Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with "healthy" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.

• Klíčová slova
• ceramide, fatty acid, glucosylsphingosine, lipid model, lysolipid, permeability, skin barrier, sphingosine-phosphorylcholine,
• MeSH
• ceramidy * metabolismus   nedostatek   MeSH
• fosforylcholin analogy a deriváty   MeSH
• kůže * metabolismus   účinky léků   MeSH
• kyseliny mastné neesterifikované metabolismus   MeSH
• lidé MeSH
• lysofosfolipidy * metabolismus   MeSH
• permeabilita MeSH
• sfingolipidy * metabolismus   MeSH
• sfingosin analogy a deriváty   metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ceramidy * MeSH
• fosforylcholin MeSH
• kyseliny mastné neesterifikované MeSH
• lysofosfolipidy * MeSH
• sfingolipidy * MeSH
• sfingosin MeSH
• sphingosine phosphorylcholine MeSH Prohlížeč

Lysophosphatidylcholine (LPC) is a bioactive lipid present at high concentrations in inflamed and injured tissues where it contributes to the initiation and maintenance of pain. One of its important molecular effectors is the transient receptor potential canonical 5 (TRPC5), but the explicit mechanism of the activation is unknown. Using electrophysiology, mutagenesis and molecular dynamics simulations, we show that LPC-induced activation of TRPC5 is modulated by xanthine ligands and depolarizing voltage, and involves conserved residues within the lateral fenestration of the pore domain. Replacement of W577 with alanine (W577A) rendered the channel insensitive to strong depolarizing voltage, but LPC still activated this mutant at highly depolarizing potentials. Substitution of G606 located directly opposite position 577 with tryptophan rescued the sensitivity of W577A to depolarization. Molecular simulations showed that depolarization widens the lower gate of the channel and this conformational change is prevented by the W577A mutation or removal of resident lipids. We propose a gating scheme in which depolarizing voltage and lipid-pore helix interactions act together to promote TRPC5 channel opening.

• Klíčová slova
• Lysophosphatidylcholine, Pain, TRP channels, TRPC channels, Voltage-dependent gating,
• MeSH
• gating iontového kanálu účinky léků   MeSH
• HEK293 buňky MeSH
• kationtové kanály TRPC * metabolismus   genetika   chemie   MeSH
• lidé MeSH
• lysofosfatidylcholiny * metabolismus   farmakologie   MeSH
• lysofosfolipidy metabolismus   farmakologie   MeSH
• membránové potenciály účinky léků   MeSH
• mutace MeSH
• simulace molekulární dynamiky * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kationtové kanály TRPC * MeSH
• lysofosfatidylcholiny * MeSH
• lysofosfolipidy MeSH
• TRPC5 protein, human MeSH Prohlížeč

Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.

• Klíčová slova
• ENPP2, LPA, autotaxin, cancer, lysophosphatidic acid, signal transduction,
• MeSH
• fosfodiesterasy * genetika   chemie   metabolismus   MeSH
• lidé MeSH
• lysofosfolipidy metabolismus   MeSH
• nádory * MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fosfodiesterasy * MeSH
• lysofosfolipidy MeSH
• lysophosphatidic acid MeSH Prohlížeč

Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

• Klíčová slova
• BMP, Bis(monoacylglycerol)phosphate, Breast cancer, Lipidomics, Lysosomal membrane permeabilization, Polyunsaturated fatty acids, Reactive oxygen species,
• MeSH
• fosfáty metabolismus   MeSH
• kyseliny dokosahexaenové * MeSH
• lidé MeSH
• lysofosfolipidy metabolismus   MeSH
• lyzozomy metabolismus   MeSH
• myši MeSH
• nádory prsu * patologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• bis(monoacylglyceryl)phosphate MeSH Prohlížeč
• fosfáty MeSH
• kyseliny dokosahexaenové * MeSH
• lysofosfolipidy MeSH
• reaktivní formy kyslíku MeSH

Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve the survival time prognosis of patients, who are often diagnosed too late at an incurable stage. Several studies report the dysregulation of lipid metabolism in tumor cells, suggesting that changes in the blood lipidome may accompany tumor growth. Here we show that the comprehensive mass spectrometric determination of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls, as visualized by multivariate data analysis. Three phases of biomarker discovery research (discovery, qualification, and verification) are applied for 830 samples in total, which shows the dysregulation of some very long chain sphingomyelins, ceramides, and (lyso)phosphatidylcholines. The sensitivity and specificity to diagnose pancreatic cancer are over 90%, which outperforms CA 19-9, especially at an early stage, and is comparable to established diagnostic imaging methods. Furthermore, selected lipid species indicate a potential as prognostic biomarkers.

