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Bayerle, Aline [Verfasser]. "Physiologische Konsequenzen eines gestörten Ceramid Stoffwechsels unter Beteiligung von Ceramidsynthase 3 und saurer Ceramidase = Physiological consequences of a disturbed ceramide metabolism due to altered activities of ceramide synthase 3 and acidic ceramidase / Aline Bayerle." Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2015. http://d-nb.info/1225685362/34.
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Goltz, Gerit. "Charakterisierung von Ceramidase-Inhibitoren an der humanen Keratinozyten-Zellinie HaCaT." [S.l.] : [s.n.], 2002. http://www.diss.fu-berlin.de/2002/180/index.html.
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Lucki, Natasha Chrystman. "Characterization of the role of acid ceramidase in adrenocortical steroid hormone biosynthesis." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42804.
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Sphingolipids modulate multiple cellular functions, including steroid hormone biosynthesis. Sphingosine is an antagonist ligand for the nuclear receptor steroidogenic factor 1 (SF-1), which is the primary transcriptional regulator of most steroidogenic genes. Furthermore, sphingosine-dependent repression of SF-1 function is dependent on the expression of acid ceramidase (ASAH1), an enzyme that forms sphingosine. Based on these data, I hypothesized that ACTH/cAMP signaling regulates ASAH1 function at both transcriptional and post-transcriptional levels. In addition, because SF-1 is predominantly a nuclear protein, I postulated that ASAH1 modulates SF-1 function and, therefore, steroidogenic gene expression by controlling the nuclear concentrations of SPH. To test these hypotheses, I first examined the effect of chronic ACTH/cAMP signaling on the transcription of the ASAH1 gene. Next, the functional significance of ASAH1 expression in adrenocortical cells was probed by generating an ASAH1-knockdown cell line. I subsequently characterized the role of ASAH1 as a transcriptional nuclear receptor coregulator. Finally, I defined the role of sphingosine-1-phosphate, a bi-product of ASAH1 activity, in the acute phase of cortisol biosynthesis. Using a variety of experimental approaches, I identified cAMP response element binding protein as an essential transcriptional activator of the ASAH1 gene. Analysis of adrenocortical cells lacking ASAH1 revealed that ASAH1 is a global regulator of steroidogenic capacity. Furthermore, I identified ASAH1 as a nuclear protein and defined the molecular determinants of the interaction between ASAH1 and SF-1. Collectively, this body of work establishes the integral role of ASAH1 in the regulation of ACTH-dependent adrenocortical cortisol biosynthesis.
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Li, Guangbi. "Podocyte Dedifferentiation and Glomerular Injury Mediated by Lysosome Dysfunction: Role of Acid Ceramidase." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5169.
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Cell differentiation and senescence in podocytes are attributed to normal autophagy and associated cellular activities. It is possible that derangement of autophagy under different pathological conditions activates or enhances podocyte dedifferentiation leading to glomerular injury and ultimate glomerular disease. To test this hypothesis, we first tested whether autophagic deficiency due to lysosome dysfunction enhances podocyte dedifferentiation and explored the molecular mechanisms by which this lysosome dysfunction trigger or enhance podocyte dedifferentiation. By Western blot and confocal analysis, lysosome inhibition using an inhibitor or siRNA of V-ATPase inhibitor was found to markedly decrease the epithelial markers (P-cadherin and ZO-1) and increase the mesenchymal markers (FSP-1 and α-SMA). This enhancement of podocyte dedifferentiation (formerly referred to as epithelial-mesenchymal transition, EMT) was accompanied by deficient autophagic flux, as demonstrated by marked increases in LC3B-II and p62/Sequestosome 1. However, inhibition of autophagosome formation using spautin-1 (SP-1) significantly attenuated both enhancement of podocyte dedifferentiation and deficiency of autophagic flux. To explore the mechanisms by which deficient autophagic flux enhances podocyte dedifferentiation, we tested the role of accumulated p62 as a signal hub in this process. Neither the nuclear factor erythroid 2-related factor 2 (Nrf2) nor nuclear factor kappa (NFκ)-light-chain-enhancer pathway regulating p62 function was found to contribute to enhanced dedifferentiation. However, inhibition of cyclin-dependent kinase 1 (CDK1) activity reduced the phosphorylation of p62 and enhanced podocyte dedifferentiation similar to lysosome dysfunction, which indicates that enhanced podocyte dedifferentiation due to lysosome dysfunction may be triggered by accumulation of p62 and associated reduction of p62 phosphorylation. Given the essential role of sphingolipid-ceramide metabolism and transient receptor potential-mucolipin-1 (TRPML1) channel activity in lysosome function, we next sought to test whether altered ceramide metabolism by acid ceramidase (AC) leads to deficient lysosome trafficking and fusion to autophagosome in podocytes and thereby results in autophagic deficiency and podocyte dedifferentiation. Inhibition of AC by a potent and selective inhibitor, carmofur markedly reduced lysosome trafficking and fusion to both autophagosomes and multivesicular bodies (MVBs). Concurrently, enhancement of podocyte AC activity or exposure of podocytes to sphingosine, a product of ceramide metabolism by AC, remarkably increased lysosome trafficking and fusion to autophagosomes and MVBs, indicating that AC activity is critical for lysosome function in podocytes. To further explore the mechanisms by which AC activity contributes to lysosome trafficking, we examined the effects of various sphingolipids related to ceramide metabolism on transient receptor potential-mucolipin-1 (TRPML1) channel, a Ca2+ channel essential for lysosome trafficking and function. It was found that sphingomyelin (SM), a precursor for ceramide production blocked TRPML1 channel activity induced by ML-SA1 (a specific TRPML1 agonist), while ceramide had no effects on TRPML1 channel activity induced by ML-SA1. Interestingly, sphingosine, an AC product of ceramide remarkably enhanced TRPML1 channel activity induced by ML-SA1. These results demonstrate that AC product of ceramide, sphingosine may enhance TRPML1 channel activity, but an upstream sphingolipid, SM may exert inhibitory action on lysosome TRPML1 channel activity. AC may be a key enzyme gating TRPML1 channels by production of sphingosine and changes in upstream substrate SM. These results from in vitro cell studies led us hypothesize that a deficient AC activity may induce podocyte injury through lysosome dysfunction, leading to glomerular damage and proteinuria. To test this hypothesis, we generated a mouse colony with podocyte-specific gene deletion of AC α subunit, namely, Asah1fl/fl/PodoCre mice. In these mice, severe proteinuria and albuminuria were shown compared to their littermates, but they were without global and even focal glomerular sclerosis. These mice also had hypoalbuminemia and edema, and under transmission electron microscopy (TEM) ultrastructural changes of podocytes from their glomeruli exhibited diffuse and flat foot process (podocyte effacement), vacuolation, and microvillus formation, which were not observed in their littermates. Treatment of corticosteroids and specific expression patterns of dystroglycans in glomeruli confirmed that albuminuria in these Asah1fl/fl/PodoCre mice may be resistant to corticosteroids. Together, these results from in vivo animal studies indicate that podocyte-specific gene deletion of AC α subunit may induce a corticosteroid-resistant minimal change disease (MCD). Based on all results from our in vitro and in vivo studies, we conclude that the normal lysosome function is essential for maintenance of autophagic flux and podocyte differentiation, which is regulated by a lysosomal AC-mediated signaling pathway through a TRPML1 channel gating mechanism. AC gene defect or deficiency of its activity induces podocyte injury, which is characterized by a corticosteroid-resistant MCD. These findings indicate an important pathological role of AC deficiency and associated lysosome dysfunction in podocytes injury and corticosteroid-resistant MCD, which may help develop novel therapeutic strategies for prevention or treatment of corticosteroid-resistant MCD.
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Camacho, Castillo Luz del Carmen. "Acid ceramidase and sphingosine-1-phosphate lyase as biomarkers and therapeutic targets in cancer. (Ceramidasa ácida y Esfingosina-1-fosfato Liasa como biomarcadores y dianas terapéuticas en cáncer)." Doctoral thesis, Universitat de Barcelona, 2011. http://hdl.handle.net/10803/21624.
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Cer and So are involved in regulation of apoptosis and cell cycle arrest while on the other hand S1P promotes cell growth and inhibits apoptosis. The antagonistic effects of these metabolites are regulated by enzymes that interconvert Cer, So, and S1P. In this work two of these enzymes were studied: sphingosine phosphate lyase and acid ceramidase. First several methods to determine the activity of these enzymes were developed and optimized, resulting in the publication of sensitive fluorogenic and chromatographic methods for enzyme activity.
Particularly the assay optimized for acid ceramidase activity was used in the finding and identification of new inhibitors in several compound libraries. As a result compounds RBM2-1B, RBM2-1D and RBM2-1E were identified as acid ceramidase and dihydroceramide desaturase inhibitors. Furthermore compounds RBM1-12, RBM1-13 and SABRAC were also described as acid ceramidase inhibitors. Since several publications described the upregulation of acid ceramidase in advanced prostate cancer, we decided to investigate the particular effect of the acid ceramidase inhibition in a cellular model of advanced prostate cancer. Using cells PC-3/Mc we inhibited acid ceramidase through two different approaches: first silencing the gen ASAH1 and comparing the effects with chemical inhibition of the enzyme using compounds RBM1-12, RBM1-13 and SABRAC.
