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1.
Biochemistry (Mosc) ; 84(10): 1166-1176, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694512

RESUMO

The aim of this study was to evaluate changes in the content of sphingoid bases - sphingosine (SPH), sphinganine, and sphingosine-1-phosphate (SPH-1-P) - and in expression of genes encoding enzymes involved in their metabolism in the brain structures (hippocampus, cortex, and cerebellum) and spinal cord of transgenic FUS(1-359) mice. FUS(1-359) mice are characterized by motor impairments and can be used as a model of amyotrophic lateral sclerosis (ALS). Lipids from the mouse brain structures and spinal cord after 2, 3, and 4 months of disease development were analyzed by chromatography/mass spectrometry, while changes in the expression of the SPHK1, SPHK2, SGPP2, SGPL1, ASAH1, and ASAH2 genes were assayed using RNA sequencing. The levels of SPH and sphinganine (i.e., sphingoid bases with pronounced pro-apoptotic properties) were dramatically increased in the spinal cord at the terminal stage of the disease. The ratio of the anti-apoptotic SPH-1-P to SPH and sphinganine sharply reduced, indicating massive apoptosis of spinal cord cells. Significant changes in the content of SPH and SPH-1-P and in the expression of genes related to their metabolism were found at the terminal ALS stage in the spinal cord. Expression of the SGPL gene (SPH-1-P lyase) was strongly activated, while expression of the SGPP2 (SPH-1-P phosphatase) gene was reduced. Elucidation of mechanisms for the regulation of sphingolipid metabolism in ALS will help to identify molecular targets for the new-generation drugs.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Proteína FUS de Ligação a RNA/metabolismo , Esfingolipídeos/metabolismo , Medula Espinal/metabolismo , Animais , Camundongos , Camundongos Transgênicos , Esfingolipídeos/química
2.
J Agric Food Chem ; 67(46): 12953-12961, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31638789

RESUMO

Most common sphingolipids are comprised of "typical" sphingoid bases (sphinganine, sphingosine, and structurally related compounds) and are produced via the condensation of l-serine with a fatty acyl-CoA by serine palmitoyltransferase. Some organisms, including mammals, also produce "atypical" sphingoid bases that lack a 1-hydroxyl group as a result of the utilization of l-alanine or glycine instead of l-serine, resulting in the formation of 1-deoxy- or 1-desoxymethylsphingoid bases, respectively. Elevated production of "atypical" sphingolipids has been associated with human disease, but 1-deoxysphingoid bases have also been found to have potential as anticancer compounds, hence, the importance of knowing more about the occurrence of these compounds in food. Most of the "typical" and "atypical" sphingoid bases are found as the N-acyl metabolites (e.g., ceramides and 1-deoxyceramides) in mammals, but this has not been uniformly assessed in previous studies nor determined in consumed food. Therefore, we developed a method for the quantitative analysis of "typical" and "atypical" sphingoid bases and their N-acyl derivatives by reverse-phase liquid chromatography coupled to electrospray ionization tandem mass spectrometry. On the basis of these analyses, there was considerable variability in the amounts and molecular subspecies of atypical sphingoid bases and their N-acyl metabolites found in different edible sources. These findings demonstrate that a broader assessment of the types of sphingolipids in foods is needed because some diets might contain sufficient amounts of atypical as well as typical sphingolipids that could have beneficial or possibly deleterious effects on human health.


Assuntos
Acil Coenzima A/química , Esfingolipídeos/química , Acil Coenzima A/metabolismo , Serina/química , Serina/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esfingolipídeos/metabolismo
3.
Adv Exp Med Biol ; 1159: 1-3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502196

RESUMO

Sphingolipid biology has enjoyed a remarkable rise to fame over the last two decades. Various molecules from this lipid family have been implicated in a variety of cellular functions in health and disease. Ceramides, which constitute the hub of sphingolipid metabolism, are apoptogenic molecules that have many proposed mechanisms of actions. Enigmas revolving around this area of research are slowly being cleared with the advent of better laboratory techniques and data analyses. In this chapter, a general introduction of the topics presented in this book is undertaken highlighting the main ideas of each chapter.


