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Article ; Online: Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice

Lara Ordóñez-Gutiérrez / Gemma Fábrias / Josefina Casas / Francisco Wandosell

International Journal of Molecular Sciences, Vol 22, Iss 10907, p

2021 Volume 10907

Abstract: Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer’s disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent ...

Abstract	Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer’s disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aβ production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).
Keywords	Alzheimer ; neurodegeneration ; amyloid ; ω-6/ω-3 ; PUFA ; ceramides ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	590
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methuosis Contributes to Jaspine-B-Induced Cell Death

Núria Bielsa / Mireia Casasampere / Jose Luis Abad / Carlos Enrich / Antonio Delgado / Gemma Fabriàs / Jose M. Lizcano / Josefina Casas

International Journal of Molecular Sciences, Vol 23, Iss 7257, p

2022 Volume 7257

Abstract: Methuosis is a type of programmed cell death in which the cytoplasm is occupied by fluid-filled vacuoles that originate from macropinosomes (cytoplasmic vacuolation). A few molecules have been reported to behave as methuosis inducers in cancer cell lines. ...

Abstract	Methuosis is a type of programmed cell death in which the cytoplasm is occupied by fluid-filled vacuoles that originate from macropinosomes (cytoplasmic vacuolation). A few molecules have been reported to behave as methuosis inducers in cancer cell lines. Jaspine B (JB) is a natural anhydrous sphingolipid (SL) derivative reported to induce cytoplasmic vacuolation and cytotoxicity in several cancer cell lines. Here, we have investigated the mechanism and signalling pathways involved in the cytotoxicity induced by the natural sphingolipid Jaspine B (JB) in lung adenocarcinoma A549 cells, which harbor the G12S K-Ras mutant. The effect of JB on inducing cytoplasmic vacuolation and modifying cell viability was determined in A549 cells, as well as in mouse embryonic fibroblasts (MEF) lacking either the autophagy-related gene ATG5 or BAX/BAK genes. Apoptosis was analyzed by flow cytometry after annexin V/propidium iodide staining, in the presence and absence of z-VAD. Autophagy was monitored by LC3-II/GFP-LC3-II analysis, and autophagic flux experiments using protease inhibitors. Phase contrast, confocal, and transmission electron microscopy were used to monitor cytoplasmic vacuolation and the uptake of Lucifer yellow to assess macropinocyosis. We present evidence that cytoplasmic vacuolation and methuosis are involved in Jaspine B cytotoxicity over A549 cells and that activation of 5′ AMP-activated protein kinase (AMPK) could be involved in Jaspine-B-induced vacuolation, independently of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 1 (PI3K/Akt/mTORC1) axis.
Keywords	autophagy ; methuosis ; apoptosis ; sphingolipids ; cytoplasmic vacuolization ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation

Sandra Torres / Estel Solsona-Vilarrasa / Susana Nuñez / Nuria Matías / Naroa Insausti-Urkia / Fernanda Castro / Mireia Casasempere / Gemma Fabriás / Josefina Casas / Carlos Enrich / José C. Fernández-Checa / Carmen Garcia-Ruiz

Redox Biology, Vol 45, Iss , Pp 102052- (2021)

2021

Abstract: Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of ... ...

Abstract	Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of mitochondrial cholesterol (mchol) content and impaired mitochondrial function and GSH depletion contribute to NPC disease. However, the underlying mechanism of mchol accumulation in NPC disease remains unknown. As STARD1 is crucial in intramitochondrial cholesterol trafficking and acid ceramidase (ACDase) has been shown to regulate STARD1, we explored the functional relationship between ACDase and STARD1 in NPC disease. Liver and brain of Npc1−/− mice presented a significant increase in mchol levels and STARD1 expression. U18666A, an amphiphilic sterol that inhibits lysosomal cholesterol efflux, increased mchol levels in hepatocytes from Stard1f/f mice but not Stard1ΔHep mice. We dissociate the induction of STARD1 expression from endoplasmic reticulum stress, and establish an inverse relationship between ACDase and STARD1 expression and LRH-1 levels. Hepatocytes from Npc1+/+ mice treated with U18666A exhibited increased mchol accumulation, STARD1 upregulation and decreased ACDase expression, effects that were reversed by cholesterol extraction with 2-hydroxypropyl-β-cyclodextrin. Moreover, transfection of fibroblasts from NPC patients with ACDase, decreased STARD1 expression and mchol accumulation, resulting in increased mitochondrial GSH levels, improved mitochondrial functional performance, decreased oxidative stress and protected NPC fibroblasts against oxidative stress-mediated cell death. Our results demonstrate a cholesterol-dependent inverse relationship between ACDase and STARD1 and provide a novel approach to target the accumulation of cholesterol in mitochondria in NPC disease.
Keywords	Cholesterol ; Acid ceramiase ; Mitochondrial function ; Oxidative stress ; NPC disease ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cholesterol in the Viral Membrane is a Molecular Switch Governing HIV‐1 Env Clustering

