New Insights into the Role of Sphingolipid Metabolism in Melanoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Carrie L
PROVIDER: S-EPMC7565650 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Human pathologies such as Alzheimer's disease, type 2 diabetes-induced insulin resistance, cancer, and cardiovascular diseases have altered lipid homeostasis. Among these imbalanced lipids, the bioactive sphingolipids ceramide and sphingosine-1 phosphate (S1P) are pivotal in the pathophysiology of these diseases. Several enzymes within the sphingolipid pathway contribute to the homeostasis of ceramide and S1P. Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known-acid ceramidase, neutral ceramidase, and alkaline ceramidase 1, 2, and 3-which are encoded by five different genes (ASAH1, ASAH2, ACER1, ACER2, and ACER3, respectively). Notably, the neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) shows considerable differences between humans and animals in terms of tissue expression levels. Besides, the subcellular localization of ASAH2 remains controversial. In this review, we sum up the results obtained for identifying gene divergence, structure, subcellular localization, and manipulating factors and address the role of ASAH2 along with other ceramidases in human diseases.
| S-EPMC6952831 | biostudies-literature
Project description:Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. However, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. The discovery of BRAF mutations in melanoma created the first opportunity to develop oncogene-directed therapy in this disease and led to the development of compounds that inhibit aberrant BRAF activity. A decade later, vemurafenib, an orally available and well-tolerated selective BRAF inhibitor, ushered in a new era of molecular treatments for advanced disease. Additional targets have been identified, and novel agents that impact on various signaling pathways or modulate the immune system hold the promise of a whole new therapeutic landscape for patients with metastatic melanoma. One of the major thrusts in melanoma therapy is now focused on understanding and targeting the network of signal transduction pathways and on attacking elements that underlie the tumor's propensity for growth and chemoresistance. In this article, we review the novel targeted anticancer approaches that are under consideration in melanoma treatment.
| S-EPMC3759013 | biostudies-literature
Project description:Sphingolipids are an important class of lipid molecules that play fundamental roles in our cells and body. Beyond a structural role, it is now clearly established that sphingolipids serve as bioactive signaling molecules to regulate diverse processes including inflammatory signaling, cell death, proliferation, and pain sensing. Sphingolipid metabolites have been implicated in the onset and progression of various diseases including cancer, lung disease, diabetes, and lysosomal storage disorders. Here we review sphingolipid metabolism to introduce basic concepts as well as emerging complexities in sphingolipid function gained from modern technological advances and detailed cell and animal studies. Furthermore, we discuss the family of neutral sphingomyelinases (N-SMases), which generate ceramide through the hydrolysis of sphingomyelin and are key enzymes in sphingolipid metabolism. Four mammalian N-SMase enzymes have now been identified. Most prominent is nSMase2 with established roles in bone mineralization, exosome formation, and cellular stress responses. Function for the other N-SMases has been more enigmatic and is an area of active investigation. The known properties and potential role(s) of each enzyme are discussed to help guide future studies.
| S-EPMC4043343 | biostudies-literature
Project description:Diabetes adversely affects multiple organs, including the kidney, eye and nerve, leading to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy, respectively. In both type 1 and type 2 diabetes, tissue damage is organ specific and is secondary to a combination of multiple metabolic insults. Hyperglycaemia, dyslipidaemia and hypertension combine with the duration and type of diabetes to define the distinct pathophysiology underlying diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. Only recently have the commonalities and differences in the metabolic basis of these tissue-specific complications, particularly those involving local and systemic lipids, been systematically examined. This review focuses on recent progress made using preclinical models and human-based approaches towards understanding how bioenergetics and metabolomic profiles contribute to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. This new understanding of the biology of complication-prone tissues highlights the need for organ-specific interventions in the treatment of diabetic complications.
| S-EPMC6679814 | biostudies-literature
Project description:Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer's and Parkinson's disease, and lysosomal storage disorders.
