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Topical Collection "Sphingolipid Signaling in Health and Disease"

Editor

Prof. Andrea Huwiler
Website
Collection Editor
Institute of Pharmacology, University of Bern, Inselspital, CH-3010 Bern, Switzerland
Interests: sphingolipid signaling, prostaglandins, chronic inflammatory kidney diseases

Topical Collection Information

Dear colleagues,

Sphingolipids have long been known as important structural components of biological membranes. This view has drastically changed after groundbreaking discoveries in the early 1990s, which showed that certain sphingolipid subspecies are bioactive and are able to induce signal transduction and regulate fundamental cellular responses such as cell proliferation and survival, differentiation, apoptosis, and migration. Evidence is now increasing that the dysregulation of sphingolipid signaling contributes to the pathogenesis of multiple diseases, including inflammation, pain, cancer, diabetes, cardiovascular dysfunction, organ fibrosis, and various neurodegenerative diseases. Nevertheless, the exact molecular mechanisms used by sphingolipids to mediate the cellular effects are still not completely understood. Also, the regulation of those enzymes that catalyze the generation and interconversion of sphingolipids, although being cloned and known for decades, are not well described.

This Topical Collection is dedicated to shedding light on the molecular mechanisms used by bioactive sphingolipids, including sphingosine, ceramides, glycosphingolipids, and phosphorylated sphingoids, and to better characterize their involvement in physiological, pathophysiological, and pathological conditions. Furthermore, advances in the development of new drugs and strategies to manipulate sphingolipid-regulating enzymes and receptors for therapeutic applications are welcome.

Prof. Andrea Huwiler
Collection Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sphingolipids
  • ceramide
  • sphingosine-1-phosphate
  • glycosphingolipids
  • disease
  • physiology

Published Papers (6 papers)

2020

Jump to: 2019

Open AccessReview
The Role of Lipid Metabolism in COVID-19 Virus Infection and as a Drug Target
Int. J. Mol. Sci. 2020, 21(10), 3544; https://doi.org/10.3390/ijms21103544 - 17 May 2020
Abstract
The current Coronavirus disease 2019 or COVID-19 pandemic has infected over two million people and resulted in the death of over one hundred thousand people at the time of writing this review. The disease is caused by severe acute respiratory syndrome coronavirus 2 [...] Read more.
The current Coronavirus disease 2019 or COVID-19 pandemic has infected over two million people and resulted in the death of over one hundred thousand people at the time of writing this review. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though multiple vaccines and treatments are under development so far, the disease is only slowing down under extreme social distancing measures that are difficult to maintain. SARS-COV-2 is an enveloped virus that is surrounded by a lipid bilayer. Lipids are fundamental cell components that play various biological roles ranging from being a structural building block to a signaling molecule as well as a central energy store. The role lipids play in viral infection involves the fusion of the viral membrane to the host cell, viral replication, and viral endocytosis and exocytosis. Since lipids play a crucial function in the viral life cycle, we asked whether drugs targeting lipid metabolism, such as statins, can be utilized against SARS-CoV-2 and other viruses. In this review, we discuss the role of lipid metabolism in viral infection as well as the possibility of targeting lipid metabolism to interfere with the viral life cycle. Full article
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Open AccessArticle
Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro
Int. J. Mol. Sci. 2020, 21(7), 2409; https://doi.org/10.3390/ijms21072409 - 31 Mar 2020
Abstract
Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, [...] Read more.
Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC. Full article
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Open AccessArticle
Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt
Int. J. Mol. Sci. 2020, 21(4), 1396; https://doi.org/10.3390/ijms21041396 - 19 Feb 2020
Abstract
Ceramide kinase (CerK) is a lipid kinase that converts the proapoptotic ceramide to ceramide 1-phosphate, which has been proposed to have pro-malignant properties and regulate cell responses such as proliferation, migration, and inflammation. We used the parental human breast cancer cell line MDA-MB-231 [...] Read more.
Ceramide kinase (CerK) is a lipid kinase that converts the proapoptotic ceramide to ceramide 1-phosphate, which has been proposed to have pro-malignant properties and regulate cell responses such as proliferation, migration, and inflammation. We used the parental human breast cancer cell line MDA-MB-231 and two single cell progenies derived from lung and bone metastasis upon injection of the parental cells into immuno-deficient mice. The lung and the bone metastatic cell lines showed a marked upregulation of CerK mRNA and activity when compared to the parental cell line. The metastatic cells also had increased migratory and invasive activity, which was dose-dependently reduced by the selective CerK inhibitor NVP-231. A similar reduction of migration was seen when CerK was stably downregulated with small hairpin RNA (shRNA). Conversely, overexpression of CerK in parental MDA-MB-231 cells enhanced migration, and this effect was also observed in the non-metastatic cell line MCF7 upon CerK overexpression. On the molecular level, CerK overexpression increased the activation of protein kinase Akt. The increased migration of CerK overexpressing cells was mitigated by the CerK inhibitor NVP-231, by inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway and the Rho kinase, but not by inhibition of the classical extracellular signal-regulated kinase (ERK) pathway. Altogether, our data demonstrate for the first time that CerK promotes migration and invasion of metastatic breast cancer cells and that targeting of CerK has potential to counteract metastasis in breast cancer. Full article
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Open AccessArticle
Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge
Int. J. Mol. Sci. 2020, 21(4), 1240; https://doi.org/10.3390/ijms21041240 - 13 Feb 2020
Abstract
Sphingosine 1-phosphate (S1P) is a key bioactive lipid that regulates a myriad of physiological and pathophysiological processes, including endothelial barrier function, vascular tone, vascular inflammation, and angiogenesis. Various S1P receptor subtypes have been suggested to be involved in the regulation of these processes, [...] Read more.
Sphingosine 1-phosphate (S1P) is a key bioactive lipid that regulates a myriad of physiological and pathophysiological processes, including endothelial barrier function, vascular tone, vascular inflammation, and angiogenesis. Various S1P receptor subtypes have been suggested to be involved in the regulation of these processes, whereas the contribution of intracellular S1P (iS1P) through intracellular targets is little explored. In this study, we used the human cerebral microvascular endothelial cell line HCMEC/D3 to stably downregulate the S1P lyase (SPL-kd) and evaluate the consequences on endothelial barrier function and on the molecular factors that regulate barrier tightness under normal and inflammatory conditions. The results show that in SPL-kd cells, transendothelial electrical resistance, as a measure of barrier integrity, was regulated in a dual manner. SPL-kd cells had a delayed barrier build up, a shorter interval of a stable barrier, and, thereafter, a continuous breakdown. Contrariwise, a protection was seen from the rapid proinflammatory cytokine-mediated barrier breakdown. On the molecular level, SPL-kd caused an increased basal protein expression of the adherens junction molecules PECAM-1, VE-cadherin, and β-catenin, increased activity of the signaling kinases protein kinase C, AMP-dependent kinase, and p38-MAPK, but reduced protein expression of the transcription factor c-Jun. However, the only factors that were significantly reduced in TNFα/SPL-kd compared to TNFα/control cells, which could explain the observed protection, were VCAM-1, IL-6, MCP-1, and c-Jun. Furthermore, lipid profiling revealed that dihydro-S1P and S1P were strongly enhanced in TNFα-treated SPL-kd cells. In summary, our data suggest that SPL inhibition is a valid approach to dampenan inflammatory response and augmente barrier integrity during an inflammatory challenge. Full article
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2019

