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https://www.readbyqxmd.com/read/28108287/antitumor-activity-of-a-novel-and-orally-available-inhibitor-of-serine-palmitoyltransferase
#1
Masahiro Yaguchi, Sachio Shibata, Yoshinori Satomi, Megumi Hirayama, Ryutaro Adachi, Yasutomi Asano, Takuto Kojima, Yasuhiro Hirata, Akio Mizutani, Atsushi Kiba, Yoji Sagiya
Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin...
January 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28104755/n-glycosylation-of-human-sphingomyelin-phosphodiesterase-acid-like-3a-smpdl3a-is-essential-for-stability-secretion-and-activity
#2
Mathew Traini, Raani Kumaran, Morten Thaysen-Andersen, Maaike Kockx, Wendy Jessup, Leonard Kritharides
Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a recently identified phosphodiesterase, which is a secreted N -linked glycoprotein. SMPDL3A is highly homologous to acid sphingomyelinase (aSMase), but unlike aSMase can not cleave sphingomyelin. Rather, SMPDL3A hydrolyzes nucleotide tri- and diphosphates and their derivatives. While recent structural studies have shed light on these unexpected substrate preferences, many other aspects of SMPDL3A biology which may give insight into its function in vivo remain obscure...
January 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28104376/lipidomic-profile-of-gm95-cell-death-induced-by-clostridium-perfringens-alpha-toxin
#3
Marco M Manni, Juan G Valero, Miriam Pérez-Cormenzana, Ainara Cano, Cristina Alonso, Félix M Goñi
Clostridium perfringens alpha-toxin (ATX) is considered as a prototype of cytotoxic bacterial phospholipases C, and is the major virulence factor in C. perfringens-induced gas gangrene. It is known that, depending on the dose, ATX causes membrane disruption and cytolysis or only limited hydrolysis of its substrates. In the latter case, toxin activity leads to the unregulated generation of bioactive lipids that can ultimately induce cell death. We have characterized apoptosis and necrosis in highly ATX-sensitive, ganglioside-deficient cells exposed to different concentrations of ATX and we have studied the lipidomic profile of cells treated with ATX as compared to native cells to detect the main changes in the lipidomic profile and the possible involvement of lipid signals in cell death...
January 16, 2017: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/28098178/lithium-accumulates-in-neurogenic-brain-regions-as-revealed-by-high-resolution-ion-imaging
#4
Giulia Zanni, Wojciech Michno, Elena Di Martino, Anna Tjärnlund-Wolf, Jean Pettersson, Charlotte Elizabeth Mason, Gustaf Hellspong, Klas Blomgren, Jörg Hanrieder
Lithium (Li) is a potent mood stabilizer and displays neuroprotective and neurogenic properties. Despite extensive investigations, the mechanisms of action have not been fully elucidated, especially in the juvenile, developing brain. Here we characterized lithium distribution in the juvenile mouse brain during 28 days of continuous treatment that result in clinically relevant serum concentrations. By using Time-of-Flight Secondary Ion Mass Spectrometry- (ToF-SIMS) based imaging we were able to delineate temporospatial lithium profile throughout the brain and concurrent distribution of endogenous lipids with high chemical specificity and spatial resolution...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28087695/novel-interconnections-in-lipid-metabolism-revealed-by-overexpression-of-sphingomyelin-synthase-1
#5
Gergana M Deevska, Patrick P Dotson, Alexander A Karakashian, Giorgis Isaac, Mark Wrona, Samuel B Kelly, Alfred H Merrill, Mariana N Nikolova-Karakashian
This study investigates the consequences of elevating sphingomyelin synthase 1 (SMS1) activity, which generates the main mammalian sphingolipid, sphingomyelin. HepG2 cells stably transfected with SMS1 (HepG2-SMS1), exhibit elevated enzyme activity in vitro and increased sphingomyelin content (mainly C22:0- and C24:0-sphingomyelin), but lower hexosylceramide (Hex-Cer) levels. HepG2-SMS1 cells have less triacylglycerols than controls but similar diacylglycerol acyltransferase activity, triacylglycerol secretion, and mitochondrial function...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28078595/method-to-measure-sphingomyelin-synthase-activity-changes-in-response-to-cd95l
#6
Fatima Bilal, Michaël Pérès, Nathalie Andrieu-Abadie, Thierry Levade, Bassam Badran, Ahmad Daher, Bruno Ségui
Sphingomyelin synthases 1 and 2 convert the anti-oncometabolite ceramide to sphingomyelin, the most abundant sphingolipid in plasma membrane. CD95L-induced ceramide increase is associated with the caspase-dependent inhibition of sphingomyelin synthesis, which enhances the mitochondrial route to apoptosis. Knocking down sphingomyelin synthase 1 or inhibiting sphingomyelin synthesis facilitates ceramide accumulation, cytochrome c release from mitochondria, and caspase-9 activation in cancer cell upon CD95L treatment...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28070042/-effect-of-jianpi-jiedu-formula-on-tumor-angiogenesis-relevant-genes-expression-in-colorectal-cancer
#7
Dan Mao, Sanlin Lei, Jin'an Ma, Li Shi, Shaofan Zhang, Jianhua Huang, Xinyi Liu, Dengfeng Ding, Yingjin Zhang, Lei Feng, Sifang Zhang
To investigate the effect of the jianpi-jiedu formula (JPJD) on the expression of angiogenesis-relevant genes in colon cancer.
 Methods: Crude extract was obtained from JPJD by water extract method. The effect of JPJD crude extract on colon cancer cell proliferation capacity was determined by MTT assays. The IC50 value was calculated by GraphPad Prism5 software. Affymetrix gene expression profiling chip was used to detect significant differences in expressions of genes after JPJD intervention, and pathway enrichment analysis was performed to analyze the differentially expressed genes...
December 28, 2016: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/28065303/dynamics-of-sphingomyelin-and-cholesterol-enriched-lipid-domains-during-cytokinesis
#8
M Abe, T Kobayashi
Sphingomyelin (SM) and cholesterol (Chol) are the major lipids in the mammalian cells, which are mainly localized to the plasma membrane. Multiple lines of evidence suggest that these lipids form local lipid domains in the plasma membrane, playing functional roles in the cell. Several observations have suggested that these lipid domains are required for cytokinesis. In this chapter, we show the methods for visualizing SM-rich and/or Chol-rich membrane domains at cytokinesis by using specific lipid-binding proteins...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28062623/a-novel-lipid-biomarker-panel-for-the-detection-of-heart-failure-with-reduced-ejection-fraction
#9
Matthias Mueller-Hennessen, Hans-Dirk Düngen, Matthias Lutz, Tobias Daniel Trippel, Michael Kreuter, Johanna Sigl, Oliver J Müller, Elvis Tahirovic, Henning Witt, Philipp Ternes, Susan Carvalho, Erik Peter, Dietrich Rein, Philipp Schatz, Felix Herth, Evangelos Giannitsis, Tanja Weis, Norbert Frey, Hugo A Katus
OBJECTIVES: In this study we aimed to identify novel metabolomic biomarkers suitable for improved diagnosis of heart failure with reduced ejection fraction (HFrEF). METHODS: We prospectively recruited 887 individuals consisting of HFrEF patients with either ischemic (ICMP, n = 257) or nonischemic cardiomyopathy (NICMP, n = 269), healthy controls (n = 327), and patients with pulmonary diseases (n = 34). A single-center identification (n = 238) was followed by a multicenter confirmation study (n = 649)...
January 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28054763/islet-amyloid-polypeptide-membrane-interactions-effects-of-membrane-composition
#10
Xiaoxue Zhang, Johnna R St Clair, Erwin London, Daniel P Raleigh
Amyloid formation by islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Perturbation of the β-cell membrane may contribute to IAPP-induced toxicity. We examine the effects of lipid composition, salt, and buffer on IAPP amyloid formation and on the ability of IAPP to induce leakage of model membranes. Even low levels of anionic lipids promote amyloid formation and membrane permeabilization. Increasing the percentage of the anionic lipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) or 1,2-dioleoyl-sn-glycero-3-phospho(1'-rac-glycerol), enhances the rate of amyloid formation and increases the level of membrane permeabilization...
January 5, 2017: Biochemistry
https://www.readbyqxmd.com/read/28053823/global-metabolic-profiling-of-plasma-shows-that-three-year-mild-caloric-restriction-lessens-an-age-related-increase-in-sphingomyelin-and-reduces-l-leucine-and-l-phenylalanine-in-overweight-and-obese-subjects
#11
Minjoo Kim, Sang-Hyun Lee, Jong Ho Lee
The effect of weight loss from long-term, mild-calorie diets (MCD) on plasma metabolites is unknown. This study was to examine whether MCD-induced weight reduction caused changes in the extended plasma metabolites. Overweight and obese subjects aged 40-59 years consumed a MCD (approximately 100 kcal/day deficit, n=47) or a weight-maintenance diet (control, n=47) in a randomized, controlled design with a three-year clinical intervention period and plasma samples were analyzed by using UPLC-LTQ-Orbitrap mass spectrometry...
December 2016: Aging and Disease
https://www.readbyqxmd.com/read/28049734/sphingosine-and-sphingosine-kinase-1-involvement-in-endocytic-membrane-trafficking
#12
Santiago Lima, Sheldon Milstien, Sarah Spiegel
The balance between cholesterol and sphingolipids within the plasma membrane has long been implicated in endocytic membrane trafficking. However, in contrast to cholesterol functions, little is still known about the roles of sphingolipids and their metabolites. Perturbing the cholesterol/sphingomyelin balance was shown to induce narrow tubular plasma membrane invaginations enriched with sphingosine kinase 1 (SphK1), the enzyme that converts the bioactive sphingolipid metabolite sphingosine to sphingosine-1-phosphate (S1P), and suggested a role for sphingosine phosphorylation in endocytic membrane trafficking...
January 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28048967/the-pore-forming-capacity-of-sticholysin-i-in-dipalmitoyl-phosphatidyl-vesicles-is-tuned-by-osmotic-stress
#13
M Ahumada, C Calderon, E Lissi, C Alvarez, M E Lanio
The osmotic condition modulates the properties of liposomes, particularly those related to their stability and response to external agents such as membrane-active proteins or peptides. In a previous work, we have demonstrated that an osmotic shock can increase, per se, water influx/efflux and the exit of the fluorophore calcein entrapped in the aqueous pool of dipalmitoylphosphatidylcholine (DPPC) and DPPC:sphingomyelin (SM) large unilamellar vesicles (LUVs), suggesting a loss of integrity of the liposome bilayer...
December 31, 2016: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/28035934/the-association-between-plasma-ceramides-and-sphingomyelins-and-risk-of-alzheimer-s-disease-differs-by-sex-and-apoe-in-the-baltimore-longitudinal-study-of-aging
#14
Michelle M Mielke, Norman J Haughey, Dingfen Han, Yang An, Veera Venkata Ratnam Bandaru, Constantine G Lyketsos, Luigi Ferrucci, Susan M Resnick
BACKGROUND: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. OBJECTIVE: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28035360/hepatic-inflammatory-cytokine-production-can-be-regulated-by-modulating-sphingomyelinase-and-ceramide-synthase-6
#15
Min Hee Kim, Hee Kyung Ahn, Eun-Ji Lee, Su-Jeong Kim, Ye-Ryung Kim, Joo-Won Park, Woo-Jae Park
Chronic inflammation is associated with the pathogenesis of type 2 diabetes and diabetic complications, and palmitate has been nominated as a candidate for the molecular link between these disorders. Recently, a crucial role of ceramide in inflammation and metabolic diseases has been reported. Therefore, in this study, we investigated whether ceramide formation is involved in palmitate‑induced hepatic inflammation in vitro and in vivo. Ceramide can be generated either by the de novo pathway or by sphingomyelin degradation, and six different ceramide synthases (CerS) determine the specific acyl chain length of ceramide in mammals...
February 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28012590/assay-to-measure-sphingomyelinase-and-ceramidase-activities-efficiently-and-safely
#16
Christiane Mühle, Johannes Kornhuber
As part of the sphingomyelin pathway, sphingomyelinases and ceramidases have attracted much attention in basic as well as clinical research. However, current assays still often rely on a radioactive substrate, extensive manual purification steps, and hazardous solvents for chromatographic analysis. We here show the equivalence of a fluorescent sphingomyelin substrate and present a new versatile solvent replacing the chloroform/methanol mixture. By further modifications including the omission of the manual extraction steps, chloroform and methanol are eliminated from the entire procedure and render the assay flexible to repeated analyses at multiple time intervals...