Jon Ander Nieto‐Garai / Aroa Arboleya / Sara Otaegi / Jakub Chojnacki / Josefina Casas / Gemma Fabriàs / F‐Xabier Contreras / Hans‐Georg Kräusslich / Maier Lorizate

Advanced Science, Vol 8, Iss 3, Pp n/a-n/a (2021)

2021

Abstract: Abstract HIV‐1 entry requires the redistribution of envelope glycoproteins (Env) into a cluster and the presence of cholesterol (chol) in the viral membrane. However, the molecular mechanisms underlying the specific role of chol in infectivity and the ... ...

Abstract	Abstract HIV‐1 entry requires the redistribution of envelope glycoproteins (Env) into a cluster and the presence of cholesterol (chol) in the viral membrane. However, the molecular mechanisms underlying the specific role of chol in infectivity and the driving force behind Env clustering remain unknown. Here, gp41 is demonstrated to directly interact with chol in the viral membrane via residues 751–854 in the cytoplasmic tail (CT751–854). Super‐resolution stimulated emission depletion (STED) nanoscopy analysis of Env distribution further demonstrates that both truncation of gp41 CT751–854 and depletion of chol leads to dispersion of Env clusters in the viral membrane and inhibition of virus entry. This work reveals a direct interaction of gp41 CT with chol and indicates that this interaction is an important orchestrator of Env clustering.
Keywords	cholesterol ; Env clustering ; gp41 cytoplasmic tails ; HIV‐1 ; protein–lipid interactions ; Science ; Q
Subject code	570
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Dihydroceramide desaturase inhibitors induce autophagy via dihydroceramide-dependent and independent mechanisms

Casasampere, Mireia / Gemma Fabrias / Josefina Casas / Yadira F. Ordóñez

Biochimica et biophysica acta. 2017 Feb., v. 1861, no. 2

2017

Abstract: Autophagy consists on the delivery of cytoplasmic material and organelles to lysosomes for degradation. Research on autophagy is a growing field because deciphering the basic mechanisms of autophagy is key to understanding its role in health and disease, ...

Abstract	Autophagy consists on the delivery of cytoplasmic material and organelles to lysosomes for degradation. Research on autophagy is a growing field because deciphering the basic mechanisms of autophagy is key to understanding its role in health and disease, and to paving the way to discovering novel therapeutic strategies. Studies with chemotherapeutic drugs and pharmacological tools support a role for dihydroceramides as mediators of autophagy. However, their effect on the autophagy outcome (cell survival or death) is more controversial.We have examined the capacity of structurally varied Des1 inhibitors to stimulate autophagy (LC3-II analysis), to increase dihydroceramides (mass spectrometry) and to reduce cell viability (SRB) in T98G and U87MG glioblastoma cells under different experimental conditions.The compounds activity on autophagy induction took place concomitantly with accumulation of dihydroceramides, which occurred by both stimulation of ceramide synthesis de novo and reduction of Des1 activity. However, autophagy was also induced by the test compounds after preincubation with myriocin and in cells with a reduced capacity to produce dihydroceramides (U87DND). Autophagy inhibition with 3-methyladenine in the de novo dihydroceramide synthesis competent U87MG cells increased cytotoxicity, while genetic inhibition of autophagy in U87DND cells, poorly efficient at synthesizing dihydroceramides, augmented resistance to the test compounds.Dihydroceramide desaturase 1 inhibitors activate autophagy via both dihydroceramide-dependent and independent pathways and the balance between the two pathways influences the final cell fate.The cells capacity to biosynthesize dihydroceramides must be taken into account in proautophagic Des1 inhibitors-including therapies.
Keywords	autophagy ; cell viability ; ceramides ; cytotoxicity ; death ; drug therapy ; drugs ; lysosomes ; mass spectrometry
Language	English
Dates of publication	2017-02
Size	p. 264-275.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	840755-1
ISSN	0304-4165
ISSN	0304-4165
DOI	10.1016/j.bbagen.2016.11.033
Database	NAL-Catalogue (AGRICOLA)

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Article: Stereoselective preparation of quaternary 2-vinyl sphingosines and ceramides and their effect on basal sphingolipid metabolism

Calderón, Raquel / Nerea Mercadal / José Luis Abad / Xavier Ariza / Antonio Delgado / Jordi Garcia / Aleix Rodríguez / Gemma Fabriàs

Chemistry and physics of lipids. 2017 June, v. 205

2017

Abstract: The dicyclohexylborane–mediated addition of allene 1 to (E)-2-tridecenal affords a quaternary protected 2-amino-2-vinyl-1,3-diol in good yield as a single diastereomer. This compound is readily transformed into the four stereoisomers of the quaternary (E) ...