Assuntos
Ceramidas/metabolismo , Metabolismo dos Lipídeos , Esfingolipídeos/metabolismo
4.
Adv Exp Med Biol ; 1159: 5-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502197

RESUMO

Mitochondria and bacteria share a myriad of properties since it is believed that the powerhouses of the eukaryotic cell have evolved from a prokaryotic origin. Ribosomal RNA sequences, DNA architecture and metabolism are strikingly similar in these two entities. Proteins and nucleic acids have been a hallmark for comparison between mitochondria and prokaryotes. In this chapter, similarities (and differences) between mitochondrial and prokaryotic membranes are addressed with a focus on structure-function relationship of different lipid classes. In order to be suitable for the theme of the book, a special emphasis is reserved to the effects of bioactive sphingolipids, mainly ceramide, on mitochondrial membranes and their roles in initiating programmed cell death.


Assuntos
Evolução Biológica , Membrana Celular/química , Lipídeos/química , Mitocôndrias/química , Células Procarióticas/química , Ceramidas , Esfingolipídeos
5.
Adv Exp Med Biol ; 1159: 49-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502199

RESUMO

The majority of enzymes in the sphingolipid (SL) biosynthetic pathway have been identified over the past couple of decades. Despite significant work, and despite their crucial and central roles in SL synthesis, significant information is still lacking concerning the enzymes that catalyze the N-acylation of sphingoid long chain bases, namely the ceramide synthases (CerS), a family of six mammalian genes originally named longevity assurance (Lass) genes. Each of these six endoplasmic reticulum (ER) membrane-bound enzymes utilizes a relatively restricted sub-set of fatty acyl-CoAs for N-acylation, but are far more promiscuous about the use of long chain bases. The reason that mammals and other species have multiple CerS, generating a specific subset of ceramides, is not yet known, but implies an important role for ceramides containing specific fatty acids in cell physiology. In this brief chapter, we will stroll down the CerS lane and discuss what is known, and what is not known, about this important enzyme family.


Assuntos
Ceramidas/biossíntese , Retículo Endoplasmático/enzimologia , Esfingosina N-Aciltransferase/fisiologia , Animais , Ácidos Graxos/química , Esfingolipídeos
6.
Adv Exp Med Biol ; 1159: 109-138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502202

RESUMO

Despite the advancements in modern medicine, there are still difficulties in diagnosing common illnesses. The invasiveness and price of the tests used to follow up certain diseases can be a barrier to proper patient follow-up. Sphingolipids are a diverse category of lipids. They are structural molecules in cell membranes and signaling molecules involved in the regulation of crucial cell functions, including cell growth, differentiation, proliferation and apoptosis. Recent research has shown that abnormal sphingolipid metabolism is associated with genetic and metabolic disease processes. Given their crucial role to maintain homeostasis within the body, sphingolipids have been investigated as potential biomarkers to predict disease in the population. Here we discuss how sphingolipids levels are altered in different diseases, thus illustrating their possible use as diagnostic and prognostic biomarkers for disease.


Assuntos
Biomarcadores , Transdução de Sinais , Esfingolipídeos , Ciclo Celular , Membrana Celular , Homeostase , Humanos
7.
Adv Exp Med Biol ; 1159: 139-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502203

RESUMO

Inflammation is a powerful immune countermeasure to tissue damage and infection. The inflammatory response is complex and requires the involvement of myriad signaling pathways and metabolic processes, all governed by a multitude of regulatory systems. Although inflammation is a vital defense against tissue injury and a necessary step in tissue healing, the mechanisms which modulate the initiation, intensity, and duration of this innate immune response can malfunction and result in inappropriate or out-of-control inflammation, even in the absence of an appropriate stimulus. Though the human eye exists in an immune-privileged microenvironment, it is not spared from this. The eye is neither devoid of immune cells nor is it fully sequestered from systemic immune responses, and is therefore fully capable of ruining itself through localized inflammatory dysfunction and systemic inflammatory disease (Taylor AW, Front Immunol 7:37, 2016; Zhou R, Caspi RR, Biol Rep 2, 2010). In fact, a wide range of ocular inflammatory diseases exist and are major causes of blindness in humans. Advances in the understanding of inflammatory processes have revealed new key pathways and molecular factors involved in the mechanisms of inflammation. Lipids and sphingolipids are increasingly being recognized as having important signaling roles in the pathophysiology of ocular inflammatory diseases. What follows below is a discussion of fundamental inflammatory processes, the place of sphingolipids as mediators of said processes, brief descriptions of major inflammatory ocular diseases, and new findings implicating sphingolipids in their pathogenesis.


