and differentiation markers of the mature myotubes, but it could facilitate only partial recovery from hypoxia-induced compromised differentiation...
January 9, 2017: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/28054036/sphingosine-1-phosphate-in-the-lymphatic-fluid-determined-by-novel-methods
#9
Masayuki Nagahashi, Akimitsu Yamada, Tomoyoshi Aoyagi, Jeremy Allegood, Toshifumi Wakai, Sarah Spiegel, Kazuaki Takabe
BACKGROUND: Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates many physiological and pathological processes. It has been suggested that S1P gradient with high concentrations in the blood and lymphatic fluid and low concentrations in the peripheral tissue plays important roles in immune cell trafficking and potentially cancer progression. However, only a few reports have assessed S1P levels in the lymphatic fluid due to lack of an established easy-to-use method...
December 2016: Heliyon
https://www.readbyqxmd.com/read/28052056/genome-wide-in-vivo-screen-identifies-novel-host-regulators-of-metastatic-colonization
#10
Louise van der Weyden, Mark J Arends, Andrew D Campbell, Tobias Bald, Hannah Wardle-Jones, Nicola Griggs, Martin Del Castillo Velasco-Herrera, Thomas Tüting, Owen J Sansom, Natasha A Karp, Simon Clare, Diane Gleeson, Edward Ryder, Antonella Galli, Elizabeth Tuck, Emma L Cambridge, Thierry Voet, Iain C Macaulay, Kim Wong, Sanger Mouse Genetics Project, Sarah Spiegel, Anneliese O Speak, David J Adams
Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome...
January 4, 2017: Nature
https://www.readbyqxmd.com/read/28049734/sphingosine-and-sphingosine-kinase-1-involvement-in-endocytic-membrane-trafficking
#11
Santiago Lima, Sheldon Milstien, Sarah Spiegel
The balance between cholesterol and sphingolipids within the plasma membrane has long been implicated in endocytic membrane trafficking. However, in contrast to cholesterol functions, little is still known about the roles of sphingolipids and their metabolites. Perturbing the cholesterol/sphingomyelin balance was shown to induce narrow tubular plasma membrane invaginations enriched with sphingosine kinase 1 (SphK1), the enzyme that converts the bioactive sphingolipid metabolite sphingosine to sphingosine-1-phosphate (S1P), and suggested a role for sphingosine phosphorylation in endocytic membrane trafficking...
January 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28039439/hypothalamic-s1p-s1pr1-axis-controls-energy-homeostasis-in-middle-aged-rodents-the-reversal-effects-of-physical-exercise
#12
Vagner Ramon Rodrigues Silva, Carlos Kiyoshi Katashima, Carla G Bueno Silva, Luciene Lenhare, Thayana Oliveira Micheletti, Rafael Ludemann Camargo, Ana Carolina Ghezzi, Juliana Alves Camargo, Alexandre Moura Assis, Natalia Tobar, Joseane Morari, Daniela S Razolli, Leandro Pereira Moura, José Rodrigo Pauli, Dennys Esper Cintra, Lício Augusto Velloso, Mario J A Saad, Eduardo Rochete Ropelle
Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice...
December 26, 2016: Aging
https://www.readbyqxmd.com/read/28039158/inhibition-of-sphingosine-1-phosphate-signaling-ameliorates-murine-nonalcoholic-steatohepatitis
#13
Amy S Mauer, Petra Hirsova, Jessica L Maiers, Vijay H Shah, Harmeet Malhi
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a lipotoxic disorder, wherein proinflammatory lipids, such as ceramide and its derivative sphingosine 1-phosphate (S1P), contribute to macrophage-associated liver inflammation. For example, we have previously demonstrated a role for S1P in steatotic hepatocyte-derived S1P enriched extracellular vesicles in macrophage chemotaxis in vitro. Therefore, we hypothesized that FTY720, an S1P antagonist, would ameliorate NASH by inhibiting proinflammatory monocyte chemotaxis...