Abstract	The dicyclohexylborane–mediated addition of allene 1 to (E)-2-tridecenal affords a quaternary protected 2-amino-2-vinyl-1,3-diol in good yield as a single diastereomer. This compound is readily transformed into the four stereoisomers of the quaternary (E)-2-vinyl analogs of sphingosine. The metabolic fate and the effect of these compounds on the basal sphingolipid metabolism in human A549 lung adenocarcinoma cells has been studied, together with the ceramide analog of the most relevant vinylsphingosine derivative.
Keywords	adenocarcinoma ; allene ; ceramides ; diastereomers ; humans ; metabolism ; sphingosine ; stereochemistry
Language	English
Dates of publication	2017-06
Size	p. 34-41.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2017.04.008
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 804: Show issues

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Article: Clearly Detectable, Kinetically Restricted Solid–Solid Phase Transition in cis-Ceramide Monolayers

Fanani, M. Laura / Alicia Alonso / Bruno Maggio / Félix M. Goñi / Gemma Fabrías / Jesús Sot / Jon V. Busto / José L. Abad / Jose M. G. Vilar / Leonor Saiz

Langmuir. 2018 Sept. 05, v. 34, no. 39

2018

Abstract: Sphingosine [(2S,3R,4E)-2-amino-4-octadecene-1,3-diol] is the most common sphingoid base in mammals. Ceramides are N-acyl sphingosines. Numerous small variations on this canonical structure are known, including the 1-deoxy, the 4,5-dihydro, and many ... ...

Abstract	Sphingosine [(2S,3R,4E)-2-amino-4-octadecene-1,3-diol] is the most common sphingoid base in mammals. Ceramides are N-acyl sphingosines. Numerous small variations on this canonical structure are known, including the 1-deoxy, the 4,5-dihydro, and many others. However, whenever there is a Δ4 double bond, it adopts the trans (or E) configuration. We synthesized a ceramide containing 4Z-sphingosine and palmitic acid (cis-pCer) and studied its behavior in the form of monolayers extended on an air–water interface. cis-pCer acted very differently from the trans isomer in that, upon lateral compression of the monolayer, a solid–solid transition was clearly observed at a mean molecular area ≤44 Å2·molecule–1, whose characteristics depended on the rate of compression. The solid–solid transition, as well as states of domain coexistence, could be imaged by atomic force microscopy and by Brewster-angle microscopy. Atomistic molecular dynamics simulations provided results compatible with the experimentally observed differences between the cis and trans isomers. The data can help in the exploration of other solid–solid transitions in lipids, both in vitro and in vivo, that have gone up to now undetected because of their less obvious change in surface properties along the transition, as compared to cis-pCer.
Keywords	atomic force microscopy ; ceramides ; chemical bonding ; cis-trans isomers ; liquid-air interface ; mammals ; molecular dynamics ; palmitic acid ; phase transition ; simulation models ; sphingosine
Language	English
Dates of publication	2018-0905
Size	p. 11749-11758.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2005937-1
ISSN	1520-5827 ; 0743-7463
ISSN (online)	1520-5827
ISSN	0743-7463
DOI	10.1021/acs.langmuir.8b02198
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Plasmalogen enrichment in exosomes secreted by a nematode parasite versus those derived from its mouse host

Fabio Simbari / Jana McCaskill / Gillian Coakley / Marissa Millar / Rick M. Maizels / Gemma Fabriás / Josefina Casas / Amy H. Buck

Journal of Extracellular Vesicles, Vol 5, Iss 0, Pp 1-

implications for exosome stability and biology

2016 Volume 16

Abstract: Extracellular vesicles (EVs) mediate communication between cells and organisms across all 3 kingdoms of life. Several reports have demonstrated that EVs can transfer molecules between phylogenetically diverse species and can be used by parasites to alter ...