Assuntos
Oftalmopatias , Inflamação , Transdução de Sinais , Esfingolipídeos/metabolismo , Olho/imunologia , Humanos
8.
N Engl J Med ; 381(15): 1422-1433, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509666

RESUMO

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).


Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação , Telangiectasia Retiniana/genética , Serina C-Palmitoiltransferase/genética , Serina/metabolismo , Esfingolipídeos/metabolismo , Adulto , Idoso , Animais , Análise Mutacional de DNA , Modelos Animais de Doenças , Exoma/genética , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/complicações , Neuropatias Hereditárias Sensoriais e Autônomas/metabolismo , Humanos , Metabolismo dos Lipídeos , Macula Lutea/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Telangiectasia Retiniana/complicações , Telangiectasia Retiniana/metabolismo , Fatores de Risco , Serina/sangue , Esfingosina/análogos & derivados , Esfingosina/análise , Adulto Jovem
9.
Adv Exp Med Biol ; 1161: 149-167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562629

RESUMO

Inflammation is a common underlying factor in a diversity of ocular diseases, ranging from macular degeneration, autoimmune uveitis, glaucoma, diabetic retinopathy and microbial infection. In addition to the variety of known cellular mediators of inflammation, such as cytokines, chemokines and lipid mediators, there is now considerable evidence that sphingolipid metabolites also play a central role in the regulation of inflammatory pathways. Various sphingolipid metabolites, such as ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and lactosylceramide (LacCer) can contribute to ocular inflammatory diseases through multiple pathways. For example, inflammation generates Cer from sphingomyelins (SM) in the plasma membrane, which induces death receptor ligand formation and leads to apoptosis of retinal pigment epithelial (RPE) and photoreceptor cells. Inflammatory stress by reactive oxygen species leads to LacCer accumulation and S1P secretion and induces proliferation of retinal endothelial cells and eventual formation of new vessels. In sphingolipid/lysosomal storage disorders, sphingolipid metabolites accumulate in lysosomes and can cause ocular disorders that have an inflammatory etiology. Sphingolipid metabolites activate complement factors in the immune-response mediated pathogenesis of macular degeneration. These examples highlight the integral association between sphingolipids and inflammation in ocular diseases.


Assuntos
Oftalmopatias , Inflamação , Esfingolipídeos , Apoptose , Células Endoteliais/citologia , Células Endoteliais/patologia , Oftalmopatias/fisiopatologia , Humanos , Inflamação/fisiopatologia , Esfingolipídeos/metabolismo
10.
Adv Exp Med Biol ; 1161: 169-191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562630

RESUMO

Ceramides are bioactive sphingolipids that support the structure of the plasma membrane and mediate numerous cell-signaling events in eukaryotic cells. The finding that ceramides act as second messengers transducing cellular signals has attracted substantial attention in several fields of Biology. Since all cells contain lipid plasma membranes, the impact of various ceramides, ceramide synthases, ceramide metabolites, and other sphingolipids has been implicated in a vast range of cellular functions including, migration, proliferation, response to external stimuli, and death. The roles of lipids in these functions widely differ among the diverse cell types. Herein, we discuss the roles of ceramides and other sphingolipids in mediating the function of various immune cells; particularly dendritic cells, neutrophils, and macrophages. In addition, we highlight the main studies describing effects of ceramides in inflammation, specifically in various inflammatory settings including insulin resistance, graft-versus-host disease, immune suppression in cancer, multiple sclerosis, and inflammatory bowel disease.


Assuntos
Ceramidas , Inflamação , Esfingolipídeos , Ceramidas/imunologia , Ceramidas/metabolismo , Humanos , Inflamação/fisiopatologia , Sistemas do Segundo Mensageiro , Transdução de Sinais , Esfingolipídeos/imunologia
11.
Kardiologiia ; 59(8): 77-87, 2019 Aug 08.
Artigo em Russo | MEDLINE | ID: mdl-31397233

