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Sphingolipid Signaling and Human Disease 2022
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Sphingolipid Signaling and Human Disease 2022

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 14422

Special Issue Editors

Dr. Nawajes Mandal

E-Mail Website
Guest Editor
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
Interests: sphingolipids; ceramides; S1P; sphingolipid metabolism; sphingolipid signaling; retina; cornea; meibomian glands; eye diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Kazuyuki Kitatani

E-Mail Website
Guest Editor
Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata 573‐0101, Japan
Interests: sphingolipids; ceramides; sphingotherapy; cancer therapy; cancer biology; cancer metastasis; cellular signaling; cell death; necroptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sphingolipids are a family of membrane lipids and many of their members are biologically active (acting as signaling molecules) and play crucial roles in the regulation of cellular events such as cell survival, proliferation, differentiation, growth, and inflammatory and apoptotic responses. The scope of the sphingolipid system’s impact on mammalian biology has been factually demonstrated to be impressive, and its roles in many human diseases associated with inflammation, neurodegeneration, neovascularization, tumorigenesis, and diabetes have just begun to be understood. Current advancements in sphingolipid research are contributing greatly toward our understanding of the pathobiology of complex human diseases and the development of novel therapies. Among several bioactive sphingolipids, the key metabolites, ceramide and sphingosine-1-phosphate (S1P), are found to be pivotal in the pathophysiology of various human diseases, such as Alzheimer’s disease, insulin resistance and diabetes, cancer, and cardiovascular diseases, and imbalance in the homeostasis of these bioactive lipids is found to be linked to the key components of the pathogenesis. Sphingolipid metabolism is complex, with several isoenzymes having been discovered for a single metabolic step; for example, there are six different ceramide synthases and five different ceramidases for anabolism and catabolism of ceramide, respectively. These enzymes are diverse in their structure, substrate specificity, and subcellular localization. Sphingolipid signaling is also complex, as exemplified in signaling mediated by S1P, which binds to five different cell surface receptors and activates a myriad of cellular pathways. This Special Issue aims to improve our knowledge with regard to the intricate mechanisms of sphingolipid metabolism and signaling in human diseases and update our understanding based on recent advancements in the field. We invite original research articles, reviews, shorter perspective articles, or expert opinions on any topics of controversy in the area of sphingolipid signaling and human diseases.

Relevant topics include but are not limited to:

  • Sphingolipid signaling
  • Ceramide metabolism and signaling
  • S1P signaling and receptors
  • Sphingolipids in human diseases (inflammatory, metabolic, neovascular, neurodegenerative, neoplastic, age-related diseases)
  • Targeting the sphingolipid pathway for therapeutic development

Dr. Nawajes Mandal
Dr. Kazuyuki Kitatani
Guest Editors

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 submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue 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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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
  • ceramides
  • S1P
  • sphingolipid metabolism
  • sphingolipid signaling
  • sphingolipid association with human diseases

Related Special Issue

Published Papers (7 papers)

