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Ceramide platforms

Yugesh Kharel, Sayeh Agah, Tao Huang, Anna J Mendelson, Oluwafunmilayo T Eletu, Peter Barkey-Bircann, James Gesualdi, Jeffrey S Smith, Webster L Santos, Kevin R Lynch
Successful medicinal chemistry campaigns to discover and optimize sphingosine kinase inhibitors require a robust assay for screening chemical libraries and for determining rank order potencies. Existing assays for these enzymes are laborious, expensive and/or low throughput. The toxicity of excessive levels of phosphorylated sphingoid bases for the budding yeast, Saccharomyces cerevisiae, affords an assay wherein inhibitors added to the culture media rescue growth in a dose-dependent fashion. Herein, we describe our adaptation of a simple, inexpensive, and high throughput assay for assessing inhibitors of sphingosine kinase types 1 and 2 as well as ceramide kinase and for testing enzymatic activity of sphingosine kinase type 2 mutants...
2018: PloS One
Lin Zhong, Erxi Liu, Chaozhu Yang, Ying Diao, Nunung Harijati, Jiangdong Liu, Zhongli Hu, Surong Jin
Amorphophallus is a perennial herbaceous plant species mainly distributed in the tropics or subtropics of Asia and Africa. It has been used as a traditional medicine for a long time and now is utilized for the pharmaceutical, chemical and agriculture industries as a valued economic crop. Recently, Amorphophallus has attracted tremendous interest because of its high ceramide content. However, the breeding and genome studies are severely limited by the arduous whole genome sequencing of Amorphophallus. In this study, the transcriptome data of A...
2018: PloS One
Amanda Migotto, Vanessa F M Carvalho, Giovanna C Salata, Fernanda W M da Silva, Chao Yun Irene Yan, Kelly Ishida, Leticia V Costa-Lotufo, Alexandre A Steiner, Luciana B Lopes
Considering that breast cancer usually begins in the lining of the ducts, local drug administration into the ducts could target cancers and pre-tumor lesions locally while reducing systemic adverse effects. In this study, a cationic bioadhesive nanoemulsion was developed for intraductal administration of C6 ceramide, a sphingolipid that mediates apoptotic and non-apoptotic cell death. Bioadhesive properties were obtained by surface modification with chitosan. The optimized nanoemulsion displayed size of 46...
November 2018: Drug Delivery
Cian Monnin, Parsram Ramrup, Carolann Daigle-Young, Dajana Vuckovic
RATIONALE: Mobile-phase additives in liquid chromatography/mass spectrometry (LC/MS) are used to improve peak shape, analyte ionization efficiency and method coverage. Both basic and acidic mobile phases have been used successfully for negative electrospray ionization (ESI), but very few systematic investigations exist to date to justify the choice of mobile phase. Acetic acid was previously shown to improve ionization in untargeted metabolomics of urine, but has not been investigated in lipidomics...
February 15, 2018: Rapid Communications in Mass Spectrometry: RCM
Xuewei Zhang, Kazuyuki Kitatani, Masafumi Toyoshima, Masumi Ishibashi, Toshinori Usui, Junko Minato, Mahy Egiz, Shogo Shigeta, Todd Fox, Tye Deering, Mark Kester, Nobuo Yaegashi
Ceramides are bioactive lipids that mediate cell death in cancer cells, and ceramide-based therapy is now being tested in dose-escalating phase I clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics, and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL), we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer...
January 2018: Molecular Cancer Therapeutics
Cristina Minnelli, Laura Cianfruglia, Emiliano Laudadio, Roberta Galeazzi, Michela Pisani, Emanuela Crucianelli, Davide Bizzaro, Tatiana Armeni, Giovanna Mobbili
Liposomes are versatile platforms to carry anticancer drugs in targeted drug delivery; they can be surface modified by different strategies and, when coupled with targeting ligands, are able to increase cellular internalisation and organelle-specific drug delivery. An interesting strategy of antitumoral therapy could involve the use of lysosomotropic ligand-targeted liposomes loaded with molecules, which can induce lysosomal membrane permeabilization (LMP), leakage of cathepsins into the cytoplasm and subsequent apoptosis...