We evaluate the effect of acid ceramidase inhibition in cell growth, invasivity and 3D growth in vitro, finding a diminished growth and 3D growth in both cells those knockdown for ASAH1 and treated with inhibitors. Finally, the effect of ASAH1 silencing in in vivo tumor growth and lung colonization was also determined. To this end male NOD-SCID mice were used for xenotransplants with cells PC-3/Mc_ASAH1_KD or control and the tumor growth or lung colonization was followed by luminometry. We found that the silencing of ASAH1 in PC-3/Mc cells delayed the growth and also the lung colonization, highlighting the potential of acid ceramidase inhibition as adjuvant in the treatment of prostate cancer and also in the prevention of metastases formation.
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Markus, Carolin [Verfasser]. "Die Funktion der putativen alkalischen Ceramidase ACER1 innerhalb des Sphingolipidstoffwechsels in Arabidopsis thaliana / Carolin Markus." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1080864571/34.
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Fuchs, Kathrin [Verfasser], and Johannes [Akademischer Betreuer] Kornhuber. "Charakterisierung der Ceramidase-Aktivität im Plasma gesunder und alkoholabhängiger Probanden / Kathrin Fuchs. Gutachter: Johannes Kornhuber." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2014. http://d-nb.info/1075478774/34.
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Meiners, Jana [Verfasser], and Astrid [Akademischer Betreuer] Westendorf. "The effect of the acid sphingomyelinase/ceramidase system on bacterial induced colitis / Jana Meiners ; Betreuer: Astrid Westendorf." Duisburg, 2019. http://d-nb.info/1191692159/34.
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Drosos, Zacharias [Verfasser], Lars [Akademischer Betreuer] Hanker, and Markus [Akademischer Betreuer] Meier. "Die prognostische Bedeutung der Expression von Acid-Ceramidase (ASAH1) und Sphingosin-Kinase 1 (SPHK1) bei Patientinnen mit Ovarialkarzinom / Zacharias Drosos ; Akademische Betreuer: Lars Hanker, Markus Meier." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2021. http://d-nb.info/1236386272/34.
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Yamakawa, Nathália Christina Gonçalves 1986. "Epilepsia e Morita-Baylis-Hillman : uma abordagem sintética para ceramidas antiepiléticas." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/250239.
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Orientador: Fernando Antonio Santos CoelhoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: A epilepsia é uma das principais doenças do sistema nervoso central, caracterizada por uma alteração na atividade elétrica do cérebro, que leva a perdas de memória e convulsões. Essa doença afeta cerca de 50 milhões de pessoas no mundo, que são discriminadas e isoladas da sociedade. Existem vários medicamentos que podem ser utilizados, no entanto, muitas vezes é necessário a administração de associações desses que apresentam severos efeitos colaterais. Esse quadro justifica a necessidade da busca por substâncias mais eficientes para o tratamento dessa doença. Em 2008, Ahmed e cols. isolaram da esponja marinha Negombata corticata duas ceramidas que apresentaram importante atividade anti-convulsiva. Assim, este trabalho teve por objetivo estabelecer uma estratégia sintética para a preparação do fragmento polar de tais ceramidas. A rota foi baseada em um aduto de Morita-Baylis-Hillman (MBH), obtido com elevada diastereosseletividade a partir de uma reação entre o aldeído de Garner e o acrilato de etila. Uma reação de ozonólise na dupla ligação do aduto de MBH fornece um a-cetoéster, cuja carbonila cetônica e reduzida conduzindo a um único produto. A proteção das hidroxilas, permitiu a confirmação da estereoquímica relativa através de análise por difração de raios-X, que também evidenciou a ocorrência de racemização na reação de MBH. O diol também foi utilizado na preparação de um aza-açúcar, potencial inibidor de glicosidase, sendo esta síntese em apenas 4 etapas com 32% de rendimento global. A fração apolar da ceramida foi sintetizada a partir de uma reação de Grignard, e a junção dos fragmentos pode ser realizada utilizando-se uma reação de Wittig. Desta maneira, foi descrita uma nova estratégia sintética que pode ser aplicada na preparação de diversos análogos das ceramidas, desenvolvendo um antiepiléptico mais potente
Abstract: Epilepsy is a chronic brain disorder that affects around 50 million people all over the world. It is characterized by recurrent seizures - which are physical reactions to sudden excessive electrical discharges in a group of brain cells. The discrimination and social stigma that surround epilepsy worldwide are often more difficult to overcome than the seizures themselves. Because of this fact and the economical impacts of the disease, the research for new biologically active compounds is still necessary. In 2008, Ahmed et al. isolated from the Red Sea sponge Negombata corticata two ceramides, which exhibit in vivo anticonvulsant activity. This work is focused on establishing of a synthetic sequence to prepare the polar fragment present in both ceramides. The strategy was based on a Morita-Baylis-Hillman reaction between a Garner¿s aldehyde and ethyl acrylate that provided a functionalized intermediate in good diastereoselectivity. The major diastereoisomer was employed as substrate in an ozonolysis reaction, followed by a stereoselective reduction that afforded 1,2-diol as a single isomer. The acetonide derived from this 1,2-diol allowed us to determine through X-Ray diffraction analysis the relative stereochemistry of this compound as being 1,2- anti. To finish the synthesis of the polar fragment, the ester group present in the acetonide was reduced to the corresponding aldehyde. The diol also was applied in a high diastereoselective preparation of an azasugar in 4 steps and 32% yield overall. In this work we also describe the synthesis of a carbon chain of the ceramide, our route includes an approach to the apolar fragment obtained by a Grignard reaction; then a Wittig reaction can couple both fragments toward the finalization of the sphingosine¿s synthesis. Our synthetic route can also be used in the preparation of several analogues of the antiepiletic ceramides
Mestrado
Quimica Organica
Mestre em Química
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Day, Jenna. "Coumarinyl-Caged Ceramides, a New Tool for Assessing the Biological Effects of Ceramide In Cells." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32336.
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Ceramide, a sphingolipid, is an important lipid second messenger that is involved in regulating a number of cellular processes, including programmed cell death, cell growth and differentiation, as well as cellular responses to stress stimuli. Many of the biological effects of ceramide are linked to its ability to modulate the biophysical properties of membranes and cause clustering of signalling molecules in ceramide-rich domains, which allows for more efficient signal transmission in the cell. However, the specific roles of different ceramide species in these signaling pathways have yet to be clearly established. Assessing the effects of long N-acyl chain ceramides in cells involves some limitations due to their poor solubility and their low membrane permeability. Caging these molecules with photolabile protecting groups allows for their delivery into cells where photochemical uncaging of the biologically active compound can be achieved with spatial and temporal control.
A series of coumarinyl-caged ceramides has been prepared in order to probe the biological effects of ceramide in cells. This unique series of compounds was used to investigate the dependence of these cellular effects on N-acyl chain length. Hereafter, I describe the photophysical and photochemical characterization of these novel caged ceramides, assess their uptake and measure the biological effects of the different ceramides which are generated photochemically in HeLa cells. The caged ceramides were shown to be taken up by the cells and to cause a decrease in viability, with UV irradiation, that can be detected after 24 hours of treatment. An investigation of the mechanism of cell death induced by coumarinyl-caged ceramides in HeLa cells revealed that cell death proceeds in a caspase-independent manner and involves the mitochondria. The role of the mitochondria in this cell death pathway, however, remains to be studied further. RIP1 kinase activity, which was also probed in the cells, was determined to not be implicated in cell death caused by photochemically generated ceramide. Intracellular ROS generation, however, was shown to occur in this system, but results primarily from UV irradiation of the free coumarin. Overall, the results from this study have provided insight into the signalling pathways triggered by treatment of HeLa cells with the bioactive lipid ceramide using coumarin photocages.
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Wijesinghe, Dayanjan. "Ceramide Kinase and Ceramide-1-Phosphate." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1621.
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Ceramide-1-phosphate (C1P) is a bioactive lipid that has been implicated in many biological processes. Our laboratory has conclusively demonstrated its role in inflammation via activation of cPLA2α. The only known enzyme to date responsible for direct synthesis of C1P is ceramide kinase. Very little was known about this enzyme in terms of its enzyme kinetics and substrate specificity. As CERK is an enzyme that acts on membrane lipids, its kinetics cannot be studied using standard bulk dilutions methods. Thus we developed a surface dilution approach using Triton X 100 mixed micelles for studying the kinetics of CERK. We discovered that ceramide kinase has an affinity for naturally occurring long chain ceramides while ceramides containing shorter than 8 carbons are very poor substrates for the enzyme. Also of note is the discovery that there is no discrimination between the naturally occurring long chain ceramides leading to the conclusion that the preponderance of D-e-C16 C1P in cells are due to an availability effect. We also investigated the chain length specificity of interaction between C1P and cPLA2α. Our data indicate that cPLA2α is activated by C1P’s containing acyl chains longer than two carbons. The study showed C2 C1P as being unable to activate cPLA2α thus establishing a tool for the investigation of cPLA2α dependent and independent effects of C1P. In the course of the study we investigated the ethanol/dodecane delivery system as a means of safely delivering lipids to cells. Our data conclusively demonstrate that this delivery system successfully delivers lipids to the internal membranes where their biological action takes place and that at low lipid concentration (<1µM), is non toxic to cells. A significant technical hurdle in the study of C1P was the lack of accurate and reproducible method of quantitatively and qualitatively analyzing the lipid. Using a mass spectrometric approach we developed an accurate technique that now allows us to quantify the lipids in cells. Using this and radiolabeling studies we discovered evidence for production of C1P from S1P via an acyl transferase pathway. Further studies are currently being carried out to identify the enzyme/s responsible for this pathway.