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Research

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17 pages, 4833 KiB  
Article
Sphingolipid-Based Synergistic Interactions to Enhance Chemosensitivity in Lung Cancer Cells
by Susana Mesén-Porras, Andrea Rojas-Céspedes, José Arturo Molina-Mora, José Vega-Baudrit, Francisco Siles, Steve Quiros and Rodrigo Mora-Rodríguez
Cells 2023, 12(22), 2588; https://doi.org/10.3390/cells12222588 - 08 Nov 2023
Viewed by 3898
Abstract
Tumor heterogeneity leads to drug resistance in cancer treatment with the crucial role of sphingolipids in cell fate and stress signaling. We analyzed sphingolipid metabolism and autophagic flux to study chemotherapeutic interactions on the A549 lung cancer model. Loaded cells with fluorescent sphingomyelin [...] Read more.
Tumor heterogeneity leads to drug resistance in cancer treatment with the crucial role of sphingolipids in cell fate and stress signaling. We analyzed sphingolipid metabolism and autophagic flux to study chemotherapeutic interactions on the A549 lung cancer model. Loaded cells with fluorescent sphingomyelin analog (BODIPY) and mCherry-EGFP-LC3B were used to track autophagic flux and assess cytotoxicity when cells are exposed to chemotherapy (epirubicin, cisplatin, and paclitaxel) together with sphingolipid pathway inhibitors and autophagy modulators. Our cell model approach employed fluorescent sphingolipid biosensors and a Gaussian Mixture Model of cell heterogeneity profiles to map the influence of chemotherapy on the sphingolipid pathway and infer potential synergistic interactions. Results showed significant synergy, especially when combining epirubicin with autophagy inducers (rapamycin and Torin), reducing cell viability. Cisplatin also synergized with a ceramidase inhibitor. However, paclitaxel often led to antagonistic effects. Our mapping model suggests that combining chemotherapies with autophagy inducers increases vesicle formation, possibly linked to ceramide accumulation, triggering cell death. However, the in silico model proposed ceramide accumulation in autophagosomes, and kinetic analysis provided evidence of sphingolipid colocalization in autophagosomes. Further research is needed to identify specific sphingolipids accumulating in autophagosomes. These findings offer insights into potential strategies for overcoming chemotherapy resistance by targeting the sphingolipid pathway. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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23 pages, 8050 KiB  
Article
Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role as a Crucial Immunopathological Factor and a Severity Prognostic Biomarker in COVID-19
by Diana Mota Toro, Pedro V. da Silva-Neto, Jonatan C. S. de Carvalho, Carlos A. Fuzo, Malena M. Pérez, Vinícius E. Pimentel, Thais F. C. Fraga-Silva, Camilla N. S. Oliveira, Glaucia R. Caruso, Adriana F. L. Vilela, Pedro Nobre-Azevedo, Thiago V. Defelippo-Felippe, Jamille G. M. Argolo, Augusto M. Degiovani, Fátima M. Ostini, Marley R. Feitosa, Rogerio S. Parra, Fernando C. Vilar, Gilberto G. Gaspar, José J. R. da Rocha, Omar Feres, Gabriel P. Costa, Sandra R. C. Maruyama, Elisa M. S. Russo, Ana Paula M. Fernandes, Isabel K. F. M. Santos, Adriana Malheiro, Ruxana T. Sadikot, Vânia L. D. Bonato, Cristina R. B. Cardoso, Marcelo Dias-Baruffi, Átila A. Trapé, Lúcia H. Faccioli, Carlos A. Sorgi and ImmunoCovid Consortium Groupadd Show full author list remove Hide full author list
Cells 2023, 12(15), 1938; https://doi.org/10.3390/cells12151938 - 26 Jul 2023
Cited by 1 | Viewed by 1754
Abstract
SARS-CoV-2 infection triggers distinct patterns of disease development characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a “lipid storm”, influencing the inflammatory process and tissue damage. Sphingolipids (SLs) play [...] Read more.
SARS-CoV-2 infection triggers distinct patterns of disease development characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a “lipid storm”, influencing the inflammatory process and tissue damage. Sphingolipids (SLs) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n = 55), COVID-19 patients (n = 204), and convalescent individuals (n = 77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, a predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, and neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) species (d18:1/24:1) and (d18:1/24:0)were associated with increased risk. Moreover, we observed the enhanced expression of key enzymes involved in the SL pathway in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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16 pages, 1692 KiB  
Article
Development of Comorbid Depression after Social Fear Conditioning in Mice and Its Effects on Brain Sphingolipid Metabolism
by Iulia Zoicas, Christiane Mühle, Fabian Schumacher, Burkhard Kleuser and Johannes Kornhuber
Cells 2023, 12(10), 1355; https://doi.org/10.3390/cells12101355 - 10 May 2023
Cited by 2 | Viewed by 1294
Abstract
Currently, there are no animal models for studying both specific social fear and social fear with comorbidities. Here, we investigated whether social fear conditioning (SFC), an animal model with face, predictive and construct validity for social anxiety disorder (SAD), leads to the development [...] Read more.
Currently, there are no animal models for studying both specific social fear and social fear with comorbidities. Here, we investigated whether social fear conditioning (SFC), an animal model with face, predictive and construct validity for social anxiety disorder (SAD), leads to the development of comorbidities at a later stage over the course of the disease and how this affects the brain sphingolipid metabolism. SFC altered both the emotional behavior and the brain sphingolipid metabolism in a time-point-dependent manner. While social fear was not accompanied by changes in non-social anxiety-like and depressive-like behavior for at least two to three weeks, a comorbid depressive-like behavior developed five weeks after SFC. These different pathologies were accompanied by different alterations in the brain sphingolipid metabolism. Specific social fear was accompanied by increased activity of ceramidases in the ventral hippocampus and ventral mesencephalon and by small changes in sphingolipid levels in the dorsal hippocampus. Social fear with comorbid depression, however, altered the activity of sphingomyelinases and ceramidases as well as the sphingolipid levels and sphingolipid ratios in most of the investigated brain regions. This suggests that changes in the brain sphingolipid metabolism might be related to the short- and long-term pathophysiology of SAD. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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15 pages, 1988 KiB  
Article
Ceramide Nanoliposomes as Potential Therapeutic Reagents for Asthma
by Harumi Sakae, Yuri Ogiso, Masaya Matsuda, Hayato Shimora, Tye Deering, Todd E. Fox, Mark Kester, Takeshi Nabe and Kazuyuki Kitatani
Cells 2023, 12(4), 591; https://doi.org/10.3390/cells12040591 - 11 Feb 2023
Cited by 2 | Viewed by 1982
Abstract
Ceramides are an emerging class of anti-inflammatory lipids, and nanoscale ceramide-delivery systems are potential therapeutic strategies for inflammatory diseases. This study investigated the therapeutic effects of ceramide nanoliposomes (CNL) on type 2 inflammation-based asthma, induced by repeated ovalbumin (OVA) challenges. Asthmatic mice intratracheally [...] Read more.
Ceramides are an emerging class of anti-inflammatory lipids, and nanoscale ceramide-delivery systems are potential therapeutic strategies for inflammatory diseases. This study investigated the therapeutic effects of ceramide nanoliposomes (CNL) on type 2 inflammation-based asthma, induced by repeated ovalbumin (OVA) challenges. Asthmatic mice intratracheally treated with ceramide-free liposomes (Ghost) displayed typical airway remodeling including mucosal accumulation and subepithelial fibrosis, whereas, in CNL-treated mice, the degree of airway remodeling was significantly decreased. Compared to the Ghost group, CNL treatment unexpectedly failed to significantly influence formation of type 2 cytokines, including IL-5 and IL-13, known to facilitate pathogenic production of airway mucus predominantly comprising MUC5AC mucin. Interestingly, CNL treatment suppressed OVA-evoked hyperplasia of MUC5AC-generating goblet cells in the airways. This suggests that CNL suppressed goblet cell hyperplasia and airway mucosal accumulation independently of type 2 cytokine formation. Mechanistically, CNL treatment suppressed cell growth and EGF-induced activation of Akt, but not ERK1/2, in a human lung epithelial cell culture system recapitulating airway goblet cell hyperplasia. Taken together, CNL is suggested to have therapeutic effects on airway remodeling in allergic asthma by targeting goblet cell hyperplasia. These findings raise the potential of ceramide-based therapies for airway diseases, such as asthma. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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21 pages, 4319 KiB  
Article
A Comprehensive Profiling of Cellular Sphingolipids in Mammalian Endothelial and Microglial Cells Cultured in Normal and High-Glucose Conditions
by Koushik Mondal, Richard C. Grambergs, Rajashekhar Gangaraju and Nawajes Mandal
Cells 2022, 11(19), 3082; https://doi.org/10.3390/cells11193082 - 30 Sep 2022
Cited by 1 | Viewed by 1558
Abstract
Sphingolipids (SPLs) play a diverse role in maintaining cellular homeostasis. Dysregulated SPL metabolism is associated with pathological changes in stressed and diseased cells. This study investigates differences in SPL metabolism between cultured human primary retinal endothelial (HREC) and murine microglial cells (BV2) in [...] Read more.
Sphingolipids (SPLs) play a diverse role in maintaining cellular homeostasis. Dysregulated SPL metabolism is associated with pathological changes in stressed and diseased cells. This study investigates differences in SPL metabolism between cultured human primary retinal endothelial (HREC) and murine microglial cells (BV2) in normal conditions (normal glucose, NG, 5 mM) and under high-glucose (HG, 25 mM)-induced stress by sphingolipidomics, immunohistochemistry, biochemical, and molecular assays. Measurable differences were observed in SPL profiles between HREC and BV2 cells. High-glucose treatment caused a >2.5-fold increase in the levels of Lactosyl-ceramide (LacCer) in HREC, but in BV2 cells, it induced Hexosyl-Ceramides (HexCer) by threefold and a significant increase in Sphingosine-1-phosphate (S1P) compared to NG. Altered SPL profiles coincided with changes in transcript levels of inflammatory and vascular permeability mediators in HREC and inflammatory mediators in BV2 cells. Differences in SPL profiles and differential responses to HG stress between endothelial and microglial cells suggest that SPL metabolism and signaling differ in mammalian cell types and, therefore, their pathological association with those cell types. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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18 pages, 2562 KiB  
Article
Ablation of Sphingosine Kinase 1 Protects Cornea from Neovascularization in a Mouse Corneal Injury Model
by Joseph L. Wilkerson, Sandip K. Basu, Megan A. Stiles, Amanda Prislovsky, Richard C. Grambergs, Sarah E. Nicholas, Dimitrios Karamichos, Jeremy C. Allegood, Richard L. Proia and Nawajes Mandal
Cells 2022, 11(18), 2914; https://doi.org/10.3390/cells11182914 - 17 Sep 2022
Cited by 2 | Viewed by 1802
Abstract
The purpose of this study was to investigate the role of sphingosine kinase 1 (SphK1), which generates sphingosine-1-phosphate (S1P), in corneal neovascularization (NV). Wild-type (WT) and Sphk1 knockout (Sphk1−/−) mice received corneal alkali-burn treatment to induce corneal [...] Read more.
The purpose of this study was to investigate the role of sphingosine kinase 1 (SphK1), which generates sphingosine-1-phosphate (S1P), in corneal neovascularization (NV). Wild-type (WT) and Sphk1 knockout (Sphk1−/−) mice received corneal alkali-burn treatment to induce corneal NV by placing a 2 mm round piece of Whatman No. 1 filter paper soaked in 1N NaOH on the center of the cornea for 20 s. Corneal sphingolipid species were extracted and identified using liquid chromatography/mass spectrometry (LC/MS). The total number of tip cells and those positive for ethynyl deoxy uridine (EdU) were quantified. Immunocytochemistry was done to examine whether pericytes were present on newly forming blood vessels. Cytokine signaling and angiogenic markers were compared between the two groups using multiplex assays. Data were analyzed using appropriate statistical tests. Here, we show that ablation of SphK1 can significantly reduce NV invasion in the cornea following injury. Corneal sphingolipid analysis showed that total levels of ceramides, monohexosyl ceramides (HexCer), and sphingomyelin were significantly elevated in Sphk−/− corneas compared to WT corneas, with a comparable level of sphingosine among the two genotypes. The numbers of total and proliferating endothelial tip cells were also lower in the Sphk1−/− corneas following injury. This study underscores the role of S1P in post-injury corneal NV and raises further questions about the roles played by ceramide, HexCer, and sphingomyelin in regulating corneal NV. Further studies are needed to unravel the role played by bioactive sphingolipids in maintenance of corneal transparency and clear vision. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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Review