March 2018: Journal of Drug Targeting
Cao Li, Yuqing Wu, Veronique Orian-Rousseau, Yang Zhang, Erich Gulbins, Heike Grassme
AIMS: Staphylococcus aureus plays an important role in sepsis, pneumonia, and wound infections. Acid sphingomyelinase (Asm)-deficient mice are highly susceptible to pulmonary S. aureus infections. Here, we investigated the role of CD44 as a molecule that mediates important aspects of the infection of macrophages with S. aureus. RESULTS: We showed that CD44 activation by S. aureus stimulated Asm via the formation of reactive oxygen species (ROS), resulting in ceramide release, clustering of CD44 in ceramide-enriched membrane platforms, CD44/Asm-dependent activation of Rho family GTPases, translocation of phospho-ezrin/radixin/moesin to the plasma-membrane, and a rapid rearrangement of the actin cytoskeleton with cortical actin polymerization...
July 26, 2017: Antioxidants & Redox Signaling
Saisudha Koka, Min Xia, Yang Chen, Owais M Bhat, Xinxu Yuan, Krishna M Boini, Pin-Lan Li
The NLRP3 inflammasome has been reported to be activated by atherogenic factors, whereby endothelial injury and consequent atherosclerotic lesions are triggered in the arterial wall. However, the mechanisms activating and regulating NLRP3 inflammasomes remain poorly understood. The present study tested whether acid sphingomyelinase (ASM) and ceramide associated membrane raft (MR) signaling platforms contribute to the activation of NLRP3 inflammasomes and atherosclerotic lesions during hypercholesterolemia. We found that 7-ketocholesterol (7-Keto) or cholesterol crystal (ChC) markedly increased the formation and activation of NLRP3 inflammasomes in mouse carotid arterial endothelial cells (CAECs), as shown by increased colocalization of NLRP3 with ASC or caspase-1, enhanced caspase-1 activity and elevated IL-1β levels, which were markedly attenuated by mouse Asm siRNA, ASM inhibitor- amitriptyline, and deletion of mouse Asm gene...
October 2017: Redox Biology
Raquela J Thomas, Natalia Oleinik, Shanmugam Panneer Selvam, Silvia G Vaena, Mohammed Dany, Rose N Nganga, Ryan Depalma, Kyla D Baron, Jisun Kim, Zdzislaw M Szulc, Besim Ogretmen
Human papillomavirus (HPV) infection is linked to improved survival in response to chemo-radiotherapy for patients with oropharynx head and neck squamous cell carcinoma (HNSCC). However, mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. Here, using molecular, pharmacologic and genetic tools, we show that HPV early protein 7 (E7) enhances ceramide-mediated lethal mitophagy in response to chemotherapy-induced cellular stress in HPV-positive HNSCC cells by selectively targeting retinoblastoma protein (RB)...
August 2017: EMBO Molecular Medicine
Heike Grassmé, Brian Henry, Regan Ziobro, Katrin Anne Becker, Joachim Riethmüller, Aaron Gardner, Aaron P Seitz, Joerg Steinmann, Stephan Lang, Christopher Ward, Edward H Schuchman, Charles C Caldwell, Markus Kamler, Michael J Edwards, Malcolm Brodlie, Erich Gulbins
Chronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that β1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. β1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap β1-integrins on the luminal pole of bronchial epithelial cells. β1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria...
June 14, 2017: Cell Host & Microbe
Anne Burgert, Jan Schlegel, Jérôme Bécam, Sören Doose, Erhard Bieberich, Alexandra Schubert-Unkmeir, Markus Sauer
The sphingolipid ceramide regulates cellular processes such as differentiation, proliferation, growth arrest, and apoptosis. Ceramide-rich membrane areas promote structural changes within the plasma membrane that segregate membrane receptors and affect membrane curvature and vesicle formation, fusion, and trafficking. Ceramides were labeled by immunocytochemistry to visualize their distribution on the plasma membrane of different cells with virtually molecular resolution by direct stochastic optical reconstruction microscopy (dSTORM)...
May 22, 2017: Angewandte Chemie
Colin Niaudet, Stéphanie Bonnaud, Maëva Guillonneau, Sébastien Gouard, Marie-Hélène Gaugler, Soizic Dutoit, Natacha Ripoche, Nolwenn Dubois, Valérie Trichet, Isabelle Corre, François Paris
The p38 MAPK signaling pathway is essential in the cellular response to stress stimuli, in particular in the endothelial cells that are major target of external stress. The importance of the bioactive sphingolipid ceramide generated by acid sphingomyelinase is also firmly established in stress-induced endothelial apoptotic cell death. Despite a suggested link between the p38 MAPK and ceramide pathways, the exact molecular events of this connection remain elusive. In the present study, by using two different activators of p38 MAPK, namely anisomycin and ionizing radiation, we depicted how ceramide generated by acid sphingomyelinase was involved in p38 MAPK-dependent apoptosis of endothelial cells...
May 2017: Cellular Signalling
Kerri J Kinghorn, Sebastian Grönke, Jorge Iván Castillo-Quan, Nathaniel S Woodling, Li Li, Ernestas Sirka, Matthew Gegg, Kevin Mills, John Hardy, Ivana Bjedov, Linda Partridge
Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD...
November 16, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Miguel A Martín-Acebes, Ángela Vázquez-Calvo, Juan-Carlos Saiz
Flaviviruses are emerging arthropod-borne pathogens that cause life-threatening diseases such as yellow fever, dengue, West Nile encephalitis, tick-borne encephalitis, Kyasanur Forest disease, tick-borne encephalitis, or Zika disease. This viral genus groups >50 viral species of small enveloped plus strand RNA virus that are phylogenetically closely related to hepatitis C virus. Importantly, the flavivirus life cycle is intimately associated to host cell lipids. Along this line, flaviviruses rearrange intracellular membranes from the endoplasmic-reticulum of the infected cells to develop adequate platforms for viral replication and particle biogenesis...
October 2016: Progress in Lipid Research
Jace W Jones, Claire L Carter, Fei Li, Jianshi Yu, Keely Pierzchalski, Isabel L Jackson, Zeljko Vujaskovic, Maureen A Kane
Lipids represent biologically ubiquitous and highly dynamic molecules in terms of abundance and structural diversity. Whereas the potential for lipids to inform on disease/injury is promising, their unique characteristics make detection and identification of lipids from biological samples analytically demanding. We report the use of ultraperformance convergence chromatography (UPC2 ), a variant of supercritical fluid chromatography, coupled to high-resolution, data-independent tandem mass spectrometry for characterization of total lipid extracts from mouse lung tissue...
March 2017: Biomedical Chromatography: BMC
Alexei Gorelik, Katalin Illes, Leonhard X Heinz, Giulio Superti-Furga, Bhushan Nagar
Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site...
July 20, 2016: Nature Communications
Zhexue Wu, Jong Cheol Shon, Doohyun Lee, Kab-Tae Park, Chang Seo Park, Taeho Lee, Hye Suk Lee, Kwang-Hyeon Liu
Skin ceramides are sphingolipids consisting of sphingoid bases, which are linked to fatty acids via an amide bond. Typical fatty acid acyl chains are composed of α-hydroxy fatty acid (A), esterified ω-hydroxy fatty acid (EO), non-hydroxy fatty acid (N), and ω-hydroxy fatty acid (O). We recently established a lipidomic platform to identify skin ceramides with non-hydroxyacyl chains using tandem mass spectrometry. We expanded our study to establish a lipidomic platform to identify skin ceramides with α-hydroxyacyl chains...
March 2016: Analytical and Bioanalytical Chemistry
Fang Bian, Bin Xiong, Xiaoyan Yang, Si Jin
Transcytosis, a widely described process concerning transport of macromolecules between the apical and basolateral sides in various cell types, is extremely important for multicellular organisms to selectively exchange materials in different microenvironments while maintaining cellular and body homeostasis. Uncontrolled transcytosis is involved in a wide range of pathophysiological processes. Lipid rafts (LRs), the sphingolipid and cholesterol-enriched membrane microdomains, enable to form different functional membrane macrodomains or platforms upon stimulations...
January 1, 2016: Frontiers in Bioscience (Landmark Edition)
Shravan Kumar Sriraman, Jiayi Pan, Can Sarisozen, Ed Luther, Vladimir Torchilin
Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous...
February 1, 2016: Molecular Pharmaceutics
Tingting Zhang, Si Chen, Xinle Liang, Hong Zhang
This article describes the development of a lipidomic platform consisting of a 4000 QTRAP mass spectrometer and a self-installed sample inlet system to indentify and quantify 12 phospholipid and five sphingolipid classes from lipid-rich brain tissues of mouse, duck, and salmon. The total mass spectrometry analysis time per sample was 30 min, including 14 min for direct infusion for phospholipids and sulfatide in precursor ion scanning mode or neutral loss scanning mode, and 16 min for liquid-chromatographic separation of ceramide, sphingomyelin, monohexosylceramide, and dihexosylceramide in multiple reaction monitoring mode...
August 2015: Analytical and Bioanalytical Chemistry
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