• MeSH
• antigen CA-19-9 krev   MeSH
• ceramidy krev   MeSH
• lidé MeSH
• lipidomika metody   MeSH
• lysofosfatidylcholiny krev   MeSH
• metabolismus lipidů genetika   MeSH
• multivariační analýza MeSH
• nádorové biomarkery krev   genetika   MeSH
• nádory slinivky břišní krev   diagnóza   mortalita   patologie   MeSH
• proporcionální rizikové modely MeSH
• senzitivita a specificita MeSH
• sfingomyeliny krev   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CA-19-9 MeSH
• ceramidy MeSH
• lysofosfatidylcholiny MeSH
• nádorové biomarkery MeSH
• sfingomyeliny MeSH

Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs' ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.

• Klíčová slova
• FAK, HCC, cancer stem cells, macroH2A1, stemness,
• MeSH
• buňky Hep G2 MeSH
• fokální adhezní kinasa 1 antagonisté a inhibitory   nedostatek   genetika   MeSH
• fosfatidylcholiny metabolismus   MeSH
• genový knockdown MeSH
• hepatocelulární karcinom genetika   metabolismus   patologie   MeSH
• histony antagonisté a inhibitory   nedostatek   genetika   MeSH
• lidé MeSH
• lipidomika MeSH
• lysofosfatidylcholiny metabolismus   MeSH
• metabolismus lipidů * genetika   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky metabolismus   patologie   MeSH
• nádory jater genetika   metabolismus   patologie   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenování transkriptomu MeSH
• sfingomyeliny metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fokální adhezní kinasa 1 MeSH
• fosfatidylcholiny MeSH
• histony MeSH
• lysofosfatidylcholiny MeSH
• MACROH2A1 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• PTK2 protein, human MeSH Prohlížeč
• sfingomyeliny MeSH

Ultrahigh-performance supercritical fluid chromatography - mass spectrometry (UHPSFC/MS), ultrahigh-performance liquid chromatography - mass spectrometry (UHPLC/MS), and matrix-assisted laser desorption/ionization (MALDI) - MS techniques were used for the lipidomic characterization of exosomes isolated from human plasma. The high-throughput methods UHPSFC/MS and UHPLC/MS using a silica-based column containing sub-2 μm particles enabled the lipid class separation and the quantitation based on exogenous class internal standards in <7 minute run time. MALDI provided the complementary information on anionic lipid classes, such as sulfatides. The nontargeted analysis of 12 healthy volunteers was performed, and absolute molar concentration of 244 lipids in exosomes and 191 lipids in plasma belonging to 10 lipid classes were quantified. The statistical evaluation of data included principal component analysis, orthogonal partial least square discriminant analysis, S-plots, p-values, T-values, fold changes, false discovery rate, box plots, and correlation plots, which resulted in the information on lipid changes in exosomes in comparison to plasma. The major changes were detected in the composition of triacylglycerols, diacylglycerols, phosphatidylcholines, and lysophosphatidylcholines, whereby sphingomyelins, phosphatidylinositols, and sulfatides showed rather similar profiles in both biological matrices.

• Klíčová slova
• Exosomes, Lipidomics, Lipids, Liquid chromatography, Mass spectrometry, Plasma, Supercritical fluid chromatography,
• MeSH
• diglyceridy krev   izolace a purifikace   metabolismus   MeSH
• dospělí MeSH
• exozómy chemie   metabolismus   MeSH
• fosfatidylcholiny krev   izolace a purifikace   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipidomika metody   MeSH
• lysofosfatidylcholiny krev   izolace a purifikace   metabolismus   MeSH
• metabolismus lipidů * MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• superkritická fluidní chromatografie metody   MeSH
• triglyceridy krev   izolace a purifikace   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• diglyceridy MeSH
• fosfatidylcholiny MeSH
• lysofosfatidylcholiny MeSH
• triglyceridy MeSH

