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https://www.readbyqxmd.com/read/29663386/decreased-serum-levels-of-sphingomyelins-and-ceramides-in-sickle-cell-disease-patients
#1
Mutay Aslan, Ebru Kıraç, Sabriye Kaya, Filiz Özcan, Ozan Salim, Osman Alphan Küpesiz
Limited data are available on the serum levels of different sphingomyelin (CerPCho) and ceramide (CER) species in sickle-cell disease (SCD). This study was aimed at identifying the levels of C16-C24 CerPCho and C16-C24 CER in serum obtained from SCD patients and controls. Circulating levels of neutral sphingomyelinase (N-SMase) activity, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate (S1P) were also determined. Blood was collected from 35 hemoglobin (Hb)A volunteers and 45 homozygous HbSS patients...
April 16, 2018: Lipids
https://www.readbyqxmd.com/read/29662200/targeting-sphingosine-1-phosphate-lyase-as-an-anabolic-therapy-for-bone-loss
#2
Sarah Weske, Mithila Vaidya, Alina Reese, Karin von Wnuck Lipinski, Petra Keul, Julia K Bayer, Jens W Fischer, Ulrich Flögel, Jens Nelsen, Matthias Epple, Marta Scatena, Edzard Schwedhelm, Marcus Dörr, Henry Völzke, Eileen Moritz, Anke Hannemann, Bernhard H Rauch, Markus H Gräler, Gerd Heusch, Bodo Levkau
Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38-GSK3β-β-catenin and WNT5A-LRP5 pathways...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29662189/akt-as-a-key-target-for-growth-promoting-functions-of-neutral-ceramidase-in-colon-cancer-cells
#3
Nicolas Coant, Mónica García-Barros, Qifeng Zhang, Lina M Obeid, Yusuf A Hannun
Despite advances in the field, colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Research into bioactive sphingolipids over the past two decades has played an important role in increasing our understanding of the pathogenesis and therapeutics of CRC. In the complex metabolic network of sphingolipids, ceramidases (CDases) have a key function. These enzymes hydrolyze ceramides into sphingosine (SPH) which in turn is phosphorylated by sphingosine kinases (SK) 1 and 2 to generate sphingosine-1 phosphate (S1P)...
April 17, 2018: Oncogene
https://www.readbyqxmd.com/read/29660940/age-dependent-changes-to-sphingolipid-balance-in-the-human-hippocampus-are-gender-specific-and-may-sensitize-to-neurodegeneration
#4
Timothy A Couttas, Nupur Kain, Collin Tran, Zac Chatterton, John B Kwok, Anthony S Don
The greatest risk factor for developing Alzheimer's disease (AD) is aging. The major genetic risk factor for AD is the ɛ4 allele of the APOE gene, encoding the brain's major lipid transport protein, apolipoprotein E (ApoE). The research community is yet to decipher why the ApoE4 variant pre-disposes to AD, and how aging causes the disease. Studies have shown deregulated levels of sphingolipids, including decreased levels of the neuroprotective signaling lipid sphingosine 1-phosphate (S1P), and increased ceramide content, in brain tissue and serum of people with pre-clinical or very early AD...
April 11, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29643998/deletion-of-sphingosine-kinase-1-inhibits-liver-tumorigenesis-in-diethylnitrosamine-treated-mice
#5
Jinbiao Chen, Yanfei Qi, Yang Zhao, Dominik Kaczorowski, Timothy A Couttas, Paul R Coleman, Anthony S Don, Patrick Bertolino, Jennifer R Gamble, Mathew A Vadas, Pu Xia, Geoffrey W McCaughan
Primary liver cancer is the 3rd leading cause of cancer deaths worldwide with very few effective treatments. Sphingosine kinase 1 (SphK1), a key regulator of sphingolipid metabolites, is over-expressed in human hepatocellular carcinoma (HCC) and our previous studies have shown that SphK1 is important in liver injury. We aimed to explore the role of SphK1 specifically in liver tumorigenesis using the SphK1 knockout ( SphK1 -/- ) mouse. SphK1 deletion significantly reduced the number and the size of DEN-induced liver cancers in mice...
March 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29643855/targeting-sphingosine-kinase-isoforms-effectively-reduces-growth-and-survival-of-neoplastic-mast-cells-with-d816v-kit
#6
Geethani Bandara, Rosa Muñoz-Cano, Araceli Tobío, Yuzhi Yin, Hirsh D Komarow, Avanti Desai, Dean D Metcalfe, Ana Olivera
Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29624476/immunotherapy-in-inflammatory-bowel-disease-novel-and-emerging-treatments
#7
Ignacio Catalan-Serra, Øystein Brenna
Inflammatory bowel disease (IBD) is a chronic disabling inflammatory process that affects young individuals, with growing incidence. The etiopathogenesis of IBD remains poorly understood. A combination of genetic and environmental factors triggers an inadequate immune response against the commensal intestinal flora in IBD patients. Thus, a better understanding of the immunological mechanisms involved in IBD pathogenesis is central to the development of new therapeutic options. Current pharmacological treatments used in clinical practice like thiopurines or anti-TNF are effective but can produce significant side effects and their efficacy may diminish over time...
April 6, 2018: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29623068/nuclear-insulin-like-growth-factor-binding-protein-3-as-a-biomarker-in-triple-negative-breast-cancer-xenograft-tumors-effect-of-targeted-therapy-and-comparison-with-chemotherapy
#8
Sohel M Julovi, Janet L Martin, Robert C Baxter
Triple-negative breast cancer (TNBC) typically has a worse outcome than other breast cancer subtypes, in part owing to a lack of approved therapeutic targets or prognostic markers. We have previously described an oncogenic pathway in basal-like TNBC cells, initiated by insulin-like growth factor binding protein-3 (IGFBP-3), in which the epidermal growth factor receptor (EGFR) is transactivated by sphingosine-1-phosphate (S1P) resulting from sphingosine kinase (SphK)-1 activation. Oncogenic IGFBP-3 signaling can be targeted by combination treatment with the S1P receptor modulator and SphK inhibitor, fingolimod, and the EGFR kinase inhibitor, gefitinib (F + G)...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29615132/neuronal-sphingosine-kinase-2-subcellular-localization-is-altered-in-alzheimer-s-disease-brain
#9
Gaëlle Dominguez, Marie-Lise Maddelein, Mélanie Pucelle, Yvan Nicaise, Claude-Alain Maurage, Charles Duyckaerts, Olivier Cuvillier, Marie-Bernadette Delisle
BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Aβ accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro-survival S1P in AD neurons...
April 3, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29610123/probing-de-novo-sphingolipid-metabolism-in-mammalian-cells-utilizing-mass-spectrometry
#10
Justin M Snider, Ashley J Snider, Lina M Obeid, Chiara Luberto, Yusuf A Hannun
Sphingolipids constitute a dynamic metabolic network that interconnects several bioactive molecules, including ceramide (Cer), sphingosine (Sph), sphingosine 1-phosphate (S1P), and ceramide 1-phosphate (C1P). The interconversion of these metabolites is controlled by a cohort of at least 40 enzymes, many of which respond to endogenous or exogenous stimuli. Typical probing of the sphingolipid pathway relies on sphingolipid mass levels or determination of the activity of individual enzymes. Either approach is unable to provide a complete analysis of flux through sphingolipid metabolism, which, given the interconnectivity of the sphingolipid pathway, is critical information to identify nodes of regulation...
April 2, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29609002/angiotensin-ii-facilitates-neointimal-formation-by-increasing-vascular-smooth-muscle-cell-migration-involvement-of-ape-ref-1-mediated-overexpression-of-sphingosine-1-phosphate-receptor-1
#11
Dong-Youb Lee, Kyung-Jong Won, Kang Pa Lee, Seung Hyo Jung, Suji Baek, Hyun Woo Chung, Wahn Soo Choi, Hwan Myung Lee, Byeong Han Lee, Byeong Hwa Jeon, Bokyung Kim
Angiotensin II (Ang II) is implicated in the development of cardiovascular disorders including hypertension and atherosclerosis. However, the role of Ang II in the interaction between apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) and sphingosine-1-phosphate (S1P) signals in relation to vascular disorders remains to be clarified. This study aimed to determine whether APE/Ref-1 plays a role in epigenetic regulation of the S1P receptor (S1PR) in response to Ang II in vascular smooth muscle cell (VSMC) migration and vascular neointima formation...
March 30, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29608575/ozanimod-rpc1063-a-selective-s1pr1-and-s1pr5-modulator-reduces-chronic-inflammation-and-alleviates-kidney-pathology-in-murine-systemic-lupus-erythematosus
#12
Kristen R Taylor Meadows, Marcos W Steinberg, Bryan Clemons, Matthew E Stokes, Gregory J Opiteck, Robert Peach, Fiona L Scott
Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus...
2018: PloS One
https://www.readbyqxmd.com/read/29605826/triple-negative-breast-cancer-depends-on-sphingosine-kinase-1-sphk1-sphingosine-1-phosphate-s1p-sphingosine-1-phosphate-receptor-3-s1pr3-notch-signaling-for-metastasis
#13
Shushu Wang, Yueyang Liang, Wenxiao Chang, Baoquan Hu, Yi Zhang
BACKGROUND Triple negative breast cancer (TNBC) has a more aggressive recurrence. Previous reports have demonstrated that sphingosine kinase 1 (SphK1) is a crucial regulator of breast cancer progression. However, the correlation of SphK1 with clinical prognosis has been poorly investigated. Thus, we aimed to elaborate the role of SphK1 in TNBC metastasis. MATERIAL AND METHODS We first determined the level of SphK1 in breast cancer tissue samples and breast cancer cells. Furthermore, the expression of HER2 and phosphor-SphK1 (pSphK1) in human breast cancer tissue samples was determined by immunohistochemical analysis...
