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https://www.readbyqxmd.com/read/28231640/mind-the-gap-mechanisms-regulating-the-endothelial-barrier
#1
REVIEW
Mariya Y Radeva, Jens Waschke
The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sieve-like manner. Both types of barrier-forming junctions, i.e. the adherens junction (AJ) serving mechanical anchorage and mechanotransduction and the tight junction (TJ) sealing the intercellular space to limit paracelullar permeability, are tethered to the actin cytoskeleton. Under resting conditions, the endothelium thereby builds a selective layer controlling the exchange of fluid and solutes with the surrounding tissue...
February 23, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28231433/discovery-of-a-potent-and-selective-sphingosine-kinase-1-inhibitor-through-the-molecular-combination-of-chemotype-distinct-screening-hits
#2
Mark E Schnute, Matthew D McReynolds, Jeffrey Carroll, Jill E Chrencik, Maureen K Highkin, Kaliapan Iyanar, Gina Jerome, John W Rains, Matthew Saabye, Jeffrey A Scholten, Matthew Yates, Marek M Nagiec
Sphingosine kinase (SphK) is the major source of the lipid mediator and GPCR agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with two orders of magnitude improved potency...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28224210/tumor-specific-regulatory-t-cells-in-the-bone-marrow-of-breast-cancer-patients-selectively-upregulate-the-emigration-receptor-s1p1
#3
Anchana Rathinasamy, Christoph Domschke, Yingzi Ge, Hans-Henning Böhm, Steffen Dettling, David Jansen, Felix Lasitschka, Ludmila Umansky, Markus H Gräler, Jennifer Hartmann, Christel Herold-Mende, Florian Schuetz, Philipp Beckhove
Regulatory T cells (Treg) hamper anti-tumor T-cell responses resulting in reduced survival and failure of cancer immunotherapy. Among lymphoid organs, the bone marrow (BM) is a major site of Treg residence and recirculation. However, the process governing the emigration of Treg from BM into the circulation remains elusive. We here show that breast cancer patients harbour reduced Treg frequencies in the BM as compared to healthy individuals or the blood. This was particularly the case for tumor antigen-specific Treg which were quantified by MHCII tumor peptide loaded tetramers...
February 21, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28218904/the-protumorigenic-potential-of-fty720-by-promoting-extramedullary-hematopoiesis-and-mdsc-accumulation
#4
Y Li, T Zhou, Y Wang, C Ning, Z Lv, G Han, J C Morris, E N Taylor, R Wang, H Xiao, C Hou, Y Ma, B Shen, J Feng, R Guo, Y Li, G Chen
FTY720 (also called fingolimod) is recognized as an immunosuppressant and has been approved by the Food and Drug Administration to treat refractory multiple sclerosis. However, long-term administration of FTY720 potentially increases the risk for cancer in recipients. The underlying mechanisms remain poorly understood. Herein, we provided evidence that FTY720 administration potentiated tumor growth. Mechanistically, FTY720 enhanced extramedullary hematopoiesis and massive accumulation of myeloid-derived suppressor cells (MDSCs), which actively suppressed antitumor immune responses...
February 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28211170/endothelial-glycocalyx-as-a-critical-signalling-platform-integrating-the-extracellular-haemodynamic-forces-and-chemical-signalling
#5
REVIEW
Ye Zeng
The glycocalyx covers the human mammalian cells and plays important roles in stroke, inflammation and atherosclerosis. It has also been shown to be involved in endothelial mechanotransduction of shear stress. Shear stress induces the remodelling of the major component of the glycocalyx including glypican-1, a cell membrane heparan sulphate proteoglycan. Other factors, such as sphingosine-1-phosphate (S1P), protect the glycocalyx against syndecan-1 ectodomain shedding and induce the synthesis of heparan sulphate...
February 17, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28209174/mouse-genomic-screen-reveals-novel-host-regulator-of-metastasis
#6
Toni Celià-Terrassa, Yibin Kang
Tumor cells have to overcome challenges in the host tissue microenvironment to metastasize successfully to distant organs. In a recent Nature study, a genome-wide functional screen demonstrated that deficiency of the sphingosine-1-phoshate (S1P) transporter gene Spns2 in endothelium increased immune-mediated cell killing by T cells and natural killer (NK) cells, thereby suppressing metastatic colonization.