The systemic anaphylactic reaction is a life-threatening allergic response initiated by activated mast cells. Sphingolipids are an essential player in the development and attenuation of this response. De novo synthesis of sphingolipids in mammalian cells is inhibited by the family of three ORMDL proteins (ORMDL1, 2, and 3). However, the cell and tissue-specific functions of ORMDL proteins in mast cell signaling are poorly understood. This study aimed to determine cross-talk of ORMDL2 and ORMDL3 proteins in IgE-mediated responses. To this end, we prepared mice with whole-body knockout (KO) of Ormdl2 and/or Ormdl3 genes and studied their role in mast cell-dependent activation events in vitro and in vivo. We found that the absence of ORMDL3 in bone marrow-derived mast cells (BMMCs) increased the levels of cellular sphingolipids. Such an increase was further raised by simultaneous ORMDL2 deficiency, which alone had no effect on sphingolipid levels. Cells with double ORMDL2 and ORMDL3 KO exhibited increased intracellular levels of sphingosine-1-phosphate (S1P). Furthermore, we found that concurrent ORMDL2 and ORMDL3 deficiency increased IκB-α phosphorylation, degranulation, and production of IL-4, IL-6, and TNF-α cytokines in antigen-activated mast cells. Interestingly, the chemotaxis towards antigen was increased in all mutant cell types analyzed. Experiments in vivo showed that passive cutaneous anaphylaxis (PCA), which is initiated by mast cell activation, was increased only in ORMDL2,3 double KO mice, supporting our in vitro observations with mast cells. On the other hand, ORMDL3 KO and ORMDL2,3 double KO mice showed faster recovery from passive systemic anaphylaxis, which could be mediated by increased levels of blood S1P presented in such mice. Our findings demonstrate that Ormdl2 deficiency potentiates the ORMDL3-dependent changes in mast cell signaling.

• Klíčová slova
• FcϵRI, ORMDL family, mast cells, passive cutaneous anaphylactic reaction, passive systemic anaphylaxis, sphingolipids, sphingosine-1-phosphate,
• MeSH
• anafylaxe etiologie   metabolismus   MeSH
• biologické markery MeSH
• chemotaxe imunologie   MeSH
• cytokiny metabolismus   MeSH
• exprese genu MeSH
• lysofosfolipidy krev   metabolismus   MeSH
• mastocyty imunologie   metabolismus   MeSH
• membránové proteiny chemie   nedostatek   genetika   metabolismus   MeSH
• multigenová rodina MeSH
• myši knockoutované MeSH
• myši MeSH
• náchylnost k nemoci MeSH
• pasivní kožní anafylaxe genetika   imunologie   MeSH
• sekvence aminokyselin MeSH
• sfingolipidy krev   metabolismus   MeSH
• sfingosin analogy a deriváty   krev   metabolismus   MeSH
• signální transdukce * MeSH
• vápník metabolismus   MeSH
• vápníková signalizace MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• cytokiny MeSH
• lysofosfolipidy MeSH
• membránové proteiny MeSH
• ORMDL3 protein, mouse MeSH Prohlížeč
• sfingolipidy MeSH
• sfingosin MeSH
• sphingosine 1-phosphate MeSH Prohlížeč
• vápník MeSH

The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.

• Klíčová slova
• colon cancer (CRC) sphingolipidomics, colon cancer cells, colorectal cancer, glycosphingolipid, lactosylceramide, sphingolipid, sphingosine-1-phosphate,
• MeSH
• alkalická ceramidasa genetika   metabolismus   MeSH
• ceramidy metabolismus   MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem genetika   metabolismus   MeSH
• kyselá ceramidasa genetika   metabolismus   MeSH
• laktosylceramidy metabolismus   MeSH
• lidé MeSH
• lysofosfolipidy metabolismus   MeSH
• metabolismus lipidů genetika   MeSH
• modely nemocí na zvířatech MeSH
• nádorové buňky kultivované MeSH
• nádory tračníku enzymologie   genetika   patologie   MeSH
• neutrální ceramidasa genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• sfingolipidy metabolismus   MeSH
• sfingosin-N-acyltransferasa genetika   metabolismus   MeSH
• sfingosin analogy a deriváty   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ACER2 protein, human MeSH Prohlížeč
• alkalická ceramidasa MeSH
• ASAH1 protein, human MeSH Prohlížeč
• ASAH2 protein, human MeSH Prohlížeč
• ceramide 1-phosphate MeSH Prohlížeč
• ceramidy MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem MeSH
• kyselá ceramidasa MeSH
• laktosylceramidy MeSH
• lysofosfolipidy MeSH
• neutrální ceramidasa MeSH
• protoonkogenní proteiny c-akt MeSH
• sfingolipidy MeSH
• sfingosin-N-acyltransferasa MeSH
• sfingosin MeSH
• sphingosine 1-phosphate MeSH Prohlížeč
• sphingosine kinase MeSH Prohlížeč

Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

• MeSH
• difúzní velkobuněčný B-lymfom genetika   metabolismus   patologie   MeSH
• endoteliální buňky metabolismus   MeSH
• imunohistochemie MeSH
• lidé MeSH
• lysofosfolipidy genetika   metabolismus   MeSH
• messenger RNA genetika   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• patologická angiogeneze genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• sfingosin analogy a deriváty   genetika   metabolismus   MeSH
• signální transdukce * MeSH
• transkriptom * MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• lysofosfolipidy MeSH
• messenger RNA MeSH
• sfingosin MeSH
• sphingosine 1-phosphate MeSH Prohlížeč