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Cristiane Bigatti Pereira, Nívea Pereira de Sá, Beatriz Martins Borelli, Carlos Augusto Rosa, Paulo Jorge Sanches Barbeira, Betania Barros Cota, Susana Johann
The antifungal effects of two eicosanoic acids, 2-amino-3,4-dihydroxy-2-25-(hydroxymethyl)-14-oxo-6,12-eicosenoic acid (compound 1) and myriocin (compound 2), isolated from Mycosphaerella sp. were evaluated against Cryptococcus neoformans and C. gattii. The compounds displayed antifungal activities against several isolates of C. neoformans and C. gattii, with minimal inhibitory concentration (MIC) values ranging from 0.49 to 7.82 μM for compound 1 and 0.48-1.95 μM for compound 2. In the checkerboard microtiter test, both compounds exhibited synergistic activity with amphotericin B against C...
September 28, 2016: Microbial Pathogenesis
Ramakrishna Edukulla, Kira Lee Rehn, Bo Liu, Jaclyn W McAlees, Gurjit K Hershey, Yui Hsi Wang, Ian Lewkowich, Andrew W Lindsley
INTRODUCTION: Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. METHODS: Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo...
September 2016: Immunity, Inflammation and Disease
Hiroyuki Ishijima, Ryuji Uchida, Masaki Ohtawa, Ariko Kondo, Kenichiro Nagai, Keisuke Shima, Kenichi Nonaka, Rokuro Masuma, Susumu Iwamoto, Hideyuki Onodera, Tohru Nagamitsu, Hiroshi Tomoda
The targets of antifungal antibiotics in clinical use are more limited than those of antibacterial antibiotics. Therefore, new antifungal antibiotics with different mechanisms of action are desired. In the course of our screening for antifungal antibiotics of microbial origins, new antifungal antibiotics, simplifungin (1) and valsafungins A (2) and B (3), were isolated from cultures of the fungal strains Simplicillium minatense FKI-4981 and Valsaceae sp. FKH-53, respectively. The structures of 1 to 3 including their absolute stereochemistries were elucidated using various spectral analyses including NMR and collision-induced dissociation (CID)-MS/MS as well as chemical approaches including modifications to the Mosher's method...
September 2, 2016: Journal of Organic Chemistry
Kuchuan Chen, Guang Lin, Nele A Haelterman, Tammy Szu-Yu Ho, Tongchao Li, Zhihong Li, Lita Duraine, Brett H Graham, Manish Jaiswal, Shinya Yamamoto, Matthew N Rasband, Hugo J Bellen
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2)...
2016: ELife
Frédéric J Zécri
Multiple sclerosis is a devastating chronic autoimmune disease affecting women and men of all ages. Inflammation of the central nervous system causes demyelination and ultimately neuropsychological dysfunction. Myriocin, a natural product with strong immunosuppressant activity was interrogated leading to a new class of immunomodulator with a unique mode of action. In this review, we will summarize these findings, the mechanism hypothesis and discuss the data's ultimately leading to the approval of Gilenya™ as the first oral treatment for multiple sclerosis...
June 2016: Current Opinion in Chemical Biology
Yi Zhang, Yan Huang, Anna Cantalupo, Paula S Azevedo, Mauro Siragusa, Jacek Bielawski, Frank J Giordano, Annarita Di Lorenzo
We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α-activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production...
April 21, 2016: JCI Insight
Sara García-Marqués, Francisca Randez-Gil, Sebastien Dupont, Elena Garre, Jose A Prieto
All cells are delimited by biological membranes, which are consequently a primary target of stress-induced damage. Cold alters membrane functionality by decreasing lipid fluidity and the activity of membrane proteins. In Saccharomyces cerevisiae, evidence links sphingolipid homeostasis and membrane phospholipid asymmetry to the activity of the Ypk1/2 proteins, the yeast orthologous of the mammalian SGK1-3 kinases. Their regulation is mediated by different protein kinases, including the PDK1 orthologous Pkh1/2p, and requires the function of protein effectors, among them Nce102p, a component of the sphingolipid sensor machinery...
June 2016: Biochimica et Biophysica Acta
Anna Caretti, Riccardo Torelli, Federica Perdoni, Monica Falleni, Delfina Tosi, Aida Zulueta, Josefina Casas, Maurizio Sanguinetti, Riccardo Ghidoni, Elisa Borghi, Paola Signorelli
BACKGROUND: Fungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs...
June 2016: Biochimica et Biophysica Acta
M R Reforgiato, G Milano, G Fabriàs, J Casas, P Gasco, R Paroni, M Samaja, R Ghidoni, A Caretti, Paola Signorelli
The injury caused by myocardial reperfusion after ischemia can be contained by interventions aimed at reducing the inflammation and the oxidative stress that underlie exacerbation of tissue damage. Sphingolipids are a class of structural and signaling lipid molecules; among them, the inflammation mediator ceramide accumulates in the myocardium upon ischemia/reperfusion. Here, we show that, after transient coronary occlusion in mice, an increased de novo ceramide synthesis takes place at reperfusion in the ischemic area surrounding necrosis (area at risk)...
March 2016: Basic Research in Cardiology
Ahmad Alsahli, Kathryn Kiefhaber, Tziporah Gold, Munira Muluke, Hongfeng Jiang, Serge Cremers, Ulrike Schulze-Späte
Obesity and impaired lipid metabolism increase circulating and local fatty acid (FA) levels. Our previous studies showed that a high high-saturated -fat diet induced greater bone loss in mice than a high high-unsaturated-fat diet due to increased osteoclast numbers and activity. The impact of elevated FA levels on osteoblasts is not yet clear. We induced obesity in 4 week old male mice using a palmitic acid (PA)- or oleic acid (OA)-enriched high fat high-fat diet (HFD) (20 % of calories from FA), and compared them to mice on a normal (R) caloric diet (10 % of calories from FA)...
May 2016: Calcified Tissue International
Aimee E Hodson, Trevor S Tippetts, Benjamin T Bikman
BACKGROUND: States of hyperinsulinemia, particularly insulin resistance and type 2 diabetes mellitus, are becoming remarkably common, with roughly half a billion people likely to suffer from the disorder within the next 15 years. Along with this rise has been an associated increased burden of cardiovascular disease. Considering type 2 diabetics treated with insulin are more likely to suffer from heart complications, we sought to determine the specific effect of insulin on ceramide-dependent cardiometabolic risk factors, including insulin resistance and altered heart mitochondrial physiology...
2015: Cardiovascular Diabetology
Erwann Salaun, Luz Lefeuvre-Orfila, Thibault Cavey, Brice Martin, Bruno Turlin, Martine Ropert, Olivier Loreal, Frédéric Derbré
Bedridden patients in intensive care unit or after surgery intervention commonly develop skeletal muscle weakness. The latter is promoted by a variety of prolonged hospitalization-associated conditions. Muscle disuse is the most ubiquitous and contributes to rapid skeletal muscle atrophy and progressive functional strength reduction. Disuse causes a reduction in fatty acid oxidation, leading to its accumulation in skeletal muscle. We hypothesized that muscle fatty acid accumulation could stimulate ceramide synthesis and promote skeletal muscle weakness...
January 15, 2016: Journal of Applied Physiology
Laura Martínez, Sandra Torres, Anna Baulies, Cristina Alarcón-Vila, Montserrat Elena, Gemma Fabriàs, Josefina Casas, Joan Caballeria, Jose C Fernandez-Checa, Carmen García-Ruiz
Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH)...
December 8, 2015: Oncotarget
Melissa E Hansen, Kurtis J Simmons, Trevor S Tippetts, Mikayla O Thatcher, Rex R Saito, Sheryl T Hubbard, Annie M Trumbull, Brian A Parker, Oliver J Taylor, Benjamin T Bikman
Lipopolysaccharides (LPS) are prevalent pathogenic molecules that are found within tissues and blood. Elevated circulating LPS is a feature of obesity and sepsis, both of which are associated with mitochondrial abnormalities that are key pathological features of LPS excess. However, the mechanism of LPS-induced mitochondrial alterations remains poorly understood. Herein we demonstrate the necessity of sphingolipid accrual in mediating altered mitochondrial physiology in skeletal muscle following LPS exposure...
