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Julika Pitsch, Julia C Kuehn, Vadym Gnatkovsky, Johannes Alexander Müller, Karen M J van Loo, Marco de Curtis, Hartmut Vatter, Susanne Schoch, Christian E Elger, Albert J Becker
Temporal lobe epilepsy (TLE) represents a devastating neurological condition, in which approximately 4/5 of patients remain refractory for anti-convulsive drugs. Epilepsy surgery biopsies often reveal the damage pattern of "hippocampal sclerosis" (HS) characterized not only by neuronal loss but also pronounced astrogliosis and inflammatory changes. Since TLE shares distinct pathogenetic aspects with multiple sclerosis (MS), we have here scrutinized therapeutic effects in experimental TLE of the immunmodulator fingolimod, which is established in MS therapy...
June 22, 2018: Molecular Neurobiology
Abudureyimujiang Aili, Jie Zhang, Jia Wu, Haoming Wu, Xiuyuan Sun, Qihua He, Rong Jin, Yu Zhang
The signal mediated by sphingosine-1-phosphate receptor 1 (S1P1) is essential but seemingly insufficient for thymic export of newly generated T cells. Here, we reported the identification of CCR2 as an additional regulator of this process. CCR2 showed a markedly increased expression in the most mature subset of single-positive (SP) thymocytes. Its deficiency led to a reduction of recent thymic emigrants in the periphery and a simultaneous accumulation of mature SP cells in the thymus. The CCR2 signaling promoted thymic emigration primarily through modulating the chemotactic responses to S1P1 engagement...
2018: Frontiers in Immunology
Chunyan Xu, Wenlu Zhang, Shiquan Liu, Wenhong Wu, Mengbin Qin, Jiean Huang
Sphingosine kinase 1 (SphK1) is a master kinase that catalyzes the synthesis of sphingosine 1 phosphate and participates in the regulation of cell proliferation and autophagy. The present study aimed to assess the effects of the activation of the SphK1/extracellular signal-regulated kinase (ERK)/phosphorylated (p-)ERK pathway in the regulation of autophagy in colon cancer (HT-29) cells. Inverted fluorescence microscopy was used to detect the expression of green fluorescent protein (GFP) in the SphK1-overexpressing HT-29 cells [SphK1(+)-HT-29] and the negative control HT-29 cells (NC-HT-29)...
June 2018: Oncology Letters
Fu-Ju Lei, Bi-Hua Cheng, Pei-Yin Liao, Hsiao-Ching Wang, Wei-Chun Chang, Hsueh-Chou Lai, Juan-Cheng Yang, Yang-Chang Wu, Li-Ching Chu, Wen-Lung Ma
Sphingosine-1-phosphate (S1P) is a bioactive lipid that exerts various pathophysiological functions through binding to its receptor family (S1PRs). Since first report of the breast cancer (BCA) promoting function by S1P production (through the function of sphingosine kinases) and S1P/S1PR signaling, their antagonists have never been successfully progress to clinics after three decades. Taking advantage of bioinformatics linking to gene expression to disease prognosis, we examined the impact of associated genes in BCA patients...
June 20, 2018: Cancer Medicine
Elena Guzzolino, Elena Chiavacci, Neha Ahuja, Laura Mariani, Monica Evangelista, Chiara Ippolito, Milena Rizzo, Deborah Garrity, Federico Cremisi, Letizia Pitto
Sphingosine-1-phosphate is a bioactive lipid and a signaling molecule integrated into many physiological systems such as differentiation, proliferation and migration. In mammals S1P acts through binding to a family of five trans-membrane, G-protein coupled receptors (S1PRs) whose complex role has not been completely elucidated. In this study we use zebrafish, in which seven s1prs have been identified, to investigate the role of s1pr1 . In mammals S1PR1 is the most highly expressed S1P receptor in the developing heart and regulates vascular development, but in zebrafish the data concerning its role are contradictory...
2018: Frontiers in Cell and Developmental Biology
Dong Kyu Lee, Young Sil Min, Seong Su Yoo, Hyun Sub Shim, Sun Young Park, Uy Dong Sohn
A comprehensive collection of proteins senses local changes in intracellular Ca2+ concentrations ([Ca2+ ]i ) and transduces these signals into responses to agonists. In the present study, we examined the effect of sphingosine-1-phosphate (S1P) on modulation of intracellular Ca2+ concentrations in cat esophageal smooth muscle cells. To measure [Ca2+ ]i levels in cat esophageal smooth muscle cells, we used a fluorescence microscopy with the Fura-2 loading method. S1P produced a concentration-dependent increase in [Ca2+ ]i in the cells...
June 19, 2018: Biomolecules & Therapeutics
Marta Budkowska, Ewa Ostrycharz, Adrianna Wojtowicz, Zuzanna Marcinowska, Jarosław Woźniak, Mariusz Z Ratajczak, Barbara Dołęgowska
The number of hematopoietic stem/progenitor cells (HSPCs) circulating in peripheral blood (PB) is regulated by a circadian rhythm, and more HSPCs circulate in PB in the morning hours than at night. Different mechanisms have been proposed that might regulate this process, including changes in tonus of β-adrenergic innervation of bone marrow (BM) tissue. Our group reported that in mice circadian changes in the number of HSPCs circulating in PB correlates with diurnal activation of the complement cascade (ComC) and that the mice deficient in C5 component of ComC (C5-KO mice) do not show circadian changes in the number of circulating HSPCs in PB...
June 17, 2018: Stem Cell Reviews
Julian Fink, Jürgen Seibel
Sphingolipids and glycosphingolipids can regulate cell recognition and signalling. Ceramide and sphingosine-1-phosphate are major players in the sphingolipid pathways and are involved in the initiation and regulation of signalling, apoptosis, stress responses and infection. Specific chemically synthesized sphingolipid derivatives containing small functionalities like azide or alkyne can mimic the biological properties of natural lipid species, which turns them into useful tools for the investigation of the highly complex sphingolipid metabolism by rapid and selective "click chemistry" using sensitive tags like fluorophores...
June 1, 2018: Biological Chemistry
Jung-Chien Cheng, Evan Y Wang, Yuyin Yi, Avinash Thakur, Shu-Huei Tsai, Pamela A Hoodless
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway; that ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined...
June 14, 2018: Molecular Cancer Research: MCR
Jeffrey W Meeusen, Leslie J Donato, Sandra C Bryant, Linnea M Baudhuin, Peter B Berger, Allan S Jaffe
OBJECTIVE: Ceramides are sphingolipids involved with cellular signaling. Synthesis of ceramides occurs in all tissues. Ceramides accumulate within tissues and the blood plasma during metabolic dysfunction, dyslipidemia, and inflammation. Elevations of ceramides are predictive of cardiovascular mortality. We sought to verify the utility of plasma concentrations of 4 ceramides: N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)], and N-lignoceroyl-sphingosine [Cer(24:0)] in predicting major adverse cardiovascular events in a diverse patient population referred for coronary angiography...
June 14, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Weina Wang, Aimei Wang, Guochang Luo, Fengqiao Ma, Xiaoming Wei, Yongyi Bi
Ischemia/reperfusion (I/R) is a major cause of acute kidney injury (AKI), along with delayed graft function, which can trigger chronic kidney injury by stimulating epithelial to mesenchymal transition (EMT) in the kidney canaliculus. Sphingosine 1-phosphate receptor 1 (S1P1) is a G protein-coupled receptor that is indispensable for vessel homeostasis. This study aimed to investigate the influence of S1P1 on the mechanisms underlying I/R-induced EMT in the kidney using in vivo and in vitro models. Wild-type (WT) and S1P1-overexpressing kidney canaliculus cells were subject to hypoxic conditions followed by reoxygenation in the presence or absence of FTY720-P, a potent S1P1 agonist...
June 13, 2018: Acta Biochimica et Biophysica Sinica
Yan Jin, Qiuyun Tu, Min Liu
The present study aimed to investigate the expression of microRNA (miR)‑125b in patients with Alzheimer's disease (AD) and to determine its potential role in AD. Mouse neuroblastoma Neuro2a APPSwe/Δ9 cells were used to generate an in vitro AD model. The results demonstrated that the expression levels of miR‑125b were markedly increased in patients with AD compared with in the normal group. In addition, overexpression of miR‑125b significantly inhibited cell proliferation, induced apoptosis, and enhanced inflammation and oxidative stress in an in vitro model of AD model...
June 13, 2018: Molecular Medicine Reports
Soo Min Cho, Ayelet Vardi, Nicolas Platt, Anthony H Futerman
Approximately 70 lysosomal storage diseases are currently known, resulting from mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in lysosomal enzymes that hydrolyze sphingolipids have been relatively well studied. Gaucher disease is caused by the loss of activity of glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease exhibits a number of subtypes, with types 2 and 3 showing significant neuropathology. Sandhoff disease results from the defective activity of β-hexosaminidase, leading to accumulation of ganglioside GM2...
June 14, 2018: Journal of Neurochemistry
Mohammed-Salleh M Ardawi, Abdulrahim A Rouzi, Nawal S Al-Senani, Mohammed H Qari, Ayman Z Elsamanoudy, Shaker A Mousa
Background: Higher sphingosine 1-phosphate (S1P) plasma levels are associated with decreased bone mineral density (BMD), and increased risk of prevalent vertebral fracture. So, we hypothesized that postmenopausal women with increased baseline plasma S1P levels have a greater risk for future incident fracture (osteoporosis-related fractures [ORFs]). Methods: This study was conducted in a prospective longitudinal cohort of 707 women recruited in 2004 and followed up annually for a mean period of 5...
May 2018: Journal of Bone Metabolism
Sascha Marx, Maximilian Splittstöhser, Frederik Kinnen, Eileen Moritz, Christy Joseph, Sebastian Paul, Heiko Paland, Carolin Seifert, Madlen Marx, Andreas Böhm, Edzard Schwedhelm, Kerstin Holzer, Stephan Singer, Christoph A Ritter, Sandra Bien-Möller, Henry W S Schroeder, Bernhard H Rauch
Patients with glioblastoma multiforme (GBM) suffer from an increased incidence of vascular thrombotic events. However, key influencing factors of the primary hemostasis have not been characterized in GBM patients to date. Thus, the present study determines the activation level of circulating platelets in GBM patients, in-vitro reactivity to agonist-induced platelet stimulation and the formation of circulating platelet-leucocyte conjugates as well as the plasma levels of the proinflammatory lipid mediator sphingosine-1-phosphate (S1P)...
May 25, 2018: Oncotarget
Mianhuan Li, Yi Lv, Feng Chen, Xiaoyan Wang, Jiang Zhu, Hao Li, Jia Xiao
BACKGROUND: One of the major obstacles facing stem cell therapy is the limited number of functional stem cells available after transplantation due to the harsh microenvironment surrounding the damaged tissue. The aim of this study was to delineate the mechanistic involvement of lysophosphatidic acid receptors (LPARs) and sphingosine-1-phosphate receptors (S1PRs) in the regulation of anti-stress and transplantation efficacy of stem cells. METHODS: Human adipose-derived mesenchymal stem cells (hADMSCs) were treated with chemical toxin or ethanol to induce cell stress...
June 14, 2018: Stem Cell Research & Therapy
Tingfang Yang, Xianfeng Zhang, Cuimei Ma, Yan Chen
Ischemia-reperfusion (IR) injury is usually associated with a high risk of cardiomyocyte death in patients with acute myocardial infarction. Sphingosine 1-phosphate (S1P) and transforming growth factor (TGF)-β are thought to be involved in the protection of cardiomyocyte and heart function following IR-induced injury. However, the possible association of S1P and S1P receptor 1 (S1PR1) with the TGF-β/Smad3 pathway as the potential protective mechanism has remained to be investigated. In the present study, an in vitro ischemia/reperfusion injury model was established and evaluated by analysis of apoptosis, lactate dehydrogenase (LDH) release and caspase3 activity...
July 2018: Experimental and Therapeutic Medicine
Lorenzo Federico, Liping Yang, Jason Brandon, Manikandan Panchatcharam, Hongmei Ren, Paul Mueller, Manjula Sunkara, Diana Escalante-Alcalde, Andrew J Morris, Susan S Smyth
Dephosphorylation of phosphatidic acid (PA) is the penultimate step in triglyceride synthesis. Adipocytes express soluble intracellular PA-specific phosphatases (Lipins) and broader specificity membrane-associated lipid phosphate phosphatases (LPPs) that can also dephosphorylate PA. Inactivation of lipin1 causes lipodystrophy in mice due to defective developmental adipogenesis. Triglyceride synthesis is diminished but not ablated by inactivation of lipin1 in differentiated adipocytes implicating other PA phosphatases in this process...
2018: PloS One
Olivia M Yu, Jorge A Benitez, Steven W Plouffe, Daniel Ryback, Andrea Klein, Jeff Smith, Jason Greenbaum, Benjamin Delatte, Anjana Rao, Kun-Liang Guan, Frank B Furnari, Olga Meiri Chaim, Shigeki Miyamoto, Joan Heller Brown
The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation...
June 11, 2018: Oncogene
İlhami Gulçin, Parham Taslimi
INTRODUCTION: Sulfonamide compounds are significant class of synthetic bacteriostatic antibiotics still which used today for the therapy of bacterial infections and those caused by other microorganisms. They are also known as sulfa drugs and were the main source of therapy against bacterial infections before the introduction of penicillin in 1941. Additionally, The first sulfonamide section is present inmany clinically used drugs such as diuretics, carbonic anhydrase inhibitors and antiepileptics...
June 10, 2018: Expert Opinion on Therapeutic Patents
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