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Tong Song, Chen Sheng-Cai, Xu Kai-Ying, Fang Bin, Wang Si-Hua, Wang Jian-Jun
14-3-3ζ is overexpressed in several cancers, including esophageal squamous cell carcinoma (ESCC), and plays an important role in tumorigenesis. However, the mechanisms underlying its tumorigenesis remain unclear. Here we report that 14-3-3ζ was upregulated in ESCC tumors, compared with adjacent normal tissues; 14-3-3ζ levels were positively correlated with ESCC lymph node metastasis and recurrence. Overexpression of 14-3-3ζ promoted the tumor growth and invasion of ESCC in vitro and in vivo, whereas depletion of 14-3-3ζ suppressed these effects...
February 16, 2018: Archives of Biochemistry and Biophysics
Chao Fang, Ganlan Bian, Pan Ren, Jie Xiang, Jun Song, Caiyong Yu, Qian Zhang, Ling Liu, Kun Chen, Fangfang Liu, Kun Zhang, Chunfeng Wu, Ruixia Sun, Dan Hu, Gong Ju, Jian Wang
Spinster homolog 2 (SPNS2) is the membrane transporter of sphingosine-1-phosphate (S1P), and it participates in several physiologic processes by activating different S1P receptors (S1PRs). However, its functions in the nervous system remain largely unclear. We explored the important role of SPNS2 in the process of retinal morphogenesis using a spns2-deficient rat model. In the absence of the functional SPNS2 transporter, we observed progressively aggravating laminar disorganization of the epithelium at the postnatal stage of retinal development...
February 8, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Fengyan Jin, Nina Hagemann, Li Sun, Jiang Wu, Thorsten R Doeppner, Yun Dai, Dirk M Hermann
High-density lipoprotein (HDL) has previously been shown to promote angiogenesis. However, the mechanisms by which HDL enhances the formation of blood vessels remain to be defined. To address this, the effects of HDL on the proliferation, transwell migration and tube formation of human umbilical vein endothelial cells were investigated. By examining the abundance and phosphorylation (i.e., activation) of the vascular endothelial growth factor receptor VEGFR2 and modulating the activity of the sphingosine-1 phosphate receptors S1P1-3 and VEGFR2, we characterized mechanisms controlling angiogenic responses in response to HDL exposure...
February 15, 2018: Angiogenesis
Jianbo Zhou, Jin Chen, Huanmiao Yu
The activity of ABC294640, a small-molecular sphingosine kinase 2 (SphK2) inhibitor, in human skin squamous cell carcinoma (SCC) cells was tested in this study. SphK2 mRNA and protein are expressed in established (A431 cell line) and primary human skin SCC cells. ABC294640 dose-dependently inhibited survival, cell cycle progression and proliferation of skin SCC cells. Furthermore, ABC294640 induced caspase-3/-9 and apoptosis activation in skin SCC cells. The SphK2 inhibitor was however non-cytotoxic to SphK2-null skin melanocytes, keratinocytes and fibroblasts...
February 8, 2018: Biochemical and Biophysical Research Communications
Simona Svajdova, Lenka Mazurova, Mariana Brozmanova
Sphingosine-1-phosphate (S1P) is an inflammatory mediator increased in the tissue in the number of inflammatory conditions. Preliminary data indicate that the vagal afferent neurons express several S1P receptors including S1PR2-3. We therefore evaluated the hypothesis that S1P induces cough and/or enhances the cough evoked by other tussive stimuli (TRPA1 and TRPV1 activators) in naïve guinea pigs. Inhalation of S1P in the concentrations of 0.1 mM and 1 mM did not evoke cough. Preinhalation and continuing inhalation of S1P (1 mM) during citric acid (0...
February 8, 2018: Respiratory Physiology & Neurobiology
Ming Ji, Nina Xue, Fangfang Lai, Xiaoying Zhang, Sen Zhang, Yuchen Wang, Jing Jin, Xiaoguang Chen
Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment...
February 7, 2018: Biological & Pharmaceutical Bulletin
Gennaro Bruno, Francesca Cencetti, Caterina Bernacchioni, Chiara Donati, Kira Vanessa Blankenbach, Dominique Thomas, Dagmar Meyer Zu Heringdorf, Paola Bruni
Skeletal muscle tissue retains a remarkable regenerative capacity due to the activation of resident stem cells that in pathological conditions or after tissue damage proliferate and commit themselves into myoblasts. These immature myogenic cells undergo differentiation to generate new myofibers or repair the injured ones, giving a strong contribution to muscle regeneration. Cytokines and growth factors, potently released after tissue injury by leukocytes and macrophages, are not only responsible of the induction of the initial inflammatory response, but can also affect skeletal muscle regeneration...
February 2, 2018: Cellular Signalling
Ivana Josipovic, Beatrice Pflüger, Christian Fork, Andrea E Vasconez, James A Oo, Juliane Hitzel, Sandra Seredinski, Elisabetta Gamen, Dagmar Meyer Zu Heringdorf, Wei Chen, Mario Looso, Soni Savai Pullamsetti, Ralf P Brandes, Matthias S Leisegang
Sphingosine-1-Phosphate (S1P) is a potent signaling lipid. The effects of S1P are mediated by the five S1P receptors (S1PR). In the endothelium S1PR1 is the predominant receptor and thus S1PR1 abundance limits S1P signaling. Recently, lncRNAs were identified as a novel class of molecules regulating gene expression. Interestingly, the lncRNA NONHSAT004848 (LISPR1, Long intergenic noncoding RNA antisense to S1PR1), is closely positioned to the S1P1 receptors gene and in part shares its promoter region. We hypothesize that LISPR1 controls endothelial S1PR1 expression and thus S1P-induced signaling in endothelial cells...
January 31, 2018: Journal of Molecular and Cellular Cardiology
Fang Li, Ruijuan Xu, Benjamin E Low, Chih-Li Lin, Monica Garcia-Barros, Jennifer Schrandt, Izolda Mileva, Ashley Snider, Catherine K Luo, Xian-Cheng Jiang, Ming-Song Li, Yusuf A Hannun, Lina M Obeid, Michael V Wiles, Cungui Mao
Sphingosine-1-phosphate (S1P) plays important roles in cardiovascular development and immunity. S1P is abundant in plasma because erythrocytes-the major source of S1P-lack any S1P-degrading activity; however, much remains unclear about the source of the plasma S1P precursor, sphingosine (SPH), derived mainly from the hydrolysis of ceramides by the action of ceramidases that are encoded by 5 distinct genes, acid ceramidase 1 ( ASAH1)/ Asah1, ASAH2/ Asah2, alkaline ceramidase 1 ( ACER1)/ Acer1, ACER2/ Acer2, and ACER3/ Acer3, in humans/mice...
January 22, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Shushan Zhao, Morayo G Adebiyi, Yujin Zhang, Jacob P Couturier, Xuegong Fan, Hongqi Zhang, Rodney E Kellems, Dorothy E Lewis, Yang Xia
Sphingosine-1-phosphate (S1P) is a biolipid involved in chronic inflammation in several inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic, genetic disorder associated with severe chronic inflammation and tissue damage. We evaluated the effect of elevated S1P in chronic inflammation and tissue damage in SCD and underlying mechanisms. First, we demonstrated that interfering with S1P receptor signaling by FTY720, a U...
January 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jeanette Eresch, Martin Stumpf, Alexander Koch, Rajkumar Vutukuri, Nerea Ferreirós, Yannick Schreiber, Katrin Schröder, Kavi Devraj, Rüdiger Popp, Lars-Olof Hattenbach, Josef Pfeilschifter, Waltraud Pfeilschifter
Purpose: Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). Methods: Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2-/-) mice were used in the OIR model, exposed to 75% O2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression...
February 1, 2018: Investigative Ophthalmology & Visual Science
Olga A Sukocheva
Sphingolipids, sphingolipid metabolizing enzymes, and their receptors network are being recognized as part of the signaling mechanisms, which govern breast cancer cell growth, migration, and survival during chemotherapy treatment. Approximately 70% of breast cancers are estrogen receptor (ER) positive and, thus, rely on estrogen signaling. Estrogen activates an intracellular network composed of many cytoplasmic and nuclear mediators. Some estrogen effects can be mediated by sphingolipids. Estrogen activates sphingosine kinase 1 (SphK1) and amplifies the intracellular concentration of sphingosine-1-phosphate (S1P) in breast cancer cells during stimulation of proliferation and survival...
January 31, 2018: International Journal of Molecular Sciences
Kiersten Giusto, Charles R Ashby
BACKGROUND: Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to prevent PTB has yet to be developed. METHODS: Our group has used an in vivo model of inflammation driven PTB, biochemical methods, pharmacological approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish the role of endothelin-1 (ET-1) in inflammation-associated PTB...
January 30, 2018: Current Pharmaceutical Design
Annabel Kleinwort, Felix Lührs, Claus-Dieter Heidecke, Martin Lipp, Tobias Schulze
Introduction: Sphingosine-1-phosphate (S1P) regulates the migration of follicular B cells (B2 cells) and directs the positioning of Marginal zone B cells (MZ B cells) within the spleen. The function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed in peritoneal B cells by real-time polymerase chain reaction (qPCR). The chemotactic response to S1P was studied in vitro. The role of S1P signalling was further explored in a s1p₄-/- mouse strain...
January 29, 2018: International Journal of Molecular Sciences
Fei Gao, Ying Gao, Fangling Meng, Chunmei Yang, Jiangfeng Fu, Yajun Li
Over-expression of P-glycoprotein (P-gp) in the brain is an important factor leading to drug-resistant epilepsy. Clinical use of P-gp inhibitors is limited by their systemic toxicity. In the present study, we tested the hypothesis that FTY720, a sphingosine 1-phosphate (S1P) analogue used for treating multiple sclerosis, modulates the up-regulation of P-gp and improves brain delivery of phenytoin (PHT) through S1P receptor 1 in the hippocampus of a pilocarpine-induced rat model of status epilepticus (SE). We administered vehicle, FTY720 or FTY720 + W146 (an S1P receptor 1 antagonist) to SE rats...
January 30, 2018: Basic & Clinical Pharmacology & Toxicology
Matthew J Justice, Irina Bronova, Kelly S Schweitzer, Christophe Poirier, Janice S Blum, Evgheny V Berdyshev, Irina Petrache
Activation of the lysosomal ceramide-producing enzyme acid sphingomyelinase (ASM) by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes the mammalian target of rapamycin (mTOR) and the transcription factor EB (TFEB). ASM inhibition with imipramine or SMPD1 siRNA in human lung cells, or by transgenic Smpd1+/- haploinsufficiency of mouse lungs, markedly reduced mTOR- and P70-S6 kinase Thr 389- phosphorylation and modified TFEB in a pattern consistent with its activation...
January 29, 2018: Journal of Lipid Research
Lan Xiao, Yinghong Zhou, Lingxin Zhu, Shasha Yang, Rong Huang, Wei Shi, Bin Peng, Yin Xiao
Accumulating evidence indicates that the immune and skeletal systems interact with each other through various regulators during the osteoclastogenic process. Among these regulators, the bioactive lipid sphingosine-1-phosphate (S1P), which is synthesized by sphingosine kinase 1/2 (SPHK1/2), has recently been recognized to play a role in immunity and bone remodeling through its receptor sphingosine-1-phosphate receptor 1 (S1PR1). However, little is known regarding the potential role of S1PR1 signaling in inflammatory bone loss...
January 26, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Panfeng Fu, David L Ebenezer, Alison W Ha, Vidyani Suryadevara, Anantha Harijith, Viswanathan Natarajan
Phospholipids, sphingolipids, and cholesterol are integral components of eukaryotic cell organelles, including the nucleus. Recent evidence shows characteristic features of nuclear lipid composition and signaling, which are distinct from that of the cytoplasm and plasma membrane. While the nuclear phosphoinositol lipid signaling in cell cycle regulation and differentiation has been well described, there is a paucity on the role of nuclear sphingolipids and sphingolipid signaling in different physiological and pathophysiological human conditions...
January 27, 2018: Journal of Cellular Biochemistry
Sinead A O'Sullivan, Catherine O'Sullivan, Luke M Healy, Kumlesh K Dev, Graham K Sheridan
Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R - S1P5R. The drug Gilenya® (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS...
January 27, 2018: Journal of Neurochemistry
Suihan Feng, Takeshi Harayama, Sylvie Montessuit, Fabrice Pa David, Nicolas Winssinger, Jean-Claude Martinou, Howard Riezman
Photoactivation ('uncaging') is a powerful approach for releasing bioactive small-molecules in living cells. Current uncaging methods are limited by the random distribution of caged molecules within cells. We have developed a mitochondria-specific photoactivation method, which permitted us to release free sphingosine inside mitochondria and thereafter monitor local sphingosine metabolism by lipidomics. Our results indicate that sphingosine was quickly phosphorylated into sphingosine 1-phosphate (S1P) driven by sphingosine kinases...
January 29, 2018: ELife
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