February 16, 2017: Genome Biology
https://www.readbyqxmd.com/read/28205387/fructose-down-regulates-mir-330-to-induce-renal-inflammatory-response-and-insulin-signaling-impairment-attenuation-by-morin
#7
Ting-Ting Gu, Lin Song, Tian-Yu Chen, Xin Wang, Xiao-Juan Zhao, Xiao-Qin Ding, Yan-Zi Yang, Ying Pan, Dong-Mei Zhang, Ling-Dong Kong
SCOPE: Fructose induces insulin resistance with kidney inflammation and injury. MicroRNAs (miRNAs) are emerged as key regulators of insulin signaling. Morin has insulin-mimetic effect with the improvement of insulin resistance and kidney injury. This study investigated the protective mechanisms of morin against fructose-induced kidney injury, with particular focus on miR-330 expression change, inflammatory response and insulin signaling impairment. METHODS AND RESULTS: miR-330, sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR)1/3 signaling, NF-κB/NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and insulin signaling were detected in kidney cortex of fructose-fed rats and fructose-exposed HK-2 cells, respectively...
February 16, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28198542/ceramide-synthase-2-facilitates-s1p-dependent-egress-of-thymocytes-into-the-circulation-in-mice
#8
Michael Rieck, Christiane Kremser, Katarzyna Jobin, Elisabeth Mettke, Christian Kurts, Markus Gräler, Klaus Willecke, Waldemar Kolanus
Well-defined gradients of the lipid mediator sphingosine-1-phosphate (S1P) direct chemotactic egress of mature thymocytes from the thymus into the circulation. Although it is known that these gradients result from low S1P levels in the thymic parenchyma and high S1P concentrations at the exit sites and in the plasma, the biochemical mechanisms that regulate these differential S1P levels remain unclear. Several studies demonstrated that ceramide synthase 2 (Cers2) regulates the levels of the S1P precursor sphingosine...
February 15, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28191815/bladder-cancer-cell-growth-and-motility-implicate-cannabinoid-2-receptor-mediated-modifications-of-sphingolipids-metabolism
#9
Arianna Bettiga, Massimo Aureli, Giorgia Colciago, Valentina Murdica, Marco Moschini, Roberta Lucianò, Daniel Canals, Yusuf Hannun, Petter Hedlund, Giovanni Lavorgna, Renzo Colombo, Rosaria Bassi, Maura Samarani, Francesco Montorsi, Andrea Salonia, Fabio Benigni
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28191010/role-of-dietary-metabolites-in-regulating-the-host-immune-response-in-gastrointestinal-disease
#10
REVIEW
Mohamad El-Zaatari, John Y Kao
The host immune response to gastrointestinal (GI) infections, hypersensitivity reactions, or GI cancers comprises numerous pathways that elicit responses on different host cells. Some of these include (1) the stimulation of mast cells via their IgE receptor, (2) the production of antibodies leading to antibody-mediated cytotoxic T/natural killer cell killing, (3) the activation of the complement pathway, and (4) the activation of the adaptive immune response via antigen-presenting cell, T cell, and B cell interactions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28188805/sphingosine-1-phosphate-signaling-axis-mediates-fibroblast-growth-factor-2-induced-proliferation-and-survival-of-murine-auditory-neuroblasts
#11
Marina Bruno, Ilaria Maria Rizzo, Ricardo Romero-Guevara, Caterina Bernacchioni, Francesca Cencetti, Chiara Donati, Paola Bruni
Hearing loss affects millions of people in the world. In mammals the auditory system comprises diverse cell types which are terminally differentiated and with no regenerative potential. There is a tremendous research interest aimed at identifying cell therapy based solutions or pharmacological approaches that could be applied therapeutically alongside auditory devices to prevent hair cell and neuron loss. Sphingosine 1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that plays key role in the regulation of many physiological and pathological functions...
February 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28188148/analysis-of-sphingolipids-in-human-corneal-fibroblasts-from-normal-and-keratoconus-patients
#12
Hui Qi, Shrestha Priyadarsini, Sarah E Nicholas, Akhee Sarker-Nag, Jeremy Allegood, Charles E Chalfant, Nawajes A Mandal, Dimitrios Karamichos
The pathophysiology of human keratoconus (KC), a bilateral progressive corneal disease, leading to protrusion of the cornea, stromal thinning, and scarring is not well understood. In this study we investigated a novel Sphingolipid (SPL) signaling pathway through which KC may be regulated. Using human corneal fibroblasts (HCF) and human keratoconus cells (HKC) we examined the SPL pathway modulation. Both cell types were stimulated by the three TGF-β isoforms: TGF-B1 (T1), B2 (T2), and B3 (T3). All samples were analyzed using lipidomics, and real time-PCR...
February 10, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28181337/deficiency-of-the-sphingosine-1-phosphate-lyase-sgpl1-is-associated-with-congenital-nephrotic-syndrome-and-congenital-adrenal-calcifications
#13
Andreas R Janecke, Ruijuan Xu, Elisabeth Steichen-Gersdorf, Siegfried Waldegger, Andreas Entenmann, Thomas Giner, Iris Krainer, Lukas A Huber, Michael W Hess, Yaacov Frishberg, Hila Barash, Shay Tzur, Nira Schreyer-Shafir, Rivka Sukenik-Halevy, Tania Zehavi, Annick Raas-Rothschild, Cungui Mao, Thomas Müller
We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1 encoding sphingosine-1-phosphate lyase 1...
February 8, 2017: Human Mutation
https://www.readbyqxmd.com/read/28181168/apoa-i-sr-bi-modulates-s1p-s1pr2-mediated-inflammation-through-the-pi3k-akt-signaling-pathway-in-huvecs
#14
Kun Ren, Yan-Ju Lu, Zhong-Cheng Mo, Xing -Liu, Zhen-Li Tang, Yue Jiang, Xiao-Shan Peng, Li Li, Qing-Hai Zhang, Guang-Hui Yi
Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway...
February 8, 2017: Journal of Physiology and Biochemistry
https://www.readbyqxmd.com/read/28179022/hdl-associated-apom-is-anti-apoptotic-by-delivering-sphingosine-1-phosphate-to-s1p1-s1p3-receptors-on-vascular-endothelium
#15
Mario Ruiz, Hiromi Okada, Björn Dahlbäck
BACKGROUND: High-density Lipoprotein (HDL) attenuates endothelial cell apoptosis induced by different cell-death stimuli such as oxidation or growth factor deprivation. HDL is the main plasma carrier of the bioactive lipid sphingosine 1-phosphate (S1P), which it is a signaling molecule that promotes cell survival in response to several apoptotic stimuli. In HDL, S1P is bound to Apolipoprotein M (ApoM), a Lipocalin that is only present in around 5% of the HDL particles. The goal of this study is to characterize ApoM-bound S1P role in endothelial apoptosis protection and the signaling pathways involved...
February 8, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/28178265/computational-investigation-of-sphingosine-kinase-1-sphk1-and-calcium-dependent-erk1-2-activation-downstream-of-vegfr2-in-endothelial-cells
#16
Hojjat Bazzazi, Aleksander S Popel
Vascular endothelial growth factor (VEGF) is a powerful regulator of neovascularization. VEGF binding to its cognate receptor, VEGFR2, activates a number of signaling pathways including ERK1/2. Activation of ERK1/2 is experimentally shown to involve sphingosine kinase 1 (SphK1) activation and its calcium-dependent translocation downstream of ERK1/2. Here we construct a rule-based computational model of signaling downstream of VEGFR2, by including SphK1 and calcium positive feedback mechanisms, and investigate their consequences on ERK1/2 activation...
February 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28172868/p369-safety-and-lymphocyte-lowering-properties-of-etrasimod-apd334-an-oral-potent-next-generation-selective-s1p-receptor-modulator-after-dose-escalation-in-healthy-volunteers
#17
L Peyrin-Biroulet, R Christopher, L Trokan, C Lassen, J Adams, T Kühbacher
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28172682/dop077-immunomodulatory-effects-of-etrasimod-apd334-an-oral-potent-next-generation-selective-s1p-receptor-modulator
#18
S D Lee, R Christopher, L Trokan, C Lassen, J Adams, M Chiorean
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28172412/dop078-pharmacology-and-safety-of-etrasimod-apd334-an-oral-potent-next-generation-selective-s1p-receptor-modulator
#19
T Kühbacher, R Christopher, L Trokan, C Lassen, J Adams, L Peyrin-Biroulet
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28168246/probing-the-origins-of-vibrational-mode-specificity-in-intramolecular-dynamics-through-picosecond-time-resolved-photoelectron-imaging-studies
#20
Julia A Davies, Laura E Whalley, Katharine L Reid
We have studied the intramolecular dynamics induced by selective photoexcitation of two near-isoenergetic vibrational states in S1p-fluorotoluene using picosecond time-resolved photoelectron imaging. We find that similar dynamics ensue following the preparation of the 13(1)1(1) and 7a(1)1(1) states that lie at 1990 cm(-1) and 2026 cm(-1), and that these dynamics are mediated by a single strongly coupled doorway state in each case. However, the lifetimes differ by a factor of three, suggesting an influence of the vibrational character of the modes involved...
February 7, 2017: Physical Chemistry Chemical Physics: PCCP
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