December 2015: Shock
Agnieszka Błachnio-Zabielska, Marcin Baranowski, Beata Wójcik, Jan Górski
PURPOSE: De novo sphingolipid synthesis does not occur in plasma, erythrocytes and platelets. The purpose of the study was to examine the effect of inhibition of sphingolipid synthesis in solid tissues on the level of the following bioactive sphingolipids: sphinganine, ceramide, sphingosine and sphingosine 1-phosphate in plasma, erythrocytes and platelets. MATERIAL/METHODS: The experiments were carried out on male Wistar rats. Myriocin was used to inhibit serine palmitoyltransferase activity (the enzyme catalyzes the first step of ceramide de novo synthesis) and nicotinic acid was used to reduce the concentration of plasma free fatty acids (a substrate for the de novo ceramide synthesis)...
March 2016: Advances in Medical Sciences
Alexandros Athanasopoulos, Christos Gournas, Sotiris Amillis, Vicky Sophianopoulou
The plasma membrane is implicated in a variety of functions, whose coordination necessitates highly dynamic organization of its constituents into domains of distinct protein and lipid composition. Eisosomes, at least partially, mediate this lateral plasma membrane compartmentalization. In this work, we show that the Nce102 homologue of Aspergillus nidulans colocalizes with eisosomes and plays a crucial role in density/number of PilA/SurG foci in the head of germlings. In addition we demonstrate that AnNce102 and PilA negatively regulate sphingolipid biosynthesis, since their deletions partially suppress the thermosensitivity of basA mutant encoding sphingolipid C4-hydroxylase and the growth defects observed upon treatment with inhibitors of sphingolipid biosynthesis, myriocin and Aureobasidin A...
2015: Scientific Reports
Erwann Salaun, Arlette Gratas-Delamarche, Frédéric Derbré
Patients admitted to the intensive care unit commonly develop skeletal muscle weakness that can exacerbate illness and complicate their recovery. Beyond the primary disease or aging, weakness is promoted by a variety of prolonged hospitalization-associated conditions. These include altered nutritional status, pharmacologic side effects, physical inactivity, and prolonged bed rest. The two latter conditions (i.e. inactivity and bed rest) are the most ubiquitous, affecting all patients during a prolonged hospitalization...
October 2014: Free Radical Biology & Medicine
Ji Na Kong, Kara Hardin, Michael Dinkins, Guanghu Wang, Qian He, Tarik Mujadzic, Gu Zhu, Jacek Bielawski, Stefka Spassieva, Erhard Bieberich
Cilia are important organelles formed by cell membrane protrusions; however, little is known about their regulation by membrane lipids. We characterize a novel activation mechanism for glycogen synthase kinase-3 (GSK3) by the sphingolipids phytoceramide and ceramide that is critical for ciliogenesis in Chlamydomonas and murine ependymal cells, respectively. We show for the first time that Chlamydomonas expresses serine palmitoyl transferase (SPT), the first enzyme in (phyto)ceramide biosynthesis. Inhibition of SPT in Chlamydomonas by myriocin led to loss of flagella and reduced tubulin acetylation, which was prevented by supplementation with the precursor dihydrosphingosine...
December 1, 2015: Molecular Biology of the Cell
Fikadu G Tafesse, Ali Rashidfarrokhi, Florian I Schmidt, Elizaveta Freinkman, Stephanie Dougan, Michael Dougan, Alexandre Esteban, Takeshi Maruyama, Karin Strijbis, Hidde L Ploegh
The ability of phagocytes to clear pathogens is an essential attribute of the innate immune response. The role of signaling lipid molecules such as phosphoinositides is well established, but the role of membrane sphingolipids in phagocytosis is largely unknown. Using a genetic approach and small molecule inhibitors, we show that phagocytosis of Candida albicans requires an intact sphingolipid biosynthetic pathway. Blockade of serine-palmitoyltransferase (SPT) and ceramide synthase-enzymes involved in sphingolipid biosynthesis- by myriocin and fumonisin B1, respectively, impaired phagocytosis by phagocytes...
October 2015: PLoS Pathogens
Lina Lindahl, Samuel Genheden, Leif A Eriksson, Lisbeth Olsson, Maurizio Bettiga
Lignocellulosic raw material plays a crucial role in the development of sustainable processes for the production of fuels and chemicals. Weak acids such as acetic acid and formic acid are troublesome inhibitors restricting efficient microbial conversion of the biomass to desired products. To improve our understanding of weak acid inhibition and to identify engineering strategies to reduce acetic acid toxicity, the highly acetic-acid-tolerant yeast Zygosaccharomyces bailii was studied. The impact of acetic acid membrane permeability on acetic acid tolerance in Z...
April 2016: Biotechnology and Bioengineering
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