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Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?
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Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 5788

Special Issue Editor

Dr. Paola Giussani

E-Mail Website
Guest Editor
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA Segrate, Via Fratelli Cervi, 93, 20090 Segrate, Italy
Interests: sphingolipids; sphingosine-1-phosphate; ceramide; signaling; cancer; multiple sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sphingolipids are ubiquitous components of cell membranes, as well as bioactive molecules involved in the control of cell fate. Sphingolipids are involved in the regulation of a huge number of physiological and pathophysiological processes; sphingolipid metabolism and signaling are crucial for the maintenance of physiological conditions. However, the deep dysregulation of sphingolipid metabolism, leading to an altered sphingolipid pattern, is associated with different pathological conditions. The control of sphingolipid levels can be achieved through the regulation of specific enzymes of their metabolism, as well as of the specific receptors or transporters involved in their transport within or outside the cells. Even though there have been important advances in our understanding of sphingolipids and their signaling, the exact molecular mechanisms mediated by sphingolipids to modulate cellular effects are still not completely understood. New knowledge on the metabolism and signaling of sphingolipids will help to find therapeutic solutions for a variety of human diseases.

For this Special Issue, “Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?”, we welcome your contributions in the form of original research and review articles on all aspects of sphingolipids and their role in physiological and pathophysiological processes.

Dr. Paola Giussani
Guest 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 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. 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
  • sphingosine-1-phosphate
  • ceramide
  • gangliosides
  • sphingosine-1-phosphate receptors
  • sphingolipid-mediated signaling
  • diseases

Published Papers (5 papers)

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Research

13 pages, 6047 KiB  
Article
Immunolocalization of Sphingolipid Catabolism Enzymes along the Nephron: Novel Early Urinary Biomarkers of Renal Damage
by Martha Franco, Agustina Cano-Martínez, María del Pilar Ramos-Godínez, Rebeca López-Marure, Luis Donis-Maturano, José Santamaría Sosa and Rocio Bautista-Pérez
Int. J. Mol. Sci. 2023, 24(23), 16633; https://doi.org/10.3390/ijms242316633 - 23 Nov 2023
Cited by 1 | Viewed by 872
Abstract
The objective of this study was to investigate whether the activity of enzymes involved in sphingolipid catabolism could be biomarkers to predict early renal damage in streptozotocin (STZ)-induced diabetic rats and Angiotensin II (Ang II)-induced hypertension rats. Diabetic and hypertensive rats had no [...] Read more.
The objective of this study was to investigate whether the activity of enzymes involved in sphingolipid catabolism could be biomarkers to predict early renal damage in streptozotocin (STZ)-induced diabetic rats and Angiotensin II (Ang II)-induced hypertension rats. Diabetic and hypertensive rats had no changes in plasma creatinine concentration. However, transmission electron microscopy (TEM) analysis showed slight ultrastructural changes in the glomeruli and tubular epithelial cells from diabetic and hypertensive rats. Our results show that the acid sphingomyelinase (aSMase) and neutral sphingomyelinase (nSMase) activity increased in the urine of diabetic rats and decreased in hypertensive rats. Only neutral ceramidase (nCDase) activity increased in the urine of diabetic rats. Furthermore, the immunofluorescence demonstrated positive staining for the nSMase, nCDase, and sphingosine kinase (SphK1) in glomerular mesangial cells, proximal tubule, ascending thin limb of the loop of Henle, thick ascending limb of Henle’s loop, and principal cells of the collecting duct in the kidney. In conclusion, our results suggest that aSMase and nCDase activity in urine could be a novel predictor of early slight ultrastructural changes in the nephron, aSMase and nCDase as glomerular injury biomarkers, and nSMase as a tubular injury biomarker in diