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https://www.readbyqxmd.com/read/29046397/lipid-metabolic-perturbation-is-an-early-onset-phenotype-in-adult-spin-mutants-a-drosophila-model-for-lysosomal-storage-disorders
#1
Sarita Hebbar, Avinash Khandelwal, Jayashree R, Samantha J Hindle, Yin Ning Chiang, Joanne Y Yew, Sean T Sweeney, Dominik Schwudke
Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. We systematically analyzed lipid perturbations in spinster (spin) mutants, a Drosophila model of LSD-like neurodegeneration. Our results highlight an imbalance in brain ceramide and sphingosine in the early stages of neurodegeneration, preceding the accumulation of endomembranous structures, manifestation of altered behaviour, and buildup of lipofuscin...
October 18, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29045386/mfsd2b-is-essential-for-the-sphingosine-1-phosphate-export-in-erythrocytes-and-platelets
#2
Thiet M Vu, Ayako-Nakamura Ishizu, Juat Chin Foo, Xiu Ru Toh, Fangyu Zhang, Ding Ming Whee, Federico Torta, Amaury Cazenave-Gassiot, Takayoshi Matsumura, Sangho Kim, Sue-Anne E S Toh, Toshio Suda, David L Silver, Markus R Wenk, Long N Nguyen
Sphingosine-1-phosphate (S1P), a potent signalling lipid secreted by red blood cells and platelets, plays numerous biologically significant roles. However, the identity of its long-sought exporter is enigmatic. Here we show that the major facilitator superfamily transporter 2b (Mfsd2b), an orphan transporter, is essential for S1P export from red blood cells and platelets. Comprehensive lipidomic analysis indicates a dramatic and specific accumulation of S1P species in Mfsd2b knockout red blood cells and platelets compared with that of wild-type controls...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29044290/protease-activated-receptor-par-4-an-inducible-switch-between-thrombosis-and-vascular-inflammation
#3
Anke C Fender, Bernhard H Rauch, Tobias Geisler, Karsten Schrör
Thrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions...
October 10, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29040968/neutrophils-kill-reactive-oxygen-species-resistant-pseudomonas-aeruginosa-by-sphingosine
#4
Katrin Anne Becker, Xiang Li, Aaron Seitz, Joerg Steinmann, Anne Koch, Edward Schuchman, Markus Kamler, Michael J Edwards, Charles C Caldwell, Erich Gulbins
BACKGROUND/AIMS: Cystic fibrosis (CF) is dominated by chronic inflammation and infection of the lung resulting in lung destruction and early death of patients. The lungs of CF patients are characterized by a massive accumulation of neutrophils. It requires definition why these massive numbers of neutrophils fail to eliminate typical CF pathogens like Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa) in CF lungs. METHODS: We determined ceramide, sphingosine and reactive oxygen species (ROS) in neutrophils from wildtype and CF mice and determined the effect of sphingosine and ROS alone or in combination on killing of different P...
October 17, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29039449/crosstalk-between-tlr2-and-sphk1-in-microglia-in-the-cerebral-ischemia-reperfusion-induced-inflammatory-response
#5
Wei Sun, Zhaoming Ding, Shengjie Xu, Zhiqiang Su, Hulun Li
Stroke is associated with high morbidity and mortality, and much remains unknown about the injury-related mechanisms that occur following reperfusion. This study aimed to explore the roles of Toll-like receptor 2 (TLR2) and sphingosine kinase 1 (Sphk1) in microglial cells in inflammatory responses induced by cerebral ischemia/reperfusion (I/R). For this purpose, C57BL/6 mice were randomly divided into 4 groups as follows: the sham-operated group, the I/R group, the I/R group treated with TLR2 antibody, and the I/R group treated with N,N-dimethylsphingosine...
September 29, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29039121/degradation-of-glycosphingolipids-in-oyster-ceramide-glycanase-and-ceramidase-in-the-hepatopancreas-of-oyster-crassostrea-virginica
#6
Nadejda V Pavlova, Su-Chen Li, Yu-Teh Li
The hepatopancreas of oyster, Crassostrea virginica, was found to contain two unique glycosphingolipid (GSL) cleaving enzymes, ceramide glycanase (CGase) and ceramidase. These two enzymes were found to be tightly associated together through the consecutive purification steps including gel filtration, hydrophobic interaction and cation-exchange chromatographies. They were separated only by preparatory SDS-PAGE. The purified CGase was found to have a molecular mass of 52 kDa and pH optimum of 3.2-3.3. This enzyme prefers to hydrolyze the acidic GSLs, II(3)SO3LacCer and gangliosides over the neutral GSLs...
October 16, 2017: Glycoconjugate Journal
https://www.readbyqxmd.com/read/29036438/a-selective-sphingosine-1-phosphate-receptor-1-agonist-sew-2871-aggravates-gastric-cancer-by-recruiting-myeloid-derived-suppressor-cells
#7
Yujing Zhou, Feng Guo
The immune status of tumor microenvironment in gastric cancer is poorly understood, which limits the development of novel strategies in this field. Sphingosine-1-phosphate (S1P) acts as an immune modulator, but the role of S1P in gastric cancer is elusive. Here, we aim to investigate S1P receptor 1 (S1P1)-mediated effect of S1P in gastric cancer. We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signaling. Tumor-infiltrating lymphocytes (TILs) were isolated and analyzed using flow cytometry...
October 3, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/29033951/sphingosine-1-phosphate-receptor-5-modulates-early-stage-processes-during-fibrogenesis-in-a-mouse-model-of-systemic-sclerosis-a-pilot-study
#8
Katrin G Schmidt, Martina Herrero San Juan, Sandra Trautmann, Lucija Berninger, Anja Schwiebs, Florian M Ottenlinger, Dominique Thomas, Frank Zaucke, Josef M Pfeilschifter, Heinfried H Radeke
Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29029455/mobilization-studies-in-mice-deficient-in-sphingosine-kinase-2-support-a-crucial-role-of-the-plasma-level-of-sphingosine-1-phosphate-in-the-egress-of-hematopoietic-stem-progenitor-cells
#9
Mateusz Adamiak, Lakshman Chelvarajan, Kevin R Lynch, Webster L Santos, Ahmed Abdel-Latif, Mariusz Z Ratajczak
Sphingosine-1-phosphate (S1P) is a bioactive lipid involved in cell signaling and, if released from cells, also plays a crucial role in regulating the trafficking of lympho-hematopoietic cells, including primitive hematopoietic stem/progenitor cells (HSPCs). It has been demonstrated that S1P chemoattracts HSPCs, and its level in peripheral blood creates a gradient directing egress of these cells during mobilization. In this paper we analyzed hematopoiesis in mice deficient in sphingosine kinase 2 (Sphk2-KO mice) and studied the effect of this mutation on plasma S1P levels...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29028945/sphingosine-kinase-1-expression-in-peritoneal-macrophages-is-required-for-colon-carcinogenesis
#10
Hideki Furuya, Paulette M Tamashiro, Yoshiko Shimizu, Kayoko Iino, Rafael Peres, Runpu Chen, Yijun Sun, Yusuf A Hannun, Lina M Obeid, Toshihiko Kawamori
Accumulating evidence suggests that the sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) pathway plays a pivotal role in colon carcinogenesis. Our previous studies indicate that the SphK1/S1P pathway mediates colon carcinogenesis at least by regulating COX-2 expression and prostaglandin E2 (PGE2) production. However, the mechanisms by which this pathway regulates colon carcinogenesis are still unclear. First, we show that SphK1 deficient mice significantly attenuated azoxymethane (AOM)-induced colon carcinogenesis as measured by colon tumor incidence, multiplicity, and volume...
September 23, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29027248/ursodeoxycholic-acid-protects-cardiomyocytes-against-cobalt-chloride-induced-hypoxia-by-regulating-transcriptional-mediator-of-cells-stress-hypoxia-inducible-factor-1%C3%AE-and-p53-protein
#11
Anis Syamimi Mohamed, Noorul Izzati Hanafi, Siti Hamimah Sheikh Abdul Kadir, Julina Md Noor, Narimah Abdul Hamid Hasani, Sharaniza Ab Rahim, Rosfaiizah Siran
In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca(2+) ]i ), and sphingosine-1-phosphate (S1P)-receptor via Gαi -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca(2+) ]i , and S1P-Gαi -coupled-receptor...
October 12, 2017: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/29023711/alteration-of-sphingolipid-metabolism-as-a-putative-mechanism-underlying-lps-induced-bbb-disruption
#12
Rajkumar Vutukuri, Robert Brunkhorst, Roxane-Isabelle Kestner, Lena Hansen, Nerea Ferreiros Bouzas, Josef Pfeilschifter, Kavi Devraj, Waltraud Pfeilschifter
Septic encephalopathy with confusion and agitation occurs early during sepsis and contributes to the severity of the disease. A decrease of the sphingosine-1-phosphate (S1P) blood levels has been shown in patients and in animal models of sepsis. The lipid mediator S1P is known to be involved in endothelial barrier function in a context-dependent manner. We utilized LPS injected mice as a model for septic encephalopathy and first performed tracer permeability assays to assess the BBB breakdown in vivo. At time points corresponding to the BBB breakdown post LPS injection, we aimed to characterize the regulation of the sphingolipid signaling pathway at the blood-brain barrier (BBB) during sepsis...
October 11, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29023478/regeneration-of-glycocalyx-by-heparan-sulfate-and-sphingosine-1-phosphate-restores-inter-endothelial-communication
#13
Solomon A Mensah, Ming J Cheng, Homa Homayoni, Brian D Plouffe, Arthur J Coury, Eno E Ebong
Vasculoprotective endothelium glycocalyx (GCX) shedding plays a critical role in vascular disease. Previous work demonstrated that GCX degradation disrupts endothelial cell (EC) gap junction connexin (Cx) proteins, likely blocking interendothelial molecular transport that maintains EC and vascular tissue homeostasis to resist disease. Here, we focused on GCX regeneration and tested the hypothesis that vasculoprotective EC function can be stimulated via replacement of GCX when it is shed. We used EC with [i] intact heparan sulfate (HS), the most abundant GCX component; [ii] degraded HS; or [iii] HS that was restored after enzyme degradation, by cellular self-recovery or artificially...
2017: PloS One
https://www.readbyqxmd.com/read/29023248/anticancer-effect-of-acid-ceramidase-inhibitor-ceranib-2-in-human-breast-cancer-cell-lines-mcf-7-mda-mb-231-by-the-activation-of-sapk-jnk-p38-mapk-apoptotic-pathways-inhibition-of-the-akt-pathway-downregulation-of-er%C3%AE
#14
Helen S Vethakanraj, Binny P Sesurajan, Vishnu P Padmanaban, Madhumathi Jayaprakasam, Suganthi Murali, Ashok K Sekar
Acid ceramidase is the key enzyme of the ceramide metabolic pathway, which plays a vital role in regulating ceramide - sphingosine-1-phosphate rheostat. Ceramide acts as a proapoptotic molecule, but its metabolite sphingosine-1-phosphate, in contrast, signals for cell proliferation, cell survival, and angiogenesis. Acid ceramidase is highly upregulated in breast tumors and treatment with an acid ceramidase inhibitor, ceranib-2, significantly induced apoptosis in human breast cancer cell lines. However, the mechanisms underlying the induction of apoptosis remain ambiguous to date...
October 11, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29018225/s1p1-deletion-differentially-affects-th17-and-regulatory-t-cells
#15
Ahmet Eken, Rebekka Duhen, Akhilesh K Singh, Mallory Fry, Jane H Buckner, Mariko Kita, Estelle Bettelli, Mohamed Oukka
Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A (Cre) and Foxp3 (Cre) mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE)...
October 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29017324/molecular-dynamics-simulations-of-ceramide-and-ceramide-phosphatidylcholine-bilayers
#16
Eric Wang, Jeffery B Klauda
Recent studies in lipid raft formation and stratum corneum permeability have focused on the role of ceramides (CER). In this study, we use the all-atom CHARMM36 (C36) force field to simulate bilayers using N-palmitoyl-sphingosine (CER16) or α-hydroxy-N-stearoyl phytosphingosine (CER[AP]) in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) which serve as general membrane models. Conditions are replicated from experimental studies for comparison purposes, and concentration (XCER) is varied to probe the effect of CER on these systems...
October 10, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28993230/the-importance-of-blood-platelet-lipid-signaling-in-thrombosis-and-in-sepsis
#17
REVIEW
Fanny Vardon Bounes, Abdulrahman Mujalli, Claire Cenac, Sonia Severin, Pauline Le Faouder, Gaëtan Chicanne, Frédérique Gaits-Iacovoni, Vincent Minville, Marie-Pierre Gratacap, Bernard Payrastre
Blood platelets are the first line of defense against hemorrhages and are also strongly involved in the processes of arterial thrombosis, a leading cause of death worldwide. Besides their well-established roles in hemostasis, vascular wall repair and thrombosis, platelets are now recognized as important players in other processes such as inflammation, healing, lymphangiogenesis, neoangiogenesis or cancer. Evidence is accumulating they are key effector cells in immune and inflammatory responses to host infection...
September 29, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28991193/sphingosine-kinase-1-and-sphingosine-1-phosphate-signaling-in-colorectal-cancer
#18
REVIEW
Yonghua Bao, Yongchen Guo, Chenglan Zhang, Fenghua Fan, Wancai Yang
Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles...
October 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28990207/a-review-of-bioanalytical-quantitative-methods-for-selected-sphingosine-1-phosphate-s1p1-receptor-modulators
#19
REVIEW
Ranjeet Prasad Dash, Nuggehally R Srinivas, Rana Rais
Sphingosine 1-phosphate (S1P1 ) modulators provide an emerging therapeutic approach for various autoimmune disorders such as multiple sclerosis and psoriasis. Fingolimod is the first approved orally active, selective and potent drug of this class. Other drugs belonging to this class include siponimod, ponesimod, ceralifimod, amiselimod, CS-0777 and GSK2018682. However, due to the high protein binding, polarity and zwitter-ionic nature of the phosphate metabolite of parent drugs, it becomes challenging to optimize the extraction method for this class of compounds...
October 9, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28986246/sphingosine-1-phosphate-alleviates-coxsackievirus-b3-induced-myocarditis-by-increasing-invariant-natural-killer-t-cells
#20
Xinggang Wang, Yong Yu, Minghui Li, Ying Yu, Guijian Liu, Yeqing Xie, Yuxi Liu, Xiangdong Yang, Yunzeng Zou, Junbo Ge, Ruizhen Chen
Sphingosine 1-phosphate (S1P), via binding to its specific receptors of S1PR1, participates in the regulation of both innate and adaptive immunity. Recent reports have identified S1P as a messenger mediating inflammation. However, roles of S1P in Coxsackievirus B3 (CVB3)-induced myocarditis were largely unknown. Here, we investigated the effect of S1P treatment on CVB3-induced myocarditis in vivo. We found that CVB3 infection downregulated S1PR1 expression in spleen and decreased the proportion of invariant natural killer T cells (iNKT) in CD3 positive T cells both in spleen and in blood from left ventricle, which accompanied by severe inflammation lesions and more virus capsid protein (VP1) expression in heart tissue...
October 3, 2017: Experimental and Molecular Pathology
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