Abstract	Extracellular vesicles (EVs) mediate communication between cells and organisms across all 3 kingdoms of life. Several reports have demonstrated that EVs can transfer molecules between phylogenetically diverse species and can be used by parasites to alter the properties of the host environment. Whilst the concept of vesicle secretion and uptake is broad reaching, the molecular composition of these complexes is expected to be diverse based on the physiology and environmental niche of different organisms. Exosomes are one class of EVs originally defined based on their endocytic origin, as these derive from multivesicular bodies that then fuse with the plasma membrane releasing them into the extracellular environment. The term exosome has also been used to describe any small EVs recovered by high-speed ultracentrifugation, irrespective of origin since this is not always well characterized. Here, we use comparative global lipidomic analysis to examine the composition of EVs, which we term exosomes, that are secreted by the gastrointestinal nematode, Heligmosomoides polygyrus, in relation to exosomes secreted by cells of its murine host. Ultra-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) analysis reveals a 9- to 62-fold enrichment of plasmalogens, as well as other classes of ether glycerophospholipids, along with a relative lack of cholesterol and sphingomyelin (SM) in the nematode exosomes compared with those secreted by murine cells. Biophysical analyses of the membrane dynamics of these exosomes demonstrate increased rigidity in those from the nematode, and parallel studies with synthetic vesicles support a role of plasmalogens in stabilizing the membrane structure. These results suggest that nematodes can maintain exosome membrane structure and integrity through increased plasmalogens, compensating for diminished levels of other lipids, including cholesterol and SM. This work also illuminates the prevalence of plasmalogens in some EVs, which has not been widely reported and could have implications for the biochemical or immunomodulatory properties of EVs. Further comparative analyses such as those described here will shed light on diversity in the molecular properties of EVs that enable them to function in cross-species communication.
Keywords	extracellular vesicles ; helminth ; host–pathogen ; ether lipids ; dynamic light scattering ; cholesterol ; cross-species communication ; Biology (General) ; QH301-705.5 ; Science ; Q ; Cytology ; QH573-671
Subject code	572
Language	English
Publishing date	2016-07-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sphingolipids as Mediators in the Crosstalk between Microbiota and Intestinal Cells: Implications for Inflammatory Bowel Disease.

Bryan, Phillips-Farfán / Karla, Carvajal / Edgar Alejandro, Medina-Torres / Sara Elva, Espinosa-Padilla / Gemma, Fabrias / Luz, Camacho

Mediators of inflammation

2016 Volume 2016, Page(s) 9890141

Abstract: Inflammatory bowel disease (IBD) describes different illnesses characterized by chronic inflammation of the gastrointestinal tract. Although the pathogenic mechanisms leading to IBD are poorly understood, immune system disturbances likely underlie its ... ...

Abstract	Inflammatory bowel disease (IBD) describes different illnesses characterized by chronic inflammation of the gastrointestinal tract. Although the pathogenic mechanisms leading to IBD are poorly understood, immune system disturbances likely underlie its development. Sphingolipids (SLs) have been identified as important players and promising therapeutic targets to control inflammation in IBD. Interestingly, it seems that microorganisms of the normal gut microbiota and probiotics are involved in sphingolipid function. However, there is a great need to investigate the role of SLs as intermediates in the crosstalk between intestinal immunity and microorganisms. This review focuses on recent investigations that describe some mechanisms involved in the regulation of cytokine profiles by SLs. We also describe the importance of gut microbiota in providing signaling molecules that favor the communication between resident bacteria and intestinal cells. This, in turn, modulates the immune response in the bowel and likely in other peripheral organs. The potential of SLs and gut microbiota as targets or therapeutic agents for IBD is also discussed.
Language	English
Publishing date	2016
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	1137605-3
ISSN	1466-1861 ; 0962-9351
ISSN (online)	1466-1861
ISSN	0962-9351
DOI	10.1155/2016/9890141
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 3575: Show issues

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Article: Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis

Caretti, Anna / Alessandra Bragonzi / Camilla Riva / Claudia Musicanti / Gemma FabriÃ s / Ida De Fino / Josefina Casas / Marcella Facchini / Paola Signorelli / Paolo Gasco / Riccardo Ghidoni

BBA - General Subjects. 2014 Jan., v. 1840

2014

Abstract: Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. ...

Abstract	Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate infection. Chronic infections result in lung damage and patient morbidity. Notably, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects.The therapeutic potential of myriocin, an inhibitor of the sphingolipid de novo synthesis rate limiting enzyme (Serine Palmitoyl Transferase, SPT),was investigated in CF cells and mice models.We treated CF human respiratory epithelial cells with myriocin, This treatment resulted in reduced basal, as well as TNFÎ±-stimulated, inflammation. In turn, TNFÎ± induced an increase in SPT in these cells, linking de novo synthesis of ceramide to inflammation. Furthermore, myriocin-loaded nanocarrier, injected intratrachea prior to P. aeruginosa challenge, enabled a significant reduction of lung infection and reduced inflammation.The presented data suggest that de novo ceramide synthesis is constitutively enhanced in CF mucosa and that it can be envisaged as pharmacological target for modulating inflammation and restoring effective innate immunity against acute infection.Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.
Keywords	adaptive immunity ; animal models ; anti-inflammatory activity ; ceramides ; cystic fibrosis ; epithelial cells ; humans ; immune response ; infectious diseases ; inflammation ; innate immunity ; metabolism ; mice ; morbidity ; mucosa ; nanocarriers ; patients ; serine ; tumor necrosis factor-alpha
Language	English
Dates of publication	2014-01
Size	p. 586-594.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	840755-1
ISSN	0304-4165
ISSN	0304-4165
DOI	10.1016/j.bbagen.2013.10.018
Database	NAL-Catalogue (AGRICOLA)

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