RESUMO

Lipid metabolism disorders are the most significant risk factor of development of cardiovascular diseases (CVD). In the process of diagnosing ischemic heart disease and other cardiovascular pathologies, levels of total cholesterol, low- and high- density lipoprotein cholesterol, triglycerides are determined. However, in recent years, close attention has been paid to the intersection of the metabolic pathways of the biosynthesis of cholesterol and sphingolipids. Sphingolipids - a group of lipids, which include a molecule of aliphatic alcohol sphingosine. This group includes sphingomyelins, cerebrosides, gangliosides and ceramides, sphingosines and sphingosine-1-phosphate (S-1-P). Ceramides and sphingosines have pro-apoptotic properties, and S-1-P protects cells from apoptosis. Particular attention as inducer CVD attracts ceramide. It has been established that aggregated lipoproteins isolated from atherosclerotic zones are enriched with ceramides. The level of ceramide and sphingosine increases with ischemia/reperfusion of the heart, in the infarction zone and in the blood, and also in hypertensive disease. S-1-P has a pronounced cardioprotective properties. Its content sharply decreases with ischemia and myocardial infarction. S-1-P performs a special function in the structure of high-density lipoproteins (HDL), being one of the main lipid components of these lipoproteins, which determines their multiple functions. Recently, work has been underway to create drugs that can correct the metabolism of S-1-P. The most successful drugs are those that use the S-1-P receptor as a target, since all of its actions are carried out through receptors. Increasing ceramide and sphingosine and reducing blood plasma level of S-1-P can be an important factor in the development of atherosclerosis. It is proposed to use the determination of the level of sphingolipids in blood plasma for early diagnosis of cardiac ischemia and in arterial hypertension. Chromatography-mass spectrometry has been suggested as the main method for testing these lipids.


Assuntos
Aterosclerose , Ceramidas , HDL-Colesterol , Humanos , Esfingolipídeos , Triglicerídeos
12.
Cancer Sci ; 110(10): 3267-3274, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444836

RESUMO

Although the proteasome inhibitor bortezomib (BTZ) shows excellent efficacy in multiple myeloma (MM), a fraction of patients has a suboptimal or no response to this agent. In addition, BTZ-induced peripheral neuropathy (BiPN), a frequent side-effect of this therapy, limits its use in some patients. This study aimed to explore serum lipid biomarker candidates to predict the response to BTZ and the severity of BiPN. Fifty-nine serum samples were collected from patients with MM prior to receiving BTZ plus low-dose dexamethasone therapy. Serum levels of phospholipids, sphingolipids, neutral lipids, and polyunsaturated fatty acids and their oxidation products were measured by a comprehensive lipidomic study. Overall, 385 lipid metabolites were identified in patients' sera; lower levels of several glycerophospholipids, sphingolipids, and cholesteryl esters were associated with a poor treatment response. Metabolites related to platelet-activating factor biosynthesis and cholesterol metabolism appeared particularly relevant. Furthermore, several lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids were significantly increased or decreased in patients with BiPN grades ranging from G0 to G3. Among these compounds, mediators reportedly inducing myelin breakdown and stimulating inflammatory responses were prominent. Although further study is necessary to validate these biomarker candidates, our results contribute to the development of predictive biomarkers for response to BTZ treatment, or ensuing severe BiPN, in patients with MM.


Assuntos
Bortezomib/administração & dosagem , Lipídeos/sangue , Metabolômica/métodos , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Bortezomib/efeitos adversos , Ésteres do Colesterol/sangue , Feminino , Glicerofosfolipídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/química , Índice de Gravidade de Doença , Esfingolipídeos/sangue , Resultado do Tratamento
13.
J Dairy Sci ; 102(9): 7619-7639, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31301829

RESUMO

The physiological control of lactation through coordinated adaptations is of fundamental importance for mammalian neonatal life. The putative actions of reduced insulin sensitivity and responsiveness and enhanced adipose tissue lipolysis spare glucose for the mammary synthesis of milk. However, severe insulin antagonism and body fat mobilization may jeopardize hepatic health and lactation in dairy cattle. Interestingly, lipolysis- and dietary-derived fatty acids may impair insulin sensitivity in cows. The mechanisms are undefined yet have major implications for the development of postpartum fatty liver disease. In nonruminants, the sphingolipid ceramide is a potent mediator of saturated fat-induced insulin resistance that defines in part the mechanisms of type 2 diabetes mellitus and nonalcoholic fatty liver disease. In ruminants including the lactating dairy cow, the functions of ceramide had remained virtually undescribed. Through a series of hypothesis-centered studies, ceramide has emerged as a potential antagonist of insulin-stimulated glucose utilization by adipose and skeletal muscle tissues in dairy cattle. Importantly, bovine data suggest that the ability of ceramide to inhibit insulin action likely depends on the lipolysis-dependent hepatic synthesis and secretion of ceramide during early lactation. Although these mechanisms appear to fade as lactation advances beyond peak milk production, early evidence suggests that palmitic acid feeding is a means to augment ceramide supply. Herein, we review a body of work that focuses on sphingolipid biology and the role of ceramide in the dairy cow within the framework of hepatic and fatty acid metabolism, insulin function, and lactation. The potential involvement of ceramide within the endocrine control of lactation is also considered.