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Park, Hyejung. "Characterization of ceramide synthases (Cers) in mammalian cells." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/29616.
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Thesis (Ph.D)--Biology, Georgia Institute of Technology, 2009.Committee Chair: Alfred H. Merrill, Jr; Committee Member: John Cairney; Committee Member: M. Cameron Sullards; Committee Member: Marion B. Sewer; Committee Member: Yuhong Fan. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Marques, Suzi Oliveira. "Estudo químico da esponja Dysidea robusta." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/75/75131/tde-11032010-111805/.
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Esponjas do gênero Dysidea (Ordem: Dictyoceratida) caracterizam-se por apresentarem grande diversidade de metabólitos secundários, muitos dos quais apresentam potentes atividades biológicas. Este trabalho descreve o estudo de duas amostras de esponjas da espécie Dysidea robusta, DR1 e DR2, coletadas no litoral da Bahia em 1999. Tal estudo consistiu no fracionamento das amostras, nas análises de seus extratos brutos por LC-MS e técnicas de RMN- mono e bidimensionais. Dentre os extratos de DR1, a fração DR1-EP-5A obtida do extrato éter de petróleo apresentou uma mistura de três ceramidas saturadas (22, 23 e 24). Já da amostra DR2, as frações do extrato aquoso DR2-AQ-6B e DR2-AQ-6D mostraram ser constituídas por derivados do ácido pirodisinóico (18, 19, 20 e 21). Com exceção do ácido pirodisinóico (18), os demais compostos isolados ainda não foram relatados na literatura.Sponges of the genus Dysidea (Order: Dyctioceratida) are characterized as sources of several biologically active secondary metabolites. This work describes the study of two samples of D.robusta, DR1 and DR2, both collected at the Bahia state coastline, in 1999. The investigation aimed the crude extract fractionation and analysis by LC-MS and by 1D and 2D NMR techniques. Among the extracts DR1, the fraction DR1-EP-5A obtained from the petroleum ether extract showed a mixture of three saturated ceramides, represented by 22, 23 and 24. From the DR2 sample, the fractions obtained from the aqueous extract DR2-AQ-6B and -6D presented pirodisinoic acid derivates 18, 19, 20 and 21. Except for pyrodisinoic acid (18), all other isolated compounds haven´t been reported in the literature yet.
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Kiefer, Kerstin 1986. "Implication of the disease-associated ORMDL3 in macrophage physiology." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/664118.
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Genome-wide association studies linked increased ORMDL3 expression levels to several inflammatory diseases via single nucleotide polymorphisms. However, the pathophysiological mechanisms underlying this association are still poorly understood. ORMDL proteins have been shown to regulate de novo sphingolipid synthesis among other functions, a process important for proper innate immune responses and its imbalance was furthermore associated to asthma disease. This thesis was aimed to provide further inside into the ORMDL-SPT complex formation and to elucidate potential involvement of ORMDL3 in macrophage physiology using a transgenic mouse model. We herein demonstrated that a structural rearrangement under high sphingolipid content takes place, in order to release SPT activity. Moreover, ORMDL3 levels decreased cellular ceramide content in macrophages, and specifically impaired the de novo synthesis during activation leading to reduced autophagy and bacterial clearance. In addition, we explore the SNP-dependent regulation of ORMDL3 gene expression in human monocytes. Taken together, this thesis contributes to a better understanding of the implication of ORMDL3 in sphingolipid homeostasis and underlines its importance in macrophage physiology.Alguns estudis d’associació genòmica han relacionat un augment dels nivells d’expressió d’ORMDL3, causat per polimorfismes d’un sol nucleòtid, amb diverses malalties inflamatòries. Tot i així, els mecanismes fisiopatològics subjacents a aquesta associació no són del tot coneguts. Les proteïnes ORMDL estan involucrades en la síntesi d’esfingolípids de novo, un procés essencial per a la resposta immunitària de tipus innat i que ha estat associat amb l’asma. Aquesta tesi té l’objectiu d’aprofundir en la formació del complex ORMDL-SPT així com d’elucidar la potencial implicació d’ORMDL3 en la fisiologia dels macròfags utilitzant un model de ratolí transgènic. Els nostres resultats demostren un rearranjament estructural quan hi ha un alt contingut d’esfingolípids, per tal d’alliberar l’activitat de l’SPT. A més, els nivells d’ORMDL3 disminueixen el contingut cel·lular de ceramides i afecten específicament la síntesi de novo durant l’activació dels macròfags, produint una reducció en l’autofàgia i la liquidació bacteriana. Addicionalment, hem explorat la regulació d’ORMDL3 depenent de polimorfismes en monòcits humans. En conjunt, aquesta tesi contribueix a un coneixement més profund de la implicació d’ORMDL3 en la homeòstasi d’esfingolípids i remarca la seva importància en la fisiologia dels macròfags.
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Barroso, Alvim Manuel Matos. "Esfingolípidos: mediadores moleculares da resposta celular e potenciais alvos terapêuticos." Master's thesis, [s.n.], 2012. http://hdl.handle.net/10284/3546.
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Trabalho apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasOs esfingolípidos, descritos em 1876 por J.L.W. Thudichum, são considerados constituintes essenciais das membranas das células eucarióticas. Para além do seu papel estrutural estão também envolvidos na sinalização celular. Do ponto de vista estrutural, os esfingolípidos derivam da esfingosina. A acilação da esfingosina com um ácido gordo de cadeia longa origina a ceramida, que constitui a base molecular de todos os esfingolípidos. O seu metabolismo integra vários compartimentos intracelulares que incluem o retículo endoplasmático, o complexo de Golgi, a membrana plasmática e o sistema endossomal/lisossomal. Alguns dos seus metabolitos, como a ceramida, a esfingosina, e a esfingosina-1-fosfato actuam como moléculas bioactivas, estando envolvidas em diversos eventos celulares, nomeadamente na regulação do crescimento celular, diferenciação, senescência, inflamação e apoptose. Uma das vias metabólicas mais interessantes do ponto de vista fisiológico e patológico é a via da esfingomielinase. Esta via permite regular o nível intracelular dos esfingolípidos bioactivos através da acção concertada de duas famílias de enzimas, as esfingomielinases, que convertem a esfingomielina em ceramida, e as ceramidases que convertem a ceramida em esfingosina. Cada uma destas famílias de enzimas exibe especificidade quanto ao compartimento celular/tecido e à natureza química do substrato. De facto, as células vivas contêm diversas espécies de ceramidas que diferem na extensão e grau de insaturação da cadeia acilo, o que parece ter grande importância e influência nas suas actividades biológicas. Nas últimas décadas, a diversidade estrutural e funcional dos SLs tem suscitado algum interesse, em grande parte devido ao seu envolvimento em patologias de etiologia muito diversa mas com considerável impacto em termos de Saúde Pública. Neste contexto, o presente trabalho de pesquisa bibliográfica foi elaborado com o objectivo de proporcionar uma visão relativamente integrada sobre a estrutura, função e metabolismo dos esfingolípidos em situações normais e em situações patológicas específicas, esperando-se que represente um contribuição útil para a difusão do conhecimento sobre estas multifacetadas e enigmáticas moléculas. The sphingolipids, described in 1876 by JLW Thudichum are considered essential constituents of the membranes of eukaryotic cells. In addition to its structural role, they are also involved in cell signaling. From the structural point of view, the sphingolipids are derived from sphingosine. Acylation of sphingosine with a long chain fatty acid gives rise to the ceramide, which is the molecular basis of all sphingolipids. Its metabolism comprises several intracellular compartments including the endoplasmic eticulum, the Golgi apparatus, the plasma membrane and the system endosomal / lysosomal system. Some of its metabolites, such as ceramide, sphingosine, and sphingosine 1-phosphate act as signaling and communication bioactive molecules, being involved in various cellular events, in particular in the regulation of cell growth, differentiation, senescence , inflammation and apoptosis. One of the metabolic pathways more interesting from the physiological and pathological standpoints is the metabolism of sphingomyelinase. This route is implicated in the regulation of the intracellular level of bioactive sphingolipids through the coordinated action of two families of enzymes, sphingomyelinases, which convert sphingomyelin into ceramide, and ceramidases, that convert ceramide in sphingosine. Each of these families of enzymes shows specificity regarding to the cell compartment / tissue and the chemical nature of the substrate. In fact, the living cells contain different species of ceramides which differ in length and degree of unsaturation of the acyl chain, which seems to have great importance and influence on their biological activities. The structural and functional diversity of sphingolipids has attracted some interest in recent decades, largely due to its involvement in diseases of diverse etiology, but with considerable impact on public health. In this context, a literature review on these topics was prepared aiming to provide an integrated vision of the structure, function and metabolism of sphingolipids in normal and disease states, expecting that this work represents an useful contribution to the diffusion of the knowledge about these multifaceted and enigmatic molecules.
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Liu, Ying. "Regulation of ceramide and its metabolites: biosynthesis and; in situ sphingolipid analysis." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33918.
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Sphingolipids are found in essentially all animals, plants and fungi, and some prokaryotic organisms and viruses. Sphingolipids function as structural components of membranes, lipoproteins, and as cell signaling modulators and mediators. To complicate matters further, sphingolipids often vary in type in different regions of tissues, and even in single cells, the subcellular localization of sphingolipids and their metabolic enzymes, transport proteins and targets may influence their functions. It is important to study sphingolipids spatial distribution within living organisms to understand how sphingolipids are involved in complex biochemical processes.