Jump to: 2020

Open AccessArticle
Feeding Stimulates Sphingosine-1-Phosphate Mobilization in Mouse Hypothalamus
Int. J. Mol. Sci. 2019, 20(16), 4008; https://doi.org/10.3390/ijms20164008 - 17 Aug 2019
Abstract
Previous studies have shown that the sphingolipid-derived mediator sphingosine-1-phosphate (S1P) reduces food intake by activating G protein-coupled S1P receptor-1 (S1PR1) in the hypothalamus. Here, we examined whether feeding regulates hypothalamic mobilization of S1P and other sphingolipid-derived messengers. We prepared lipid extracts from the [...] Read more.
Previous studies have shown that the sphingolipid-derived mediator sphingosine-1-phosphate (S1P) reduces food intake by activating G protein-coupled S1P receptor-1 (S1PR1) in the hypothalamus. Here, we examined whether feeding regulates hypothalamic mobilization of S1P and other sphingolipid-derived messengers. We prepared lipid extracts from the hypothalamus of C57Bl6/J male mice subjected to one of four conditions: free feeding, 12 h fasting, and 1 h or 6 h refeeding. Liquid chromatography/tandem mass spectrometry was used to quantify various sphingolipid species, including sphinganine (SA), sphingosine (SO), and their bioactive derivatives SA-1-phosphate (SA1P) and S1P. In parallel experiments, transcription of S1PR1 (encoded in mice by the S1pr1 gene) and of key genes of sphingolipid metabolism (Sptlc2, Lass1, Sphk1, Sphk2) was measured by RT-PCR. Feeding increased levels of S1P (in pmol-mg−1 of wet tissue) and SA1P. This response was accompanied by parallel changes in SA and dihydroceramide (d18:0/18:0), and was partially (SA1P) or completely (S1P) reversed by fasting. No such effects were observed with other sphingolipid species targeted by our analysis. Feeding also increased transcription of Sptlc2, Lass1, Sphk2, and S1pr1. Feeding stimulates mobilization of endogenous S1PR1 agonists S1P and SA1P in mouse hypothalamus, via a mechanism that involves transcriptional up-regulation of de novo sphingolipid biosynthesis. The results support a role for sphingolipid-mediated signaling in the central control of energy balance. Full article
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Open AccessArticle
A Role for Neutral Sphingomyelinase in Wound Healing Induced by Keratinocyte Proliferation upon 1α, 25-Dihydroxyvitamin D3 Treatment
Int. J. Mol. Sci. 2019, 20(15), 3634; https://doi.org/10.3390/ijms20153634 - 25 Jul 2019
Cited by 1
Abstract
The skin has many functions, such as providing a barrier against injury and pathogens, protecting from ultraviolet light, and regulating body temperature. Mechanical causes and many different pathologies can lead to skin damage. Therefore, it is important for the skin to be always [...] Read more.
The skin has many functions, such as providing a barrier against injury and pathogens, protecting from ultraviolet light, and regulating body temperature. Mechanical causes and many different pathologies can lead to skin damage. Therefore, it is important for the skin to be always adaptable and renewable and for cells to undergo proliferation. Here, we demonstrate that 1α, 25-dihydroxyvitamin D3 (VD3) stimulates keratinocyte proliferation, leading to wound closure in a simulation model of injury. Functionally, our results show that VD3 acts by stimulating cyclin D1, a cyclin that promotes the G1/S transition of the cell cycle. The study on the mechanism underlying cyclin D1 expression upon VD3 stimulation clearly demonstrates a key role of neutral sphingomyelinase. The enzyme, whose gene and protein expression is stimulated by VD3, is itself able to induce effects on cyclin D1 and wound healing similar to those obtained with VD3. These results could be very useful in the future to better understand wound mechanisms and improve therapeutic interventions. Full article
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