Assuntos
Bovinos/fisiologia , Ceramidas/fisiologia , Esfingolipídeos/fisiologia , Animais , Indústria de Laticínios , Dieta/veterinária , Ácidos Graxos/metabolismo , Feminino , Insulina/fisiologia , Lactação/fisiologia , Fígado/metabolismo , Leite/metabolismo
14.
Nat Commun ; 10(1): 2752, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227693

RESUMO

Various studies have demonstrated that the two leaflets of cellular membranes interact, potentially through so-called interdigitation between the fatty acyl groups. While the molecular mechanism underlying interleaflet coupling remains to be fully understood, recent results suggest interactions between the very-long-chain sphingolipids in the outer leaflet, and phosphatidylserine PS18:0/18:1 in the inner leaflet, and an important role for cholesterol for these interactions. Here we review the evidence that cross-linking of sphingolipids may result in clustering of phosphatidylserine and transfer of signals to the cytosol. Although much remains to be uncovered, the molecular properties and abundance of PS 18:0/18:1 suggest a unique role for this lipid.


Assuntos
Membrana Celular/fisiologia , Bicamadas Lipídicas/metabolismo , Fosfatidilserinas/metabolismo , Esfingolipídeos/metabolismo , Animais , Linhagem Celular , Colesterol/metabolismo , Reagentes para Ligações Cruzadas/metabolismo , Citosol/fisiologia , Humanos
16.
Nat Plants ; 5(6): 604-615, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31182845

RESUMO

During phloem unloading, multiple cell-to-cell transport events move organic substances to the root meristem. Although the primary unloading event from the sieve elements to the phloem pole pericycle has been characterized to some extent, little is known about post-sieve element unloading. Here, we report a novel gene, PHLOEM UNLOADING MODULATOR (PLM), in the absence of which plasmodesmata-mediated symplastic transport through the phloem pole pericycle-endodermis interface is specifically enhanced. Increased unloading is attributable to a defect in the formation of the endoplasmic reticulum-plasma membrane tethers during plasmodesmal morphogenesis, resulting in the majority of pores lacking a visible cytoplasmic sleeve. PLM encodes a putative enzyme required for the biosynthesis of sphingolipids with very-long-chain fatty acid. Taken together, our results indicate that post-sieve element unloading involves sphingolipid metabolism, which affects plasmodesmal ultrastructure. They also raise the question of how and why plasmodesmata with no cytoplasmic sleeve facilitate molecular trafficking.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas de Membrana/metabolismo , Floema/metabolismo , Plasmodesmos/ultraestrutura , Esfingolipídeos/biossíntese , Arabidopsis/genética , Arabidopsis/ultraestrutura , Proteínas de Arabidopsis/genética , Genes de Plantas , Glucanos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Membrana/genética , Mutação , Raízes de Plantas/metabolismo , Plasmodesmos/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
17.
Crit Rev Oncol Hematol ; 138: 104-111, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31092365

RESUMO

BACKGROUND: Sphingolipids have been shown to play a key part in cancer cell growth and death and have increasingly become the subject of novel anti-cancer therapies. Acid ceramidase, a sphingolipid enzyme, has an important role in the regulation of apoptosis. In this review we aim to assess the current evidence supporting the role of sphingolipids in cancer and the potential role that acid ceramidase may play in cancer treatment. METHODS: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string "acid ceramidase", "sphingolipid", "cancer". Additional papers were detected by scanning the references of relevant papers. A summary of the evidence for each cancer subgroup was then formed. Given the nature of the data extracted, no meta-analysis was performed. RESULTS: Over expression of acid ceramidase has been demonstrated in a number of human cancers. In vitro data demonstrate that manipulation of acid ceramidase may present a useful therapeutic target. In the clinical setting, a number of drugs have been investigated with the ability to target acid ceramidase, with the most promising of those being small molecular inhibitors, such as LCL521. CONCLUSION: The role of the sphingolipid pathway in cancer is becoming very clearly established by promoting ceramide accumulation in response to cancer or cellular stress. Acid ceramidase is over expressed in a variety of cancers and has a role as a potential target for inhibition by novel specific inhibitors or off-target effects of traditional anti-cancer agents. Further work is required to develop acid ceramidase inhibitors safe for progression to clinical trials.


Assuntos
Ceramidase Ácida/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Esfingolipídeos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico
18.
Methods Mol Biol ; 1978: 137-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119661

RESUMO

HPLC-MS/MS has enabled the quantitative analysis of complex mixtures of lipid molecular species. Several separate analyses, using methods that have been optimized for individual lipid classes, provide good lipidomic profiles, but may not be desirable for laboratories constrained by available instrumentation and wanting a higher throughput. Here we describe two methods using binary gradient HiLiC HPLC and triple quadrupole MS that together provide a lipidomic profile for lipids of interest in type 2 diabetes research. Methods for analysis of molecular species of diacylglycerol, ceramide, dihydroceramide, sphingosine, glucosyl- and lactosylceramide, sphingomyelin, and acylcarnitine from skeletal muscle and primary culture cells are described.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Diglicerídeos/isolamento & purificação , Esfingolipídeos/isolamento & purificação , Espectrometria de Massas em Tandem/métodos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diglicerídeos/metabolismo , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Esfingolipídeos/metabolismo
19.
Medicina (Kaunas) ; 55(5)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067829

RESUMO

Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical activity, and periodic cardiac arrhythmia. Echocardiography revealed left ventricular hypertrophy with normal diastolic function. The patient had experienced acroparesthesia in her upper limbs and abdominal pain since childhood, and in the last decade had experienced mild proteinuria without renal failure. Her renal biopsy was typical for Fabry disease. The patient's brain magnetic resonance imaging (MRI) (T2 flair) showed white matter hyperintensities lesions. DNA sequencing of the proband, her mother and one of her sons showed a novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp). All three patients had decreased α-galactosidase A activity and specific FD manifestations. Conclusion: A novel GLA mutation, c.270C>G (p.Cys90Trp), was found in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac involvement. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.


Assuntos
Doença de Fabry/genética , alfa-Galactosidase/análise , Dispneia/etiologia , Eletrocardiografia/métodos , Doença de Fabry/epidemiologia , Feminino , Glicolipídeos/análise , Glicolipídeos/sangue , Humanos , Lituânia , Pessoa de Meia-Idade , Mutação/fisiologia , Esfingolipídeos/análise , Esfingolipídeos/sangue , alfa-Galactosidase/sangue
20.
Cell Host Microbe ; 25(5): 668-680.e7, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071294

RESUMO

Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently identified as the most differentially abundant metabolite in stool from inflammatory bowel disease (IBD) patients. Commensal bacteria from the Bacteroidetes phylum also produce sphingolipids, but the impact of these metabolites on host pathways is largely uncharacterized. To determine whether bacterial sphingolipids modulate intestinal health, we colonized germ-free mice with a sphingolipid-deficient Bacteroides thetaiotaomicron strain. A lack of Bacteroides-derived sphingolipids resulted in intestinal inflammation and altered host ceramide pools in mice. Using lipidomic analysis, we described a sphingolipid biosynthesis pathway and revealed a variety of Bacteroides-derived sphingolipids including ceramide phosphoinositol and deoxy-sphingolipids. Annotating Bacteroides sphingolipids in an IBD metabolomic dataset revealed lower abundances in IBD and negative correlations with inflammation and host sphingolipid production. These data highlight the role of bacterial sphingolipids in maintaining homeostasis and symbiosis in the gut.


Assuntos
Bacteroides thetaiotaomicron/crescimento & desenvolvimento , Bacteroides thetaiotaomicron/metabolismo , Interações entre Hospedeiro e Microrganismos , Intestinos/microbiologia , Intestinos/fisiologia , Esfingolipídeos/metabolismo , Simbiose/efeitos dos fármacos , Animais , Vida Livre de Germes , Homeostase/efeitos dos fármacos , Doenças Inflamatórias Intestinais/prevenção & controle , Intestinos/efeitos dos fármacos , Camundongos
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