As part of this thesis, procedures were optimized for the use of matrix assisted laser desorption/ionization (MALDI) tissue mass spectrometry (TIMS) to visualize the location of several types of lipids including sulfatides (ST), gangliosides and phosphoglycerolipids in brains from a mouse model for Tay-Sachs/Sandhoff disease.
MALDI-TIMS was next applied to human ovarian carcinoma tissue to detect sulfatide location and established that ST are associated specifically with the regions of the ovarian tissue that bear the carcinoma. Electrospray ionization tandem mass spectrometry (ESI-MS-MS) was also used to confirm that ST and galactosylceramide (GalCer) are elevated in ovarian cancer. Gene expression data using tumor cells collected using laser capture microdissection revealed greater expression of mRNAs for GalCer synthase, GalCer sulfotransferase (Gal3ST1) and other enzymes of ST biosynthesis in epithelial ovarian carcinoma cells. This is a unique combination of two complementary, profiling technologies--mass spectrometry (metabolomic approach) with analysis of gene expression to study complex cancer pathology.
The next study focused on the subcellular location of sphingolipids. In comparison with wild type Hek293 cells, a Hek293 cell line stably overexpressing serine palmitoyltransferase (SPT1/2 cells) was found to have elevated amounts of all subspecies of ceramide (Cer), but produces disproportionately higher amounts of C18-Cer and GalCer. Since Cer is known to inhibit protein ER/Golgi trafficking, these studies found that the higher production of Cer caused impairment of ER/Golgi trafficking of Ceramide synthase 1 (CerS1), thus increased C18-Cer. In addition, since GalCer is only synthesized in the lumen of the ER, this impairement of ER/Golgi trafficking also gave GalCer synthase access to its substrate and increased GalCer biosynthesis.
These studies illustrate the complexity of sphingolipid biology and the usefulness of multiple tools to understand sphingolipid complex biological processes.
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Munick, Michael. "Stereoselektive Synthese von lipophilen Inositolen und Ceramiden." Doctoral thesis, [S.l.] : [s.n.], 2007. http://deposit.ddb.de/cgi-bin/dokserv?idn=983917183.
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Zankl, Claudia. "Stereoselektive Synthese von Sphingolipiden zur Inhibierung der Degranulation von Mastzellen." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-23408.
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Die Degranulation von Mastzellen soll durch Glycosphingolipide, welche mit der Zellmembran wechselwirken inhibiert werden. Der Sphingosingrundkörper wurde in zehn-stufigen Synthese ausgehend von N-Boc-Serin, aufgebaut. Die anschließende Glycosylierung erfolgte nach der Trichloracetimidatmethode in sehr guten Ausbeuten und stellte den Schlüsselschritt dar. Durch die Variation von unter Anderem der Amidseitenkette, der Glycosylkopfgruppe und des Sphingosingrundkörpers wurde eine Vielzahl an Derivaten für das Screening im Degranulationsassay bereitgestelltThe present dissertation covers the synthesis of glycosphingolipids which interact with the cell membrane in order to inhibit the degranulation of mast cells. The sphingosin body was synthesized in ten steps starting from N-Boc-Serin. The key step, the glycosylation was achieved using the trichloracetimidat method. The variation of the amid sidechain, the gylcosyl headgroup and the sphingosin body created a number of derivatives that were tested in the degranulation assay
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Tepper, Annemiek Delina. "The role of ceramide in apoptosis." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/84270.
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Seedlock, Kyle Elizabeth. "Calcium Mediated Regulation of Ceramide Kinase." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd_retro/173.
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Ceramide-1-phosphate (C1P) has proven to be a bioactive sphingolipid with diverse functions within the cell. At this time, ceramide kinase (CERK) is the only known enzyme known to generate C1P in mammalian cells, and this bioactive lipid is responsible for the activation and translocation of cytosolic phospholipase A2, the initial rate limiting step in eicosanoid synthesis. These studies investigate the regulation of ceramide kinase by calcium. While CERK activity has been shown to be calcium sensitive, little is known about how CERK is activated within the cell; one possibility is the interaction with calcium "sensor" proteins such as calmodulin. In this study, we develop two protocols to efficiently examine the interaction of CERK with calcium dependent proteins: V5 co-immunoprecipitation and Ni-NTA affinity purification. The methods utilize either adenoviral infection or Effectene© transfection of cells to ectopically express CERK with both a 6x His and V5 tag on its C terminus. Unlike the report of Igarashi and co-workers, our findings reveal that CERK does not specifically interact with the calcium sensor, calmodulin, in three different cell types. We also show that the calcium dependent membrane organizer, annexin A2, also does not bind to CERK. In light of these findings, we illustrate that while CERK may be sensitive to calcium, it does not, as previously reported by another laboratory, specifically bind to calmodulin. These studies eliminate possible calcium mediator proteins and are suggestive of another method for the calcium sensitive regulation of CERK lending to new avenues of investigation (i.e. CaMKII). This report also firmly established two successful protocols for investigating protein partners of CERK. Ultimately, through providing a clearer picture behind the calcium regulation of CERK, we can elucidate possible novel therapeutic targets within the inflammatory pathway.
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Kim, Shang-U. "Synthesis of diene ceramides with organozirconium reagents." Thesis, The University of Arizona, 2004. http://hdl.handle.net/10150/292081.
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Ceramide serves as a precursor to sphingomyelins and glycosphingolipids, and as an important intermediate in the de novo biosynthesis. Ceramide will act as second messenger in cell systems to induce programmed cell death (apoptosis). Ceramide is composed of a sphingosine backbone and fatty acid linked in an amide bond, and its structural variations have been modified and synthesized by many research group. The diene ceramide, unusual analogues of ceramide with a conjugated diene may have higher reactivity than other novel ceramide in mitochondria by facilitated oxidation at C3. One of the most important synthetic methodologies for diene ceramide was organozirconocene hydrochloride (Schwartz reagents) used for forming long chain dienyl sphingosine backbone. The organozirconocene complexes are also known for the transmetalation with other metal complexes for further nucleophilic additions. In this thesis, the synthesis of diene ceramide with chiral aldehyde for sphingosine head group and organozirconocene complexes will be described.
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Pedrero, Cisterna Andrea R. "Efecto de ceramidas sintéticas sobre la inducción de necrosis en células HTC." Tesis, Universidad de Chile, 2005. http://repositorio.uchile.cl/handle/2250/105423.
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Memoria para optar el título de BioquímicoLos organismos regulan su número de células a través de un balance entre la división y muerte celular. Con respecto a este último, existen diversos mecanismos de muerte celular, como la apoptosis, autofagia y necrosis, presentando cada uno características morfológicas y moleculares diferentes. Se ha considerado a la necrosis como un mecanismo de muerte celular “accidental” y, por tanto, menos regulado. Sin embargo existen evidencias de que la necrosis también puede ser considerada un tipo de muerte celular programada. Es así que las ceramidas, precursores de los esfingolípidos eucariontes, han sido reconocidas como importantes segundos mensajeros implicados en el gatillamiento de procesos apoptótico/necróticos en diversos tipos celulares. Recientemente se ha descrito que células de linfoma B humano (línea celular A20) al ser estimuladas con ligando de Fas en presencia de ceramidas van a un destino de muerte necrótico. Además de esto, se ha descrito una relación entre estrés oxidativo y la generación de ceramidas, relación que se encontraría íntimamente ligada a procesos de señalización de muerte celular. Con estos datos se postuló que las ceramidas intervienen en la decisión apoptóticonecrótica en células epiteliales. Utilizando métodos de citometría de flujo y ensayos enzimáticos se encontró que las ceramidas aumentaron la muerte por necrosis en el tiempo tanto para células HeLa como para HTC, este aumento es dosis dependiente. Ácido flufenámico, un inhibidor inespecífico de canales catiónicos no selectivos involucrados en regulación del volumen celular por estrés oxidativo, en conjunto con ceramidas no cambió el porcentaje de muerte por necrosis y aumentó la población apoptótica. Al reemplazar el Na+ extracelular por el catión monovalente NMDG+ no se observó diferencia entre los porcentajes de las distintas poblaciones celulares. La aplicación en conjunto de H2O2 con ceramidas aumentó la muerte celular, pero sólo a altas concentraciones (10 mM). El efecto de ceramidas sobre la apoptosis se ensayó utilizando el inhibidor genérico de caspasas zVAD-fmk. No hubo cambios significativos en los porcentajes de muerte celular. Efectos similares se observaron al depletar los depósitos intracelulares de calcio. Estos resultados permiten concluir que las ceramidas inducen muerte celular necrótica de manera tiempo y dosis dependiente
Organisms regulate their number of cells through fine a balance between cell division and cell death. In respect to cell death, diverse mechanisms exist, such as apoptosis, autophagia and necrosis, presenting each one different morphologic and molecular characteristics. Necrosis has been considered as a mechanism of "accidental" cell death and therefore, less regulated. Nevertheless, evidences exist of which necrosis can be also considered as a type of programmed cell death. For example, ceramides, precursors of sphingolipids in euchariotic cells, have been recognized as important second messengers implicated in the development of apoptotic/necrotic processes in diverse cell types. It has been recentely described that human lymphoma B cells (A20 cell line),upon stimulation with Fas ligand in the presence of ceramides, induce necrotic cell death. Also, it has been described a relationship between oxidative stress and the generation of ceramides which are intimately linked to cell death signaling processes. Based on this information, it was postulated that ceramides take part in the apoptotic-necrotic decision in epithelial cells. Using flow citometry and enzymatic assays we found that ceramides increased cell death by necrosis in HeLa and HTC cells in a dose-dependent manner. Flufenamic acid, a non specific inhibitor of nonselective cation channels involved in regulation of the oxidative stress-dependent cell volume, used in conjunction with ceramides did not produce changes in the percentage of necrotic cell death and increased the population of apoptotic cells. Upon replacement of external Na+ by the monovalent cation NMDG+, the percentage of different cell populations was not altered. The application of ceramides with H2O2 produced an increase in the cell death, but only at high concentrations of H2O2 (10 mM). The effect of ceramides upon apoptosis was assayed using the generic caspase inhibitor zVAD- fmk. No significant changes were observed in the percentage of cell death. Similar effects were observed when depleting the intracellular calcium stores. These results allow us to conclude that ceramides induces necrotic cell death in a time and dose-dependent manner
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Munick, Michael. "Stereoselektive Synthese von lipophilen Inositolen und Ceramiden." Doctoral thesis, Technische Universität Dresden, 2006. https://tud.qucosa.de/id/qucosa%3A23910.
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Die Arbeit umfasst die Synthese von lipophilen Inositolen und Glycerollipiden, welche auf ihre Raftophilie getestet wurden. Des weiteren wurden eine Reihe neuer Ceramide synthetisiert und diese in Bioassays auf ihre Wirksamkeit gegenüber diversen Krankheiten wie Influenza getestet.
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Almeida, Josà Gustavo Lima de. "Constituintes QuÃmicos dos ZoantÃdeos Palythoa caribaeorum (Duchassaing & Michelotti, 1860) e Protopalythoa Variabilis (Duerden, 1898)." Universidade Federal do CearÃ, 2011. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=7953.
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nÃo hÃEste trabalho descreve a composiÃÃo quÃmica das espÃcies marinha Palythoa caribaeorum e Protopalythoa variabilis, coletadas no municÃpio de Paracuru-CE. O fracionamento cromatogrÃfico do extrato hexÃnico de P. caribaeorum, resultou no isolamento de quatro esterÃides tetracÃclico de esqueleto ergostano: 24(R)-ergost-5-en-3-ol (P-1); 5,8-epidioxi-24(R)-ergost-6-en-3-ol (P-2); 24(R)-ergost-5-en-3,7-diol (P-4) e 24(R)-7-hidroperoxi-ergost-5-en-3-ol (P-7), um derivado do glicerol, 1-O-hexadecilglicerol (P-3) e quatro ceramidas: N-(2S,3R,4E,8E,1,3-dihidroxi-4,8-octadecadieno)hexadecanamida (P-5); N-(2S,3R,4E,1,3-dihidroxi-4-octadeceno)-hexadecanamida (P-6), N-[2S,3R,4E,8E,1-(2â-metilamino-etanosulfonila)-3-hidroxi-4,8-octadecaÂdieno]hexadecanamida (P-8) e N-[2S,3R,4E,1-(2â-metilaminoetano-sulfonila)-3-hidroxi-4-octadeceno]hexadecanamida (P-9). Do fracionamento cromatogrÃfico do extrato etanÃlico, foi possÃvel isolar o esterÃide 24(R)-ergost-7-en-3,56-triol (P-10) e o nucleosÃdeo 2-metil-timidina (P-11). Do estudo quÃmico do extrato hexÃnico de P. variabilis obteve-se os mesmos constituintes quÃmicos isolados de P. caribaeorum (P-1, P-2, P-3 e P-4) e as quatro ceramidas (P-5, P-6, P-8 e P-9). AlÃm destes compostos foi isolado um Ãster de cadeia alifÃtica, hexadecanoato de nonila (P-12) e o esterÃide Ãcido 24(R)-B-norergostan-3-5-diol-6-carboxÃlico (P-13). O potencial citotÃxico e antifÃngico das ceramidas foi avaliado, entretanto, estas nÃo apresentaram atividade. Os compostos foram isolados atravÃs de cromatografia de adsorÃÃo em gel de sÃlica e cromatografia lÃquida de alta eficiÃncia. As estruturas dos compostos obtidos foram elucidadas utilizando tÃcnicas espectroscÃpicas e espectromÃtricas, tais como: espectrometria de massa acoplada a cromatografia gasosa (CG/EM); espectrometria de massa de alta resoluÃÃo (EMAR); espectroscopia na regiÃo do infravermelho (IV) e RessonÃncia MagnÃtica Nuclear (RMN 1H, 13C e 15N) atravÃs de sequÃncias de pulsos uni e bidimensionais e comparaÃÃo com dados de RMN na literatura.
This work describes the chemical composition of the marine species Palythoa caribaeorum and Protopalythoa variabilis, both collected at Paracuru beach, state of CearÃ. The cromatographic fractionation of the hexane extract from P. caribaeorum resulted in the isolation of four tetracyclic sterols possessing the ergostan skeleton: 24(R)-ergost-5-en-3b-ol (P-1); 5 a,8a-epidioxy-24(R)-ergost-6-en-3b-ol (P-2); 24(R)- ergost-5-en-3b,7a-diol (P-4) and 24(R)-7a-hydroperoxy-ergost-5-en-3b-ol (P-7), a glycerol derivative, 1-O-hexadecylglycerol (P-3) and four ceramides: N- (2S,3R,4E,8E,1,3-dihydroxy-4,8-octadecadienyl)hexadecanamide (P-5); N- (2S,3R,4E,1,3-dihydroxy-4-octadecenyl)hexadecanamide (P-6); N-[2S,3R,4E,8E,1-(2â- methylamino-ethanosulfonyl)-3-hydroxy-4,8-octadecaenyl]hexadecanamide (P-8) and N-[2S,3R,4E,1-(2â-methylaminoethano-sulfonyl)-3-hydroxy-4-octadecenyl]hexadecanamide (P-9). The cromatographic fractionation of the ethanol extract permited the isolation of a steroid, 24(R)-ergost-7-en-3b,5a,6b-triol (P-10) and a nucleoside 2- methyltimidine (P-11). Column chromatography of the hexane extract of P. variabilis led to the isolation of nonyl hexadecanoate (P-12), the sterol 24(R)-B-norergostan-3b- 5b-diol-6b-carboxylic acid (P-13) and the same chemical constituents previously isolated from P. caribaeorum (P-1, P-2, P-3 e P-4) including the four ceramides (P-5, P-6, P-8 e P-9). The citotoxic and antifungal properties of all ceramides were evaluated, nevertheless none of them showed any activity. All compounds were isolated through adsorption column cromatography over silica gel followed by high performance liquid chromatography. The structures of the isolated compounds were elucidated using spectrometric techniques, such as: GC/MS, HRESIMS, IR and NMR (1H, 13C and 15N) through 1D and 2D pulse sequences and, whenever the case, comparison with literature data
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Tronco, Cristiana de Melo Trinconi. "Tamoxifeno no tratamento de leishmaniose: atividade em esquemas terapéuticos combinados e estudo do mecanismo de ação." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-19042016-171456/.
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A leishmaniose é uma doença parasitária de ampla distribuição, para a qual se dispõe de um limitado arsenal terapêutico. Trabalhos recentes mostraram que tamoxifeno é eficaz no tratamento de leishmaniose experimental. Nesse trabalho, avaliamos a terapia combinada de tamoxifeno com os fármacos utilizados atualmente no tratamento desta enfermidade. A interação entre os fármacos mostrou-se aditiva, tanto in vitro como in vivo. Em paralelo, analisamos os efeitos de tamoxifeno na biossíntese de esfingolipídios em Leishmania, sendo identificada a redução da síntese de fosfatidilinositol e inositolfosforil ceramida (IPC) e acúmulo de ceramida acilada. A redução na biossíntese de IPC não pode ser atribuída a redução no transporte de inositol, mas provavelmente está relacionada à inibição da enzima IPC sintase. Estes resultados indicam novas estratégias para superar as deficiências encontradas no tratamento de leishmaniose utilizando tamoxifeno, um fármaco clinicamente bem conhecido que exerce ações em múltiplos alvos em Leishmania.Leishmaniasis is a parasitic disease with wide distribution and limited treatment. Recent reports demonstrate that tamoxifen is an effective drug for experimental leishmaniasis treatment. In this work, we evaluated the combined therapy of tamoxifen with current drugs used in leishmaniasis chemotherapy. The drug interaction was additive both, in vitro and in vivo. We also evaluated tamoxifen effect on in Leishmania sphingolipids biosynthesis. We found a reduction in phosphatidylinositol and inositol phosphorylceramide (IPC) synthesis and an accumulation of acilceramide. The reduction in IPC biosynthesis could not be assigned to the reduction observed in inositol transport, but probably is related to IPC synthase inhibition. These results show new strategies to circumvent shortcomings of leishmaniasis treatment using tamoxifen, a multitarget drug in Leishmania and widely used in the chemotherapy of breast cancer.
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Turnbull, Kenneth James. "The effect of Daunorubicin on human lymphoblastic leukaemia cells and the role of ceramide and ceramide-sensitive protein kinases." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312330.
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Lau, Kent G. "Formulation of novel double-chain lipid vesicles." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272376.
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Subramanian, Preeti. "Role of Ceramide-1-Phosphate as a Specific and Potent Activator of Group IVA Cytosolic Phospholipase A2 Alpha." VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1404.
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López, Crisosto Camila. "Regulación de la respuesta a insulina por ceramidas en el cardiomiocito a nivel de la dinámica mitocondrial." Tesis, Universidad de Chile, 2012. http://repositorio.uchile.cl/handle/2250/113540.
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Magíster en Bioquímica,
área de especialización Bioquímica Toxicológica y Diagnóstico MolecularMemoria para optar al Título de Bioquímica
La obesidad y la diabetes son condiciones altamente prevalentes que representan un importante factor de riesgo para el desarrollo de patologías cardiovasculares, principal causa de muerte entre los pacientes diabéticos. La lipotoxicidad y las alteraciones metabólicas juegan un papel fundamental en la resistencia a la hormona insulina y el daño cardiaco en estos pacientes. Los cardiomiocitos son las unidades funcionales del corazón y poseen un alto requerimiento energético que depende en su mayor parte de la función mitocondrial. Las mitocondrias forman una red dinámica que se remodela constantemente por eventos de fisión y fusión. La mantención de una morfología mitocondrial balanceada es fundamental para mantener una funcionalidad adecuada de este organelo. El objetivo de este trabajo fue investigar el efecto de las ceramidas, que derivan del metabolismo lipídico, en la señalización de la insulina y la dinámica mitocondrial en cultivos primarios de cardiomiocitos de rata. La señalización de insulina se evaluó mediante Western blot para Akt fosforilada y la morfología mitocondrial por microscopía confocal en células teñidas con Mitotracker Green. El tratamiento de los cardiomiocitos con C2-ceramida (40 μM, 3 h) disminuyó la fosforilación de Akt basalmente y en respuesta a insulina y favoreció la fisión mitocondrial, aumentando la translocación de la proteína de fisión Drp-1 hacia este organelo. Para evaluar si ambos efectos estaban relacionados, se inhibió la actividad de Drp-1 mediante el uso de un dominante negativo y de un inhibidor químico, antes del tratamiento con C2-ceramida. La inhibición de Drp-1 mediante ambas herramientas previno la fisión mitocondrial causada por C2-ceramida y rescató la fosforilación de Akt en respuesta a insulina. Trabajos previos de nuestro laboratorio muestran que el tratamiento de los cardiomiocitos con palmitato 500 μM durante 3 h también induce fisión de la red mitocondrial. En este trabajo se mostró que al inhibir la síntesis de ceramidas a partir de palmitato se previene, en parte, los efectos de este ácido graso sobre la dinámica mitocondrial de los cardiomiocitos. En conclusión, la fragmentación de la red mitocondrial inducida por ceramidas es necesaria para la disminución de la señalización de insulina en los cardiomiocitos. Además, la fisión mitocondrial inducida por palmitato en este modelo depende en parte de la generación de ceramidas.
Obesity and diabetes are highly prevalent conditions that represent an important risk factor for the development of cardiovascular diseases, the main cause of death in diabetic patients. Lipotoxicity and metabolic alterations take part in insulin resistance and heart damage in these patients. Cardiomyocytes are the functional basic units of the heart and have a high energy requirement that depends largely on mitochondrial function. Mitochondria form a dynamic network that is constantly remodelled by fission and fusion events. The maintenance of a balanced mitochondrial morphology is critical to maintain a proper functionality of this organelle. The aim of this study was to investigate the effect of ceramides, derived from lipid metabolism, in insulin signalling and mitochondrial dynamics in primary cultures of rat cardiomyocytes. Insulin signalling was assessed by Western blot for phosphorylated Akt and mitochondrial morphology by confocal microscopy in Mitotracker Green-stained cells. Treatment of cardiomyocytes with C2-ceramide (40 μM, 3 h) decreased the phosphorylation of Akt at baseline and in response to insulin and induced mitochondrial fission, increasing the translocation of the fission protein Drp-1 to this organelle. To assess whether both effects were related, Drp-1 activity was inhibited by using a dominant negative and a chemical inhibitor, before treatment with C2-ceramide. The inhibition of Drp-1 by both tools prevented mitochondrial fission caused by C2-ceramide and rescued Akt phosphorylation in response to insulin. Previous work in our laboratory showed that treatment of cardiomyocytes with palmitate 500 μM for 3 h also induces mitochondrial fission. We showed that inhibiting the synthesis of ceramides from palmitate prevented in part the effects of this fatty acid on mitochondrial dynamics in cardiomyocytes. In conclusion, the mitochondrial network fragmentation induced by ceramides is required for the decrease of insulin signalling in cardiomyocytes. Furthermore, palmitate-induced mitochondrial fission in this model depends in part on the generation of ceramides.
Fondap, Fondecyt
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Fletcher, Sarah Jayne. "Investigating the role of ceramides in plant signal transduction." Thesis, Lancaster University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436752.
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Souza, Sofia Leite. "On the physical-chemical properties of ceramide C16." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2012. http://hdl.handle.net/10362/12024.
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Dissertation presented to obtain the Ph.D degree in Chemistry.Ceramides are known to be involved in cell signalling and are proposed to assist in the formation of laterally segregated membrane domains, known as ceramide rich domains in cell lipid bilayers. The lipid matrix of the stratum corneum, the uppermost layer of the skin, which is responsible for its water barrier properties, is mainly composed of ceramides, associated with cholesterol, long chain fatty acids and cholesteryl esters.(...)
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Sawai, Hirofumi. "Role for ceramide in apoptosis of leukemia cells." Kyoto University, 1997. http://hdl.handle.net/2433/202164.
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Hansen, Melissa Ellen. "The Role of Ceramides in Mediating Endotoxin-Induced Mitochondrial Disruption." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/5495.
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Ceramides are sphingolipids that serve as important second messengers in an increasing number of stress-induced pathways. Ceramide has long been known to affect the mitochondria, altering both morphology and physiology. Lipopolysaccharide (LPS) is a prevalent circulating inflammatory agent in obesity, potentially mediating some of the pathologies associated with weight gain. Given previous findings of TLR4-mediated ceramide accrual and ceramide-mediated mitochondrial disruption, we questioned whether ceramide is necessary for LPS-induced mitochondrial disruption. We found that LPS treatment increased gene transcript levels of ceramide synthesis enzymes and mitochondrial fission proteins and increased ceramide content in cultured myotubes and in mouse tissue. Mitochondrial respiration from permeabilized red gastrocnemius was reduced from animals receiving LPS injections when compared with those receiving vehicle (PBS). However, respiration from mice receiving both LPS and myriocin, a ceramide inhibitor, (0.3 mg/kg) was similar to PBS-injected animals. We treated murine myotubes with similar LPS conditions. These cells demonstrated increased ceramide synthesis and increased levels of mitochondrial fission with LPS treatment; these effects were mitigated with the addition of myriocin. However, in contrast to the whole gastrocnemius response in animals receiving LPS, respiration from myotubes was increased with LPS alone, and even higher with both myriocin alone and myriocin with LPS. We also sought to assess the impact of ceramide on skeletal muscle mitochondrial structure and function. A primary observation was the rapid and dramatic division of mitochondria in ceramide-treated cells. This effect is likely a result of increased Drp1 action, as ceramide increased Drp1 expression and Drp1 inhibition prevented ceramide-induced mitochondrial fission. Further, we found that ceramide treatment reduced mitochondrial O2 consumption (i.e., respiration) in cultured myotubes and permeabilized red gastrocnemius muscle fiber bundles. Ceramide treatment also increased H2O2 levels and reduced Akt/PKB phosphorylation in myotubes. However, inhibition of mitochondrial fission via Drp1 knockdown completely protected the myotubes and fiber bundles from ceramide-induced metabolic disruption, including maintained mitochondrial respiration, reduced H2O2 levels, and unaffected insulin signaling. These data suggest that the forced and sustained mitochondrial fission that results from ceramide accrual may alter metabolic function in skeletal muscle, which is a prominent site not only of energy demand (via the mitochondria), but also of ceramide accrual with weight gain.
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Sridevi, Priya Alexander Hannah Ben-Ze'ev Alexander Stephen. "Regulation of ceramide synthase 1 in cellular stress response." Diss., Columbia, Mo. : University of Missouri--Columbia, 2008. http://hdl.handle.net/10355/6690.
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Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 25, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Stephen Alexander and Dr. Hannah Alexander. Vita. Includes bibliographical references.
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Holopainen, Juha. "Ceramide - a messenger of cell death : a biophysical approach." Helsinki : University of Helsinki, 2001. http://ethesis.helsinki.fi/julkaisut/laa/biola/vk/holopainen/.
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Sant'anna, Ana Luisa Silva. "Estudo da deposição de ceramidas sobre a fibra capilar para o combate a danos cuticulares." [s.n.], 2000. http://repositorio.unicamp.br/jspui/handle/REPOSIP/250433.
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Orientador: Ines JoekesDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica
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Thatcher, Mikayla Orton. "HMGB1 and Ceramides: Potential Mediators of Cigarette Smoke-induced Metabolic Dysfunction." BYU ScholarsArchive, 2015. https://scholarsarchive.byu.edu/etd/6041.
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While cigarette smoking is a common-knowledge way to stay lean, it has long been known as a risk factor for diabetes and obesity. Here we establish that smoking causes fat gain and metabolic disruption in mice, effects which are exacerbated by a high-fat, high-sugar diet. We found that smoke exposure increases levels of ceramide—the lipid responsible for diet-induced insulin resistance—and that blocking ceramide production with the pharmacological inhibitor myriocin restored insulin sensitivity, stopped weight gain, and rescued mitochondrial respiration in vivo and in vitro.We also sought to assess the impact of the RAGE ligand HMGB1 on skeletal muscle metabolism. We found that respiration between vehicle and HMGB1-injected red gastrocnemius was comparable. In myotubes, adding myriocin treatment to the HMGB1 cells increased respiration above HMGB1 treatment alone. HMGB1 increased oxidative stress in cultured myotubes and increased the transcript levels of Spt2, the enzyme responsible for the rate-limiting step in ceramide synthesis, although transcript levels of markers of mitochondrial fission and fusion leave us unsure of HMGB1's impact on mitochondrial dynamics. HMGB1, even at an exceptionally low dose over only 2 weeks, did cause significant impairment in glucose and insulin tolerance tests. Considering HMGB1's accessibility as a therapeutic target, its involvement in metabolic disruption is worth pursuing further.
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Izquierdo, García Eduardo. "Chemical approaches to the study of the ceramide synthase activity." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671426.
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Sphingolipids (SLs) are one of the major classes of lipids in eukaryotes. In addition to being essential structural components of cell membranes, SLs also play capital roles as signalling molecules. Ceramides (Cer) are a family of bioactive SLs consisting of a long chain base (LCB), known as the sphingoid base, linked to a fatty acid (FA) of variable chain length via an amide bond. Due to their metabolic inter-relations with other SL species, Cer are considered key intermediates in the SL pathway. Cer are important second messengers in several cellular processes including apoptosis, autophagy, cell differentiation and sensescence. Ceramide synthases (CerS) are a group of enzymes, primarily localised at the endoplasmic reticulum, that catalyse the N–acylation of sphingoid bases such as sphingosine (So) and dihydrosphingosine (dhSo), using acyl CoA thioesters of variable chain lengths, to afford Cer and dihydroceramides (dhCer), respectively. Six isoforms of CerS (CerS1–6) have been identified in mammals. Each CerS isoform utilizes a small subset of FA-CoAs of defined chain lengths and, thus, each of them produces specific Cer populations. In the recent years, it has become apparent that Cer with different acyl chains vary in their biophysical properties and in the signalling pathways they participate. Furthermore, Cer with defined acyl chain lengths have been found to be implicated in the onset of a variety of human diseases, including cancer, type-2 diabetes mellitus, Alzheimer’s disease, multiple sclerosis and cardiomyopathy. In this context, the development of appropriate tools to study the activity of CerS enzymes, which is crucial to decipher the molecular mechanisms by which Cer elicit their effects, was the ultimate goal of the present doctoral thesis. The first part of this thesis was devoted to the development of a new CerS activity assay based on the Förster Resonance Energy Transfer (FRET) phenomenon. To that end, we designed and synthesized a series of fluorescently labelled (or labelable) 1-deoxy sphingoid probes derived from spisulosine, a small library of clickable FA analogues of different chain lengths, and a collection of bicyclo[6.1.0]nonyne (BCN) or 1,2,4,5-tetrazine (Tz) based fluorescent reagents. The absorption and fluorescence emission properties of these compounds was thoroughly studied in various solvents by means of cuvette-based experiments. Based on these studies, we anticipated that a highly efficient FRET process would take place between the donor-acceptor fluorophore pairs that had been selected, namely MCC/NBD and NBD/NR. Next, the metabolic incorporation of the different spisulosin-based probes and the FA analogues was evaluated in various biological contexts. Mass spectrometry analysis evidenced an extensive metabolization of the synthetic LCB probes and the FA analogues by CerS enzymes to form the corresponding Cer metabolites. Unfortunately, the FA analogues were also incorporated into other lipidic metabolic pathways, resulting in the generation of a strong fluorescence background after the fluorescent labelling reactions. Our different attempts to solve this issue were unfruitful and, thus, the development of the FRET based fluorescence assay to determine the CerS activity could not be achieved. The second part of this thesis was aimed at the development of new click-formed proteolysis targeting chimeras (CLIPTACs) targeting the ubiquitination and proteasomal degradation of CerS, as an alternative to small molecule inhibitors for the modulation of the CerS activity. To this end, we designed and synthesized four BCN derivatives containing known ligands for recruiting different E3 ubiquitin ligases. These BCN-tagged E3 ligase recruiters will be used in future studies in combination with an azido-functionalized analogue of the CerS substrate Jaspine B to obtain the desired CLIPTACs.Los esfingolípidos (SLs) son una de las principales categorías de lípidos presentes en los organismos eucariotas. Los SL no sólo son componentes estructurales esenciales de las membranas celulares, sino que también actúan como moléculas señalizadoras. Las ceramidas (Cer) son una tipología de SL que están formadas por una base esfingoide y una cadena de ácido graso de longitud variable unidos a través de un enlace amida. Las Cer participan como segundos mensajeros en procesos celulares como la apoptosis, la autofagia, la diferenciación celular y la senescencia. Las ceramida sintasas (CerS) son un grupo de enzimas del retículo endoplasmático que catalizan la N-acilación de bases esfingoides, como la esfingosina, utilizando acil-CoAs de distintas longitudes, para dar Cer. En los mamíferos se han descrito seis isoformas de la CerS y cada una de ellas tiene preferencia por un pequeño grupo de ácidos grasos de longitud de cadena definida, por lo que cada una produce perfiles de Cer característicos. En los últimos años se ha visto que la longitud de la cadena acilo de las Cer influye en sus propiedades biofísicas y en las cascadas de señalización en las que participan. Además, se sabe que ciertas Cer están involucradas en el desarrollo de distintas enfermedades como el cáncer, la diabetes, el Alzheimer o la esclerosis múltiple. En este sentido, el desarrollo de herramientas adecuadas para el estudio de la actividad de CerS es fundamental para descifrar los mecanismos moleculares a través de los cuáles actúan las Cer, siendo este el objetivo principal que se persiguió en la presente tesis doctoral. La primera parte de la tesis se centró en el desarrollo de un nuevo ensayo para determinar la actividad CerS por medio del fenómeno de FRET. Para ello, se diseñaron y sintetizaron una serie de sondas esfingoides derivadas de la espisulosina, una pequeña quimioteca de análogos de ácidos grasos “clicables” de distintas longitudes de cadena y una colección de reactivos fluorescentes marcados con un grupo biciclo[6.1.0]nonino (BCN) o 1,2,4,5-tetrazina (Tz). Las propiedades de absorción y emisión de fluorescencia de estos compuestos fueron estudiadas en varios disolventes a través de experimentos “en cubeta”. En base a estos experimentos anticipamos que las parejas de fluoróforos seleccionadas eran adecuadas para su uso en experimentos de FRET. A continuación, se evaluó la incorporación metabólica de las distintas sondas esfingoides y de los varios análogos de ácidos grasos en medios biológicos. Los estudios de lipidómica mostraron que tanto las sondas como los análogos de ácidos grasos eran procesados por las CerS para dar las Cer correspondientes. Sin embargo, los análogos de ácidos grasos también entraron en otras rutas metabólicas de los lípidos dando lugar a un elevado ruido de fondo tras la reacción de marcaje de fluorescencia. Nuestros intentos para solventar este problema fueron en vano y, por tanto, finalmente no fue posible la implementación del ensayo de fluorescencia para medir la actividad CerS. En la segunda parte de la tesis se propuso el desarrollo de nuevos CLIPTACs dirigidos a la degradación de CerS, como alternativa a los inhibidores clásicos para la modulación de la actividad CerS. Para ello se diseñaron y sintetizaron cuatro derivados de BCN que contuvieran un ligando para reclutar distintos enzimas E3 ligasas de ubiquitina. Estos reclutadores de E3 ligasa serán utilizados en un futuro en combinación con un derivado de la Jaspina B, un análogo del sustrato de las CerS, para obtener los CLIPTACs deseados.
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Stiban, Johnny Pierre. "Ceramide metabolism and transport implications on the initiation of apoptosis /." College Park, Md. : University of Maryland, 2006. http://hdl.handle.net/1903/6658.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2006.Thesis research directed by: Biology. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Sociale, Mariangela [Verfasser]. "Ceramide Synthase in Transcriptional Regulation and Lipid Sensing / Mariangela Sociale." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1188731017/34.
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Narita, Keishi. "Study of ceramide glucosyltransferase : mechanism of inhibition by imino sugars." Thesis, University of Oxford, 2001. http://ora.ox.ac.uk/objects/uuid:a96eb6ad-9058-485f-91c3-d7cde9762e81.
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Ceramide glucosyltransferase (CGT) is a key enzyme in glycosphingolipid (GSL) biosynthesis in eukaryotic cells. Inhibition of enzyme activity by an N-alkylated imino sugar, N-butyl-deoxynojirimycin (NB-DNJ), has been evaluated for the therapeutic treatment of inherited glycosphingolipid lysosomal storage diseases. To develop more selective drugs for potential clinical use, further investigation of possible side effects and the design of a more selective inhibitor is required. One concern for clinical use of NB-DNJ is the potential activation of CGT in vivo. When rats were treated with various concentrations of NB-DNJ for 13 weeks to assess the depletion of glycosphingolipids and up-regulation of CGT activity, the reduction of ganglioside levels was observed following an increase in NB-DNJ dose level up to 180 mg/kg/day. However, CGT activity levels were not significantly affected by NB-DNJ treatment. The lack of CGT up-regulation while reducing GSLs by NB-DNJ would be desirable in the clinic to avoid a rapid accumulation of GSLs if patient treatment was concluded. To aid in design of highly selective inhibitors for CGT, enzyme kinetic studies were performed using recombinant human CGT and five different imino sugars. The recombinant enzyme showed similar enzyme kinetics to a native enzyme from HL-60 cells. All the tested imino sugars showed a mixed-type inhibition for ceramide, and an increase in N-alkyl chain provided an improved uncompetitive inhibition. These data suggest that CGT may have two different sites for binding of imino sugars, and the N-alkyl chain length may affect the preference for binding site. When the protein sequence of CGT was analysed using www server programs to predict protein structure, a Rossman fold was predicted in the nucleotide-binding domain as observed in other nucleotide-sugar glycosyltransferase structures. Also, a significant folding similarity to bacterial glycosyltransferase SpsA was predicted. Based on these observations, a possible inhibitor-binding mechanism is discussed that may aid the design of highly selective inhibitors for CGT.