December 14, 2016: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28008947/self-assembly-of-hiv-1-gag-protein-on-lipid-membranes-generates-pi-4-5-p2-cholesterol-nanoclusters
#17
Naresh Yandrapalli, Quentin Lubart, Hanumant S Tanwar, Catherine Picart, Johnson Mak, Delphine Muriaux, Cyril Favard
The self-assembly of HIV-1 Gag polyprotein at the inner leaflet of the cell host plasma membrane is the key orchestrator of virus assembly. The binding between Gag and the plasma membrane is mediated by specific interaction of the Gag matrix domain and the PI(4,5)P2 lipid (PIP2). It is unknown whether this interaction could lead to local reorganization of the plasma membrane lipids. In this study, using model membranes, we examined the ability of Gag to segregate specific lipids upon self-assembly. We show for the first time that Gag self-assembly is responsible for the formation of PIP2 lipid nanoclusters, enriched in cholesterol but not in sphingomyelin...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28006722/new-insights-into-the-effects-of-onion-consumption-on-lipid-mediators-using-a-diet-induced-model-of-hypercholesterolemia
#18
Diana González-Peña, Antonio Checa, Begoña de Ancos, Craig E Wheelock, Concepción Sánchez-Moreno
The levels and roles of lipid mediators can be modified in response to nutritional stimuli. The aim of this study was to investigate shifts in oxylipin and sphingolipid profiles stimulated by a hypercholesterolemic (HC) diet along with the modulating effects of onion introduced as an antioxidant functional ingredient characterized in the diet (HCO). Oxylipin and sphingolipid profiles were determined in plasma and tissues from Wistar rats using LC-MS/MS. Plasma ω-3 and ω-6 PUFA-derived oxylipins decreased in rats after 7 weeks of HC feeding, but did not evidence a further shift with HCO diet...
December 9, 2016: Redox Biology
https://www.readbyqxmd.com/read/28004822/mass-spectrometry-imaging-of-biomarker-lipids-for-phagocytosis-and-signalling-during-focal-cerebral-ischaemia
#19
Mette M B Nielsen, Kate L Lambertsen, Bettina H Clausen, Morten Meyer, Dhaka R Bhandari, Søren T Larsen, Steen S Poulsen, Bernhard Spengler, Christian Janfelt, Harald S Hansen
Focal cerebral ischaemia has an initial phase of inflammation and tissue injury followed by a later phase of resolution and repair. Mass spectrometry imaging (desorption electrospray ionization and matrix assisted laser desorption ionization) was applied on brain sections from mice 2 h, 24 h, 5d, 7d, and 20d after permanent focal cerebral ischaemia. Within 24 h, N-acyl-phosphatidylethanolamines, lysophosphatidylcholine, and ceramide accumulated, while sphingomyelin disappeared. At the later resolution stages, bis(monoacylglycero)phosphate (BMP(22:6/22:6)), 2-arachidonoyl-glycerol, ceramide-phosphate, sphingosine-1-phosphate, lysophosphatidylserine, and cholesteryl ester appeared...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28001077/interaction-forces-between-lipid-rafts
#20
James Kurniawan, João Ventrici, Gregory Kittleson, Tonya L Kuhl
Cellular membranes containing sphingolipids and cholesterol have been shown to self-organize into lipid rafts-specialized domains that host integral membrane proteins and modulate the bioactivity of cells. In this work, force-distance profiles between raft membranes in the liquid-ordered phase consisting of singly unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a complex mixture of brain sphingomyelin (BSM), and cholesterol were measured using the surface force apparatus (SFA). Two distinct force profiles were detected corresponding to uniform raft membranes and raft membranes with a higher level of topological membrane defects (heterogeneous) as corroborated by atomic force microscopy (AFM) scans...
December 21, 2016: Langmuir: the ACS Journal of Surfaces and Colloids
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