April 1, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29576505/siponimod-versus-placebo-in-secondary-progressive-multiple-sclerosis-expand-a-double-blind-randomised-phase-3-study
#14
Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, Robert J Fox, Gavin Giovannoni, Ralf Gold, Patrick Vermersch, Douglas L Arnold, Sophie Arnould, Tatiana Scherz, Christian Wolf, Erik Wallström, Frank Dahlke
BACKGROUND: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. METHODS: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries...
March 22, 2018: Lancet
https://www.readbyqxmd.com/read/29572542/aryl-hydrocarbon-receptor-signaling-promotes-ormdl3-dependent-generation-of-sphingosine-1-phosphate-by-inhibiting-sphingosine-1-phosphate-lyase
#15
Hsueh-Chun Wang, Tzu-Hsuan Wong, Li-Ting Wang, Hsiang-Han Su, Hsiu-Yueh Yu, Ai-Hsuan Wu, Yu-Chun Lin, Hua-Ling Chen, Jau-Ling Suen, Shih-Hsien Hsu, Li-Chen Chen, Yufeng Zhou, Shau-Ku Huang
Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge...
March 23, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29567661/quality-control-of-serum-and-plasma-by-quantification-of-4e-14z-sphingadienine-c18-1-phosphate-uncovers-common-preanalytical-errors-during-handling-of-whole-blood
#16
Xinyu Liu, Miriam Hoene, Peiyuan Yin, Louise Fritsche, Peter Plomgaard, Jakob S Hansen, Christos T Nakas, Andreas M Niess, Jens Hudemann, Michael Haap, Maimuna Mendy, Cora Weigert, Xiaolin Wang, Andreas Fritsche, Andreas Peter, Hans-Ulrich Häring, Guowang Xu, Rainer Lehmann
BACKGROUND: Nonadherence to standard operating procedures (SOPs) during handling and processing of whole blood is one of the most frequent causes affecting the quality of serum and plasma. Yet, the quality of blood samples is of the utmost importance for reliable, conclusive research findings, valid diagnostics, and appropriate therapeutic decisions. METHODS: UHPLC-MS-driven nontargeted metabolomics was applied to identify biomarkers that reflected time to processing of blood samples, and a targeted UHPLC-MS analysis was used to quantify and validate these biomarkers...
March 22, 2018: Clinical Chemistry
https://www.readbyqxmd.com/read/29563527/mfsd2b-is-a-sphingosine-1-phosphate-transporter-in-erythroid-cells
#17
Naoki Kobayashi, Shoko Kawasaki-Nishi, Masato Otsuka, Yu Hisano, Akihito Yamaguchi, Tsuyoshi Nishi
Sphingosine 1-phosphate (S1P) is an intercellular signaling molecule present in blood. Erythrocytes have a central role in maintaining the S1P concentration in the blood stream. We previously demonstrated that S1P is exported from erythrocytes by a glyburide-sensitive S1P transporter. However, the gene encoding the S1P transporter in erythrocytes is unknown. In this study, we found that the mouse erythroid cell line, MEDEP-E14, has S1P export activity and exhibits properties that are consistent with those of erythrocytes...
March 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29561262/the-signaling-lipid-sphingosine-1-phosphate-regulates-mechanical-pain
#18
Rose Z Hill, Benjamin U Hoffman, Takeshi Morita, Stephanie M Campos, Ellen A Lumpkin, Rachel B Brem, Diana M Bautista
Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli...
March 21, 2018: ELife
https://www.readbyqxmd.com/read/29559169/the-s1p-axis-new-exciting-route-for-treating-huntington-s-disease
#19
REVIEW
Alba Di Pardo, Vittorio Maglione
Huntington's disease (HD) is a single-gene inheritable neurodegenerative disorder with an associated complex molecular pathogenic profile that renders it the most 'curable incurable' brain disorder. Continuous effort in the field has contributed to the recent discovery of novel potential pathogenic mechanisms. Findings in preclinical models of the disease as well as in human post-mortem brains from affected patients demonstrate that alteration of the sphingosine-1-phosphate (S1P) axis may represent a possible key player in the pathogenesis of the disease and may act as a potential actionable drug target for the development of more targeted and effective therapeutic approaches...
March 17, 2018: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29556726/new-treatment-options-for-inflammatory-bowel-diseases
#20
REVIEW
Bram Verstockt, Marc Ferrante, Séverine Vermeire, Gert Van Assche
The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn's disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al...
March 19, 2018: Journal of Gastroenterology
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