| S-EPMC8198874 | biostudies-literature
Project description:Melanoma is one of the leading cancers worldwide, distinguished for its malignancy and low survival rates. Although the poor outcome could improve with an early diagnosis and a good monitoring of the disease, current melanoma biomarkers display several limitations which make them useless. Interestingly, long-noncoding RNAs are secreted into the bloodstream inside exosomes by a wide range of malignant cells, and several of them have been validated as promising circulating molecular signatures of other tumors, but not melanoma. In this review we propose to explore the booming field of long-noncoding RNAs in order to find potential candidates to be tested as novel melanoma biomarkers, with the ultimate goal of improving melanoma detection, diagnosis and prognosis.
| S-EPMC6094599 | biostudies-literature
Project description:We analyzed the transcriptional profile by RNA-sequencing of exosomal content isolated from blood plasma of three astronauts who flew on various ISS missions between 1998-2001. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with possible functions and clinical implications.
2022-01-18 | GSE193490 | GEO
Project description:Phagocytosis is an important physiological process, which, in higher organisms, is a means of fighting infections and clearing cellular debris. During phagocytosis, detrimental foreign particles (e.g. pathogens and apoptotic cells) are engulfed by phagocytes (e.g. macrophages), enclosed in membrane-bound vesicles called phagosomes, and transported to the lysosome for eventual detoxification. During this well-choreographed process, the nascent phagosome (also called early phagosome, EP) undergoes a series of spatiotemporally regulated changes in its protein and lipid composition and matures into a late phagosome (LP), which subsequently fuses with the lysosomal membrane to form the phagolysosome. While several elegant proteomic studies have identified the role of unique proteins during phagosomal maturation, the corresponding lipidomic studies are sparse. Recently, we reported a comparative lipidomic analysis between EPs and LPs and showed that ceramides are enriched on the LPs. Further, we found that this ceramide accumulation on LPs was orchestrated by ceramide synthase 2, inhibition of which hampers phagosomal maturation. Following up on this study, here, using biochemical assays, we first show that the increased ceramidase activity on EPs also significantly contributes to the accumulation of ceramides on LPs. Next, leveraging lipidomics, we show that de novo ceramide synthesis does not significantly contribute to the ceramide accumulation on LPs, while concomitant to increased ceramides, glucosylceramides are substantially elevated on LPs. We validate this interesting finding using biochemical assays and show that LPs indeed have heightened glucosylceramide synthase activity. Taken together, our studies provide interesting insights and possible new roles of sphingolipid metabolism during phagosomal maturation.
| S-EPMC7612119 | biostudies-literature
Project description:Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
2024-06-04 | GSE180249 | GEO
Project description:Metabolism is involved in both pharmacology and toxicology of most xenobiotics including drugs. Yet, visualization tools facilitating metabolism exploration are still underused, despite the availibility of pertinent bioinformatics solutions. Since molecular networking appears as a suitable tool to explore structurally related molecules, we aimed to investigate its interest in in vitro metabolism exploration. Quetiapine, a widely prescribed antipsychotic drug, undergoes well-described extensive metabolism, and is therefore an ideal candidate for such a proof of concept. Quetiapine was incubated in metabolically competent human liver cell models (HepaRG) for different times (0 h, 3 h, 8 h, 24 h) with or without cytochrom P450 (CYP) inhibitor (ketoconazole as CYP3A4/5 inhibitor and quinidine as CYP2D6 inhibitor), in order to study its metabolism kinetic and pathways. HepaRG culture supernatants were analyzed on an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (LC-HRMS/MS). Molecular networking approach on LC-HRMS/MS data allowed to quickly visualize the quetiapine metabolism kinetics and determine the major metabolic pathways (CYP3A4/5 and/or CYP2D6) involved in metabolite formation. In addition, two unknown putative metabolites have been detected. In vitro metabolite findings were confirmed in blood sample from a patient treated with quetiapine. This is the first report using LC-HRMS/MS untargeted screening and molecular networking to explore in vitro drug metabolism. Our data provide new evidences of the interest of molecular networking in drug metabolism exploration and allow our in vitro model consistency assessment.
| S-EPMC7669884 | biostudies-literature