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Trinconi, Cristiana de Melo. "Investigação sobre a atividade de Ceramida Sintase em Leishmania amazonensis." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-13022012-091618/.
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A leishmaniose é uma doença parasitária de ampla distribuição e de difícil tratamento. Recentemente foi identificada a atividade leishmanicida de tamoxifeno, levando à proposta de sua utilização como alternativa para o tratamento de leishmaniose. Neste trabalho, propusemo-nos a caracterizar a atividade de ceramida sintase (CerS) em L. amazonensis e testar a interferência do tamoxifeno nesta enzima. Identificamos, no genoma de L. amazonensis, uma ORF que codifica uma proteína similar à CerS de Saccharomyces cerevisiae, com seis domínios transmembrana e um motivo Lag1 característico. A caracterização da atividade enzimática in vitro mostrou que a enzima reconhece esfingosina/esfinganina e palmitoil/miristoil CoA como precursores. A enzima não é sensível à fumonisina B2 ou a tamoxifeno. Isto indica que esta droga não atua através da inibição da CerS. A caracterização completa desta enzima fornecerá dados valiosos sobre o metabolismo de esfingolipídeos nestes protozoários.Leishmaniasis is a widely distributed parasitic disease with difficult treatment. The leishmanicidal activity of tamoxifen was recently identified, leading to its proposal as an alternative treatment for leishmaniasis. In this work, we aimed at characterizing the activity of ceramide synthase (CerS) in L. amazonensis and testing whether this enzymatic activity in inhibited by tamoxifen. We have identified, in the L. amazonensis genome, an ORF which encodes a protein similar to the Saccharomyces cerevisiae CerS, with six transmembrane domains and a characteristic Lag1 motif. The characterization of the in vitro enzymatic activity showed that the enzyme recognizes sphingosine/sphinganine as well as palmitoyl/miristoyl CoA as precursors. This enzyme is not sensitive to fumonisin B2 or tamoxifen. This indicates that this drug does not act through the inibition of CerS. The complete characterization of this enzyme will provide valuable information about the sphingolipid methabolism of these protozoa.
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Hodson, Aimee Elizabeth. "Insulin Treatment Increases Myocardial Ceramide Accumulation and Disrupts Cardiometabolic Function." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/5954.
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Prevalence of diabetes, especially type 2 diabetes mellitus (T2DM) is increasing worldwide. Millions of people are already affected by T2DM and estimates predict over half a billion people will likely be suffering from the disease by 2030. T2DM is associated with an increased risk of developing cardiovascular disease. Cardiovascular dysfunction is the leading cause of mortality among type 2 diabetics. Treatment for T2DM has changed over time. Though it was once known as insulin independent, a large portion of type 2 diabetics are now treated with insulin injections. However, type 2 diabetics treated with insulin are more likely to suffer from heart complications. Due to this, we sought to determine the specific effect of insulin and insulin-induced ceramide accrual on heart mitochondrial bioenergetics. To do so we used both in vitro and in vivo models. H9c2 cardiomyocytes and adult male mice were treated with insulin with or without the ceramide biosynthesis inhibitor myriocin. Mitochondrial bioenergetics were determined in permeabilized cardiomyocytes and myocardium. In this study we demonstrate that insulin induced ceramide accrual in both isolated cardiomyocytes and whole murine myocardium. We further found that insulin treatment is sufficient to disrupt mitochondrial respiration in both models. Inhibition of the ceramide accrual rescued mitochondrial respiration, indicating that ceramide is necessary for the insulin-induced alterations in heart mitochondrial respiration. These results suggest that insulin has a role in the development of heart complications associated with T2DM due to cardiomyocyte mitochondrial disruption. They also implicate ceramide as a possible mediator in the development of insulin-related heart disorders.
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Tippetts, Trevor Stanley. "Cigarette Smoke Increases Cardiomyocyte Ceramide Accumulation and Inhibits Mitochondrial Respiration." BYU ScholarsArchive, 2015. https://scholarsarchive.byu.edu/etd/5596.
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Cigarette smoking is a common and lethal worldwide habit, with considerable mortality stemming from its deleterious effects on heart function. While current theories posit altered blood lipids and fibrinogen metabolism as likely mediators, none have explored the role of the sphingolipid ceramide in exacerbating heart function with smoke exposure. Ceramide production is a consequence of cigarette smoke in the lung, and considering ceramide's harmful effects on mitochondrial function, we sought to elucidate the role of ceramide in mediating smoke-induced altered heart mitochondrial respiration. Lung cells were exposed to cigarette smoke extract and heart cells were exposed to the lung-cell conditioned medium. Adult male mice were exposed sidestream cigarette smoke for 8 weeks with dietary intervention and ceramide inhibition. Ceramides and heart cell or myocardial mitochondrial respiration were determined. Lung cell cultures revealed a robust response to cigarette smoke extract in both production and secretion of ceramides. Heart cells incubated with lung-cell conditioned medium revealed a pronounced inhibition of myocardial mitochondrial respiration, though this effect was mitigated with ceramide inhibition via myriocin. In vivo, heart ceramides increased roughly 600% in adult mice with long-term sidestream cigarette smoke exposure. This resulted in a significant ceramide-dependent reduction in left myocardial mitochondrial respiration, as heart mitochondria from the mice exposed to both smoke and myriocin injections respired normally. These results suggest ceramide to be an important mediator of altered myocardial mitochondrial function with cigarette smoke exposure. Thus, anti-ceramide therapies might be considered in the future to protect heart mitochondrial function with smoke exposure.
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Dupre, Tess V., Mark A. Doll, Parag P. Shah, Cierra N. Sharp, Deanna Siow, Judit Megyesi, James Shayman, et al. "Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury." AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2017. http://hdl.handle.net/10150/624924.
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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. Pretreatment 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. To determine the role of ceramide metabolism to hexosylceramides in kidney injury, we treated mice with a potent and highly specific inhibitor of glucosylceramide synthase, the enzyme responsible for catalyzing the glycosylation of ceramides to form glucosylceramides. Inhibition of glucosylceramide synthase attenuated the accumulation of the hexosylceramides and exacerbated ceramide accumulation in the renal cortex following treatment of mice with cisplatin. Increasing ceramides and decreasing glucosylceramides in the renal cortex sensitized mice to cisplatin-induced AKI according to markers of kidney function, kidney injury, inflammation, cell stress, and apoptosis. Under conditions of high ceramide generation, data suggest that metabolism of ceramides to glucosylceramides buffers kidney ceramides and helps attenuate kidney injury.-Dupre, T. V., M. A. Doll, P. P. Shah, C. N. Sharp, D. Siow, J. Megyesi, J. Shayman, A.Bielawska, J. Bielawski, L. J. Beverly, M. Hernandez-Corbacho, C. J. Clarke, A. J. Snider, R. G. Schnellmann, L. M. Obeid, Y. A. Hannun, and L. J. Siskind. Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury.
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BIZOT, FOULON VALERIE. "Influence des ceramides d'origine vegetales sur la regulation de l'expression et de l'activite des proteinases neutres : encapsulation de l'acide all-trans retinoique et effet intrinseque des ceramides." Paris 11, 1995. http://www.theses.fr/1995PA114838.
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Ito, Mitsuru. "Possible role of ceramide as an indicator of chemoresistance : decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia." Kyoto University, 2003. http://hdl.handle.net/2433/148774.
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Tomonaga, Nami. "Studies on marine sphingophosphonolipids as new food ingredients." Kyoto University, 2019. http://hdl.handle.net/2433/242681.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第21804号
農博第2317号
新制||農||1065(附属図書館)
学位論文||H31||N5176(農学部図書室)
京都大学大学院農学研究科応用生物科学専攻
(主査)教授 菅原 達也, 教授 佐藤 健司, 教授 松井 徹
学位規則第4条第1項該当
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Ramírez, Flores Sara. "Hypothalamic Ceramide Levels regulated by CPT1C mediate the Orexigenic effect of Ghrelin." Doctoral thesis, Universitat Internacional de Catalunya, 2014. http://hdl.handle.net/10803/276184.
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Recent data suggest that ghrelin exerts its orexigenic action through regulation of hypothalamic AMP-activated protein kinase pathway, leading to a decline in malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately enhances the expression of the orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of neurons, may play a role in this action. Here, we demonstrate that the orexigenic action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having the canonical ghrelin signaling pathway activated. We also demonstrate that ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels mediated by CPT1C. Notably, central inhibition of ceramide synthesis with myriocin negated the orexigenic action of ghrelin and normalized the levels of AgRP and NPY, as well as their key transcription factors phosphorylated cAMP-response element-binding protein and forkhead box O1. Furthermore, central treatment with ceramide induced food intake and orexigenic neuropeptides expression in CPT1C KO mice. Third, we demonstrate that ceramides act increasing the BSX expression, the transcription factor that works coordinately with pCREB and FoxO1 to increase orexigenic neuropeptides. Finally we link CPT1C and longevity as we have seen that CPT1CKO mice have reduced lifespan. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism