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Myriocin

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https://www.readbyqxmd.com/read/28531105/high-mobility-group-box-1-disrupts-metabolic-function-with-cigarette-smoke-exposure-in-a-ceramide-dependent-manner
#1
Oliver J Taylor, Mikayla O Thatcher, Sheryl T Carr, Jonathan L Gibbs, Annie M Trumbull, Mitchell E Harrison, Duane R Winden, Mackenzie J Pearson, Trevor S Tippetts, William L Holland, Paul R Reynolds, Benjamin T Bikman
We have previously found that cigarette smoke disrupts metabolic function, in part, by increasing muscle ceramide accrual. To further our understanding of this, we sought to determine the role of the cytokine high-mobility group box 1 (HMGB1), which is increased with smoke exposure, in smoke-induced muscle metabolic perturbations. To test this theory, we determined HMGB1 from lungs of human smokers, as well as from lung cells from mice exposed to cigarette smoke. We also treated cells and mice directly with HMGB1, in the presence or absence of myriocin, an inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in ceramide biosynthesis...
May 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28490444/inhibiting-glucosylceramide-synthase-exacerbates-cisplatin-induced-acute-kidney-injury
#2
Tess V Dupre, Mark A Doll, Parag P Shah, Cierra N Sharp, Deanna Siow, Judit Megyesi, James Shayman, Alicja Bielwska, Jacek Bielawski, Levi J Beverly, Maria Hernandez-Corbacho, Christopher J Clarke, Ashley J Snider, Rick G Schnellmann, Lina M Obeid, Yusuf A Hannun, Leah J Siskind
Acute kidney injury (AKI), resulting from chemotherapeutic agents such as cisplatin, remains an obstacle in the treatment of cancer. Cisplatin-induced AKI involves apoptotic and necrotic cell death, pathways regulated by sphingolipids such as ceramide and glucosylceramide. Results from this study indicate that C57BL/6J mice treated with cisplatin had increased ceramide and hexosylceramide levels in the renal cortex 72 h following cisplatin treatment. Pre-treatment of mice with inhibitors of acid sphingomyelinase and de novo ceramide synthesis (amitriptyline and myriocin, respectively) prevented accumulation of ceramides and hexosylceramide in the renal cortex and protected from cisplatin-induced AKI...
May 10, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28474276/sphingosine-toxicity-in-eae-and-ms-evidence-for-ceramide-generation-via-serine-palmitoyltransferase-activation
#3
Lawrence G Miller, Jennifer A Young, Swapan K Ray, Guanghu Wang, Sharad Purohit, Naren L Banik, Somsankar Dasgupta
Multiple sclerosis (MS) is a demyelinating disorder characterized by massive neurodegeneration and profound axonal loss. Since myelin is enriched with sphingolipids and some of them display toxicity, biological function of sphingolipids in demyelination has been investigated in MS brain tissues. An elevation of sphingosine with a decrease in monoglycosylceramide and psychosine (myelin markers) was observed in MS white matter and plaque compared to normal brain tissue. This indicated that sphingosine toxicity might mediate oligodendrocyte degeneration...
May 5, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28469091/increased-de-novo-ceramide-synthesis-and-accumulation-in-failing-myocardium
#4
Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J Kennel, Danielle L Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y Deng, Shunichi Homma, Isaac J George, Hiroo Takayama, Yoshifumi Naka, Ira J Goldberg, P Christian Schulze
Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28439630/myriocin-treatment-of-cf-lung-infection-and-inflammation-complex-analyses-for-enigmatic-lipids
#5
Anna Caretti, Michele Vasso, Fabiola Tecla Bonezzi, Andrea Gallina, Marco Trinchera, Alice Rossi, Raffaella Adami, Josefina Casas, Monica Falleni, Delfina Tosi, Alessandra Bragonzi, Riccardo Ghidoni, Cecilia Gelfi, Paola Signorelli
Our aim was to use quantitative and qualitative analyses to gain further insight into the role of ceramide in cystic fibrosis (CF). Sphingolipid ceramide is a known inflammatory mediator, and its accumulation in inflamed lung has been reported in different types of emphysema, chronic obstructive pulmonary disease and CF. CF is caused by a mutation of the chloride channel and associated with hyperinflammation of the respiratory airways and high susceptibility to ongoing infections. We have previously demonstrated that de novo ceramide synthesis is enhanced in lung inflammation and sustains Pseudomonas aeruginosa pulmonary infection in a CF murine model...
April 24, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28409208/inhibitors-of-ceramide-de-novo-biosynthesis-rescue-damages-induced-by-cigarette-smoke-in-airways-epithelia
#6
Aida Zulueta, Anna Caretti, Giuseppe Matteo Campisi, Andrea Brizzolari, Jose Luis Abad, Rita Paroni, Paola Signorelli, Riccardo Ghidoni
Exposure to cigarette smoke represents the most important risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation of the airways, imbalance of proteolytic activity resulting in the destruction of lung parenchyma, alveolar hypoxia, oxidative stress, and apoptosis. Sphingolipids are structural membrane components whose metabolism is altered during stress. Known as apoptosis and inflammation inducer, the sphingolipid ceramide was found to accumulate in COPD airways and its plasma concentration increased as well...
April 13, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28268212/inhibition-of-ceramide-decreased-the-expression-of-atp-binding-cassette-transporter-g5-8-mrna-in-an-animal-model-of-cholesterol-gallstone
#7
Hyo Jung Kim, Jae Seon Kim, Seikwan Oh, Hwan-Soo Yoo
BACKGROUND: The increased risk of gallstone has been reported in patients with ATP-binding cassette (ABC) transporter polymorphism. The half-transporters ABCG5 and ABCG8 mediate the efflux of cholesterol in hepatocytes and the intestine. We investigated whether ceramide plays a role in cholesterol efflux through the ABC transporters. METHODS: Six-week-old C57BL/6J mice were assigned to 3 groups. The normal group (n = 5) was fed a normal chow diet, the cholesterol group (n = 10) was fed a lithogenic diet, and the myriocin group (n = 15) was fed the lithogenic diet and myriocin, a specific inhibitor of serine-palmitoyl transferase...
March 8, 2017: Digestive Diseases
https://www.readbyqxmd.com/read/28236661/fam20c-is-under-the-control-of-sphingolipid-signaling-in-human-cell-lines
#8
Giorgio Cozza, Mauro Salvi, Vincent S Tagliabracci, Lorenzo A Pinna
Fam20C, also termed DMP-4 (dentin matrix protein 4) and G-CK (Golgi casein kinase) is an atypical protein kinase committed with the phosphorylation of casein and a plethora of other secreted proteins. Fam20C has been implicated in a number of human pathologies related to biomineralization, phosphate homeostasis, and neoplasia. The mode of regulation of Fam20C is still a matter of conjecture. In in vitro, Fam20C activity is stimulated several fold by sphingosine. To gain in vivo information about the physiological relevance of this observation, three cell lines expressing endogenous Fam20C, and one in which Fam20C has been knocked out with CRISPR/Cas9 technology have been examined for Fam20C activity under basal conditions and where sphingosine has been depleted by treatment with myriocin...
April 2017: FEBS Journal
https://www.readbyqxmd.com/read/28189121/myriocin-treatment-affects-lipid-metabolism-in-skeletal-muscles-of-rats-with-streptozotocin-induced-type-1-diabetes
#9
Krzysztof Kurek, Marta Garbowska, Dominika M Ziembicka, Bartłomiej Łukaszuk, Jakub Rogowski, Adrian Chabowski, Jan Górski, Małgorzata Żendzian-Piotrowska
PURPOSE: The aim of this work was to assess the effect(s) of de novo ceramide synthesis inhibition on lipid metabolism in skeletal muscle tissue of type 1 diabetic rats. The latter seems to be of vital importance, since previous works have shown its positive influence on lipid metabolism and glucose homeostasis in the case of its counterpart - type 2 diabetes. MATERIALS/METHODS: The animals were randomly assigned to one of the following groups: C - control, M - myriocin (ceramide de novo synthesis inhibitor), D - diabetes (induced by streptozotocin injections); D+M - diabetes+myriocin...
March 2017: Advances in Medical Sciences
https://www.readbyqxmd.com/read/28152593/combining-deep-sequencing-proteomics-phosphoproteomics-and-functional-screens-to-discover-novel-regulators-of-sphingolipid-homeostasis
#10
Nicolas Lebesgue, Márton Megyeri, Alba Cristobal, Arjen Scholten, Silvia G Chuartzman, Yoav Voichek, Richard A Scheltema, Shabaz Mohammed, Anthony H Futerman, Maya Schuldiner, Albert J R Heck, Simone Lemeer
Sphingolipids (SLs) are essential components of cell membranes and are broad-range bioactive signaling molecules. SL levels must be tightly regulated as imbalances affect cellular function and contribute to pathologies ranging from neurodegenerative and metabolic disorders to cancer and aging. Deciphering how SL homeostasis is maintained and uncovering new regulators is required for understanding lipid biology and for identifying new targets for therapeutic interventions. Here we combine omics technologies to identify the changes of the transcriptome, proteome, and phosphoproteome in the yeast Saccharomyces cerevisiae upon SL depletion induced by myriocin...
February 3, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28123341/downregulation-of-lipin-1-induces-insulin-resistance-by-increasing-intracellular-ceramide-accumulation-in-c2c12-myotubes
#11
Shujuan Huang, Suling Huang, Xi Wang, Qingli Zhang, Jia Liu, Ying Leng
Dysregulation of lipid metabolism in skeletal muscle is involved in the development of insulin resistance. Mutations in lipin-1, a key lipid metabolism regulator leads to significant systemic insulin resistance in fld mice. However, the function of lipin-1 on lipid metabolism and insulin sensitivity in skeletal muscle is still unclear. Herein we demonstrated that downregulation of lipin-1 in C2C12 myotubes by siRNA transfection suppressed insulin action, characterized by reduced insulin stimulated Akt phosphorylation and glucose uptake...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28030368/sphingolipids-ormdl3-and-asthma-what-is-the-evidence
#12
Tilla S Worgall
PURPOSE OF REVIEW: Genome-wide association studies identified ORMDL3, a protein of the endoplasmic reticulum, as a significant asthma risk factor. ORMDL3 is one of three ORMDL proteins that integrate multiple signals to maintain sphingolipid homeostasis. Studies that investigated potential mechanisms for how increased ORMDL3 might affect asthma are summarized. RECENT FINDINGS: Investigations focused on decreased sphingolipid synthesis and on the unfolded protein response because ORMDL3 had been implicated in both...
March 2017: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/27960149/the-crucial-role-of-c18-cer-in-fat-induced-skeletal-muscle-insulin-resistance
#13
Agnieszka U Blachnio-Zabielska, Marta Chacinska, Mikkel H Vendelbo, Piotr Zabielski
BACKGROUND/AIMS: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. METHODS: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27894925/dihydroceramide-desaturase-inhibitors-induce-autophagy-via-dihydroceramide-dependent-and-independent-mechanisms
#14
Mireia Casasampere, Yadira F Ordóñez, Josefina Casas, Gemma Fabrias
BACKGROUND: Autophagy consists on the delivery of cytoplasmic material and organelles to lysosomes for degradation. Research on autophagy is a growing field because deciphering the basic mechanisms of autophagy is key to understanding its role in health and disease, and to paving the way to discovering novel therapeutic strategies. Studies with chemotherapeutic drugs and pharmacological tools support a role for dihydroceramides as mediators of autophagy. However, their effect on the autophagy outcome (cell survival or death) is more controversial...
February 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27693577/antifungal-activity-of-eicosanoic-acids-isolated-from-the-endophytic-fungus-mycosphaerella-sp-against-cryptococcus-neoformans-and-c-%C3%A2-gattii
#15
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...
November 2016: Microbial Pathogenesis
https://www.readbyqxmd.com/read/27621809/intratracheal-myriocin-enhances-allergen-induced-th2-inflammation-and-airway-hyper-responsiveness
#16
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
https://www.readbyqxmd.com/read/27400027/simplifungin-and-valsafungins-antifungal-antibiotics-of-fungal-origin
#17
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
https://www.readbyqxmd.com/read/27343351/loss-of-frataxin-induces-iron-toxicity-sphingolipid-synthesis-and-pdk1-mef2-activation-leading-to-neurodegeneration
#18
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)...
June 25, 2016: ELife
https://www.readbyqxmd.com/read/27258401/from-natural-product-to-the-first-oral-treatment-for-multiple-sclerosis-the-discovery-of-fty720-gilenya%C3%A2
#19
REVIEW
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
https://www.readbyqxmd.com/read/27158676/endothelial-nogo-b-regulates-sphingolipid-biosynthesis-to-promote-pathological-cardiac-hypertrophy-during-chronic-pressure-overload
#20
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
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