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14 pages, 1234 KiB  
Review
The Role of Sphingolipids and Sphingosine-1-phosphate—Sphingosine-1-phosphate-receptor Signaling in Psoriasis
by Kana Masuda-Kuroki, Shahrzad Alimohammadi and Anna Di Nardo
Cells 2023, 12(19), 2352; https://doi.org/10.3390/cells12192352 - 26 Sep 2023
Cited by 1 | Viewed by 1389
Abstract
Psoriasis is a long-lasting skin condition characterized by redness and thick silver scales on the skin’s surface. It involves various skin cells, including keratinocytes, dendritic cells, T lymphocytes, and neutrophils. The treatments for psoriasis range from topical to systemic therapies, but they only [...] Read more.
Psoriasis is a long-lasting skin condition characterized by redness and thick silver scales on the skin’s surface. It involves various skin cells, including keratinocytes, dendritic cells, T lymphocytes, and neutrophils. The treatments for psoriasis range from topical to systemic therapies, but they only alleviate the symptoms and do not provide a fundamental cure. Moreover, systemic treatments have the disadvantage of suppressing the entire body’s immune system. Therefore, a new treatment strategy with minimal impact on the immune system is required. Recent studies have shown that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), play a significant role in psoriasis. Specific S1P–S1P-receptor (S1PR) signaling pathways have been identified as crucial to psoriasis inflammation. Based on these findings, S1PR modulators have been investigated and have been found to improve psoriasis inflammation. This review will discuss the metabolic pathways of sphingolipids, the individual functions of these metabolites, and their potential as a new therapeutic approach to psoriasis. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease 2022)
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