December 30, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28038379/high-density-lipoprotein-hdl-associated-sphingosine-1-phosphate-s1p-inhibits-macrophage-apoptosis-by-stimulating-stat3-activity-and-survivin-expression
#14
Renata Feuerborn, Susen Becker, Francesco Potì, Petra Nagel, Martin Brodde, Harmut Schmidt, Christina Christoffersen, Uta Ceglarek, Ralph Burkhardt, Jerzy-Roch Nofer
BACKGROUND AND AIMS: Macrophage apoptosis is critically involved in atherosclerosis. We here examined the effect of anti-atherogenic high density lipoprotein (HDL) and its component sphingosine-1-phosphate (S1P) on apoptosis in RAW264.7 murine macrophages. METHODS: Mitochondrial or endoplasmic reticulum-dependent apoptosis was induced by exposure of macrophages to etoposide or thapsigargin/fukoidan, respectively. RESULTS: Cell death induced by these compounds was inhibited by S1P as inferred from reduced annexin V binding, TUNEL staining, and caspase 3, 9 and 12 activities...
December 9, 2016: Atherosclerosis
https://www.readbyqxmd.com/read/28036019/lymph-nodes-and-cancer-metastasis-new-perspectives-on-the-role-of-intranodal-lymphatic-sinuses
#15
REVIEW
Rui-Cheng Ji
The lymphatic system is essential for transporting interstitial fluid, soluble antigen, and immune cells from peripheral tissues to lymph nodes (LNs). Functional integrity of LNs is dependent on intact lymphatics and effective lymph drainage. Molecular mechanisms that facilitate interactions between tumor cells and lymphatic endothelial cells (LECs) during tumor progression still remain to be identified. The cellular and molecular structures of LNs are optimized to trigger a rapid and efficient immune response, and to participate in the process of tumor metastasis by stimulating lymphangiogenesis and establishing a premetastatic niche in LNs...
December 28, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28035084/sphingosine-1-phosphate-receptor-modulators-and-drug-discovery
#16
REVIEW
Soo-Jin Park, Dong-Soon Im
Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P₁₋₅. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28026131/sphingosine-1-phosphate-receptor-3-supports-hematopoietic-stem-and-progenitor-cell-residence-within-the-bone-marrow-niche
#17
Molly E Ogle, Claire E Olingy, Anthony O Awojoodu, Anusuya Das, Rafael A Ortiz, Hoi Yin Cheung, Edward A Botchwey
Hematopoietic stem and progenitor cells (HSPCs) egress from bone marrow (BM) during homeostasis and at increased rates during stress; however, the mechanisms regulating their trafficking remain incompletely understood. Here we describe a novel role for lipid receptor, sphingosine-1-phosphate receptor 3 (S1PR3), in HSPC residence within the BM niche. HSPCs expressed increased levels of S1PR3 compared to differentiated BM cells. Pharmacological antagonism or knockout (KO) of S1PR3 mobilized HSPCs into blood circulation, suggesting that S1PR3 influences niche localization...
December 27, 2016: Stem Cells
https://www.readbyqxmd.com/read/28018969/hdl-activation-of-endothelial-sphingosine-1-phosphate-receptor-1-s1p1-promotes-regeneration-and-suppresses-fibrosis-in-the-liver
#18
Bi-Sen Ding, Catherine H Liu, Yue Sun, Yutian Chen, Steven L Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R Schwab, Shahin Rafii, Timothy Hla
Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28017639/selective-coupling-of-the-s1p3-receptor-subtype-to-s1p-mediated-rhoa-activation-and-cardioprotection
#19
Bryan S Yung, Cameron S Brand, Sunny Y Xiang, Charles B B Gray, Christopher K Means, Hugh Rosen, Jerold Chun, Nicole H Purcell, Joan Heller Brown, Shigeki Miyamoto
Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD...
December 23, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28013223/site-1-protease-is-required-for-the-generation-of-soluble-pro-renin-receptor
#20
Tsutomu Nakagawa, Chiharu Suzuki-Nakagawa, Akiko Watanabe, Eriko Asami, Mizuki Matsumoto, Mami Nakano, Akio Ebihara, Mohammad Nasir Uddin, Fumiaki Suzuki
The extracellular domain of the (pro)renin receptor [(P)RR] is cleaved to generate the soluble form of (P)RR [s(P)RR]. Multiple clinical studies have revealed the association between serum/plasma s(P)RR levels and certain diseases, thereby suggesting a potential role for s(P)RR as a disease biomarker. Here, we investigated whether site-1 protease (S1P) is responsible for cleaving (P)RR to generate s(P)RR. Reduction of endogenous S1P with siRNA attenuated s(P)RR generation in Chinese hamster ovary (CHO) cells exogenously expressing human (P)RR with a C-terminal decahistidine tag [CHO/h(P)RR-10His cells]; conversely, overexpression of S1P by transient transfection increased s(P)RR generation...
December 24, 2016: Journal of Biochemistry
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