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Ceramide synthases

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https://www.readbyqxmd.com/read/27881717/localization-of-1-deoxysphingolipids-to-mitochondria-induces-mitochondrial-dysfunction
#1
Irina Alecu, Andrea Tedeschi, Natascha Behler, Klaus Wunderling, Christian Lamberz, Mario A R Lauterbach, Anne Gaebler, Daniela Ernst, Paul P Van Veldhoven, Ashraf Al-Amoudi, Eicke Latz, Alaa Othman, Lars Kuerschner, Thorsten Hornemann, Frank Bradke, Christoph Thiele, Anke Penno
1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases. However, very little is known about the biology of these lipids and the underlying pathomechanism. We synthesized an alkyne analogue of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, to trace the metabolism and localization of deoxySLs...
November 23, 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27853511/molecular-docking-and-molecular-dynamics-simulation-study-of-inositol-phosphorylceramide-synthase-inhibitor-complex-in-leishmaniasis-insight-into-the-structure-based-drug-design
#2
Vineetha Mandlik, Shailza Singh
Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis...
2016: F1000Research
https://www.readbyqxmd.com/read/27842800/anti-candida-albicans-natural-products-sources-of-new-antifungal-drugs-a-review
#3
REVIEW
A Zida, S Bamba, A Yacouba, R Ouedraogo-Traore, R T Guiguemdé
INTRODUCTION: Candida albicans is the most prevalent fungal pathogen in humans. Due to the development of drug resistance, there is today a need for new antifungal agents for the efficient management of C. albicans infections. Therefore, we reviewed antifungal activity, mechanisms of action, possible synergism with antifungal drugs of all natural substances experimented to be efficient against C. albicans for future. METHODS: An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analyzed and included in the review...
November 11, 2016: Journal de Mycologie Médicale
https://www.readbyqxmd.com/read/27836537/possible-roles-of-long-chain-sphingomyelines-and-sphingomyelin-synthase-2-in-mouse-macrophage-inflammatory-response
#4
Hideaki Sakamoto, Tetsuya Yoshida, Takao Sanaki, Shuhei Shigaki, Hirotoshi Morita, Miki Oyama, Masaru Mitsui, Yoshikazu Tanaka, Toru Nakano, Susumu Mitsutake, Yasuyuki Igarashi, Hiroshi Takemoto
To evaluate the precise role of sphingomyelin synthase 2 (SMS2) in sphingomyelin (SM) metabolism and their anti-inflammatory properties, we analyzed species of major SM and ceramide (Cer) (18:1, 18:0 sphingoid backbone, C14 - C26 N-acyl part) in SMS2 knockout and wild-type mouse plasma and liver using HPLC-MS. SMS2 deficiency significantly decreased very long chain SM (SM (d18:1/22:0) and SM (d18:1/24:0 or d18:0/24:1)) and increased very long chain Cer (Cer (d18:1/24:0 or d18:0/24:1) and Cer (d18:1/24:1)), but not long chain SM (SM (d18:1/16:0), SM (d18:1/18:0 or d18:0/18:1) and SM (d18:1/18:1)) in plasma...
November 9, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27809764/cross-phenotype-association-tests-uncover-genes-mediating-nutrient-response-in-drosophila
#5
Christopher S Nelson, Jennifer N Beck, Kenneth A Wilson, Elijah R Pilcher, Pankaj Kapahi, Rachel B Brem
BACKGROUND: Obesity-related diseases are major contributors to morbidity and mortality in the developed world. Molecular diagnostics and targets of therapies to combat nutritional imbalance are urgently needed in the clinic. Invertebrate animals have been a cornerstone of basic research efforts to dissect the genetics of metabolism and nutrient response. We set out to use fruit flies reared on restricted and nutrient-rich diets to identify genes associated with starvation resistance, body mass and composition, in a survey of genetic variation across the Drosophila Genetic Reference Panel (DGRP)...
November 4, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27806293/sphingosine-kinase-1-cooperates-with-autophagy-to-maintain-endocytic-membrane-trafficking
#6
Megan M Young, Yoshinori Takahashi, Todd E Fox, Jong K Yun, Mark Kester, Hong-Gang Wang
Sphingosine kinase 1 (Sphk1) associates with early endocytic membranes during endocytosis; however, the role of sphingosine or sphingosine-1-phosphate as the critical metabolite in endocytic trafficking has not been established. Here, we demonstrate that the recruitment of Sphk1 to sphingosine-enriched endocytic vesicles and the generation of sphingosine-1-phosphate facilitate membrane trafficking along the endosomal pathway. Exogenous sphingosine and sphingosine-based Sphk1 inhibitors induce the Sphk1-dependent fusion of endosomal membranes to accumulate enlarged late endosomes and amphisomes enriched in sphingolipids...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27775668/role-of-intracellular-lipid-logistics-in-the-preferential-usage-of-very-long-chain-ceramides-in-glucosylceramide
#7
Toshiyuki Yamaji, Aya Horie, Yuriko Tachida, Chisato Sakuma, Yusuke Suzuki, Yasunori Kushi, Kentaro Hanada
Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20-26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It is known that the proportion of VLC species in GSLs is higher than that in SM. To address the mechanism of the VLC-preference of GSLs, we used genome editing to establish three HeLa cell mutants that expressed different amounts of CERS2 and compared the acyl chain lengths of SM and GSLs by metabolic labeling experiments...
October 21, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27728904/hypothalamic-lipids-key-regulators-of-whole-body-energy-balance
#8
Ismael González-García, Johan Fernø, Carlos Diéguez, Rubén Nogueiras, Miguel López
Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase (FAS) and AMP-activated protein kinase (AMPK), impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues non suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases, such as insulin resistance, cardiomyopathy, atherosclerosis and steatohepatitis...
October 11, 2016: Neuroendocrinology
https://www.readbyqxmd.com/read/27703011/a-role-for-ceramides-but-not-sphingomyelins-as-antagonists-of-insulin-signaling-and-mitochondrial-metabolism-in-c2c12-myotubes
#9
Min Park, Vincent Kaddai, Jianhong Ching, Kevin T Fridianto, Ryan J Sieli, Shigeki Sugii, Scott A Summers
The accumulation of sphingolipids in obesity leads to impairments in insulin sensitivity and mitochondrial metabolism, but the precise species driving these defects is unclear. We have modeled these obesity-induced effects in cultured C2C12 myotubes, using BSA-conjugated palmitate to increase synthesis of endogenous sphingolipids and to inhibit insulin signaling and oxidative phosphorylation. Palmitate (a) induced the accumulation of sphingomyelin (SM) precursors such as sphinganine, dihydroceramide, and ceramide; (b) inhibited insulin stimulation of a central modulator of anabolic metabolism, Akt/PKB; (c) inhibited insulin-stimulated glycogen synthesis; and (d) decreased oxygen consumption and ATP synthesis...
November 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27647482/spinal-muscular-atrophy-associated-with-progressive-myoclonus-epilepsy
#10
Haluk Topaloglu, Judith Melki
A rare syndrome characterized by lower motor neuron disease associated with progressive myoclonic epilepsy, referred to as "spinal muscular atrophy associated with progressive myoclonic epilepsy" (SMA-PME), has been described in childhood and is inherited as an autosomal recessive trait. SMA-PME is caused by mutation in the ASAH1 gene encoding acid ceramidase. Ceramide and the metabolites participate in various cellular events as lipid mediators. The catabolism of ceramide in mammals occurs in lysosomes through the activity of ceramidase...
September 1, 2016: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/27634569/developmental-inhibition-of-mir-iab8-3p-disrupts-mushroom-body-neuron-structure-and-adult-learning-ability
#11
Germain U Busto, Tugba Guven-Ozkan, Molee Chakraborty, Ronald L Davis
MicroRNAs are small non-coding RNAs that inhibit protein expression post-transcriptionally. They have been implicated in many different physiological processes, but little is known about their individual involvement in learning and memory. We recently identified several miRNAs that either increased or decreased intermediate-term memory when inhibited in the central nervous system, including miR-iab8-3p. We report here a new developmental role for this miRNA. Blocking the expression of miR-iab8-3p during the development of the organism leads to hypertrophy of individual mushroom body neuron soma, a reduction in the field size occupied by axonal projections, and adult intellectual disability...
September 12, 2016: Developmental Biology
https://www.readbyqxmd.com/read/27618929/autosomal-recessive-progressive-myoclonus-epilepsy-due-to-impaired-ceramide-synthesis
#12
Edoardo Ferlazzo, Pasquale Striano, Domenico Italiano, Tiziana Calarese, Sara Gasparini, Nicola Vanni, Floriana Fruscione, Pierre Genton, Federico Zara
Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis is an extremely rare condition, so far reported in a single family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. Genetic study allowed to identify a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides...
September 1, 2016: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/27591968/regulation-of-glucose-homeostasis-and-insulin-action-by-ceramide-acyl-chain-length-a-beneficial-role-for-very-long-chain-sphingolipid-species
#13
Magdalene K Montgomery, Simon H J Brown, Xin Y Lim, Corrine E Fiveash, Brenna Osborne, Nicholas L Bentley, Jeremy P Braude, Todd W Mitchell, Adelle C F Coster, Anthony S Don, Gregory J Cooney, Carsten Schmitz-Peiffer, Nigel Turner
In a recent study, we showed that in response to high fat feeding C57BL/6, 129X1, DBA/2 and FVB/N mice all developed glucose intolerance, while BALB/c mice displayed minimal deterioration in glucose tolerance and insulin action. Lipidomic analysis of livers across these five strains has revealed marked strain-specific differences in ceramide (Cer) and sphingomyelin (SM) species with high-fat feeding; with increases in C16-C22 (long-chain) and reductions in C>22 (very long-chain) Cer and SM species observed in the four strains that developed HFD-induced glucose intolerance...
November 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27551807/defects-in-stratum-corneum-desquamation-are-the-predominant-effect-of-impaired-abca12-function-in-a-novel-mouse-model-of-harlequin-ichthyosis
#14
Lei Zhang, Michael Ferreyros, Weiguo Feng, Melanie Hupe, Debra A Crumrine, Jiang Chen, Peter M Elias, Walter M Holleran, Lee Niswander, Daniel Hohl, Trevor Williams, Enrique C Torchia, Dennis R Roop
Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis...
2016: PloS One
https://www.readbyqxmd.com/read/27548800/the-effect-of-glycation-on-epidermal-lipid-content-its-metabolism-and-change-in-barrier-function
#15
Mami Yokota, Yoshihiro Tokudome
BACKGROUND/AIMS: Advanced glycation end products, which are linked to both aging and hyperglycemia, cause marked functional and structural alterations in human skin. Though it is well known that the metabolism of glucose is closely associated with that of fatty acid (FA), sharing the same energy-yielding reaction pathways as glucose, its effect on the epidermis has been unclear so far. METHODS: Content of ceramides, cholesterol and FA in a reconstructed epidermal model glycated by glyoxal was analyzed by high-performance thin-layer chromatography...
August 23, 2016: Skin Pharmacology and Physiology
https://www.readbyqxmd.com/read/27539961/cholesterol-dependent-increases-in-glucosylceramide-synthase-activity-in-niemann-pick-disease-type-c-model-cells-abnormal-trafficking-of-endogenously-formed-ceramide-metabolites-by-inhibition-of-the-enzyme
#16
Naohiro Hashimoto, Ikiru Matsumoto, Hiromasa Takahashi, Hitomi Ashikawa, Hiroyuki Nakamura, Toshihiko Murayama
Sphingolipids such as sphingomyelin and glycosphingolipids (GSLs) derived from glucosylceramide (GlcCer), in addition to cholesterol, accumulate in cells/neurons in Niemann-Pick disease type C (NPC). The activities of acid sphingomyelinase and lysosomal glucocerebrosidase (GCase), which degrade sphingomyelin and GlcCer, respectively, are down-regulated in NPC cells, however, changes in GlcCer synthase activity have not yet been elucidated. We herein demonstrated for the first time that GlcCer synthase activity for the fluorescent ceramide, 4-nitrobenzo-2-oxa-1,3-diazole-labeled C6-ceramide (NBD-ceramide) increased in intact NPC1((-/-)) cells and cell lysates without affecting the protein levels...
November 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27517620/inhibition-of-glucosylceramide-synthase-eliminates-the-oncogenic-function-of-p53-r273h-mutant-in-the-epithelial-mesenchymal-transition-and-induced-pluripotency-of-colon-cancer-cells
#17
Salman B Hosain, Sachin K Khiste, Mohammad B Uddin, Vindya Vorubindi, Catherine Ingram, Sifang Zhang, Ronald A Hill, Xin Gu, Yong-Yu Liu
Missense mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF), not only promotes tumor progression, but also diminishes therapeutic efficacies of cancer treatments. However, it remains unclear how a p53 missense mutant contributes to induced pluripotency of cancer stem cells (CSCs) in tumors exposed to chemotherapeutic agents. More importantly, it may be possible to abrogate the GOF by restoring wild-type p53 activity, thereby overcoming the deleterious effects resulting from heterotetramer formation, which often compromises the efficacies of current approaches being used to reactivate p53 function...
August 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27517489/suppression-of-c-myc-and-rrm2-expression-in-pancreatic-cancer-cells-by-the-sphingosine-kinase-2-inhibitor-abc294640
#18
Clayton S Lewis, Christina Voelkel-Johnson, Charles D Smith
Pancreatic cancer remains extremely difficult to treat, with the average lifespan following diagnosis being only 3-6 months, resulting in a death to incidence ratio of 0.94. A major reason for this high mortality rate is resistance to the main chemotherapeutic agent used to treat this disease, gemcitabine. Alterations in nucleoside and gemcitabine metabolism, specifically over-expression of ribonucleotide reductase, have been implicated as a major mechanism of resistance to this drug. Here, we show that inhibition of sphingosine kinase-2 by the specific inhibitor ABC294640 is synergistically cytotoxic with gemcitabine toward three human pancreatic cancer cell lines...
August 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27517152/a-recombinantly-tailored-%C3%AE-defensin-that-displays-intensive-macropinocytosis-mediated-uptake-exerting-potent-efficacy-against-k-ras-mutant-pancreatic-cancer
#19
Salman B Hosain, Sachin K Khiste, Mohammad B Uddin, Vindya Vorubindi, Catherine Ingram, Sifang Zhang, Ronald A Hill, Xin Gu, Yong-Yu Liu
Missense mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF), not only promotes tumor progression, but also diminishes therapeutic efficacies of cancer treatments. However, it remains unclear how a p53 missense mutant contributes to induced pluripotency of cancer stem cells (CSCs) in tumors exposed to chemotherapeutic agents. More importantly, it may be possible to abrogate the GOF by restoring wild-type p53 activity, thereby overcoming the deleterious effects resulting from heterotetramer formation, which often compromises the efficacies of current approaches being used to reactivate p53 function...
August 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27506241/orm-expression-alters-sphingolipid-homeostasis-and-differentially-affects-ceramide-synthase-activity
#20
Athen N Kimberlin, Gongshe Han, Kyle D Luttgeharm, Ming Chen, Rebecca E Cahoon, Julie M Stone, Jonathan E Markham, Teresa M Dunn, Edgar B Cahoon
Sphingolipid synthesis is tightly regulated in eukaryotes. This regulation in plants ensures sufficient sphingolipids to support growth while limiting the accumulation of sphingolipid metabolites that induce programmed cell death. Serine palmitoyltransferase (SPT) catalyzes the first step in sphingolipid biosynthesis and is considered the primary sphingolipid homeostatic regulatory point. In this report, Arabidopsis (Arabidopsis thaliana) putative SPT regulatory proteins, orosomucoid-like proteins AtORM1 and AtORM2, were found to interact physically with Arabidopsis SPT and to suppress SPT activity when coexpressed with Arabidopsis SPT subunits long-chain base1 (LCB1) and LCB2 and the small subunit of SPT in a yeast (Saccharomyces cerevisiae) SPT-deficient mutant...
October 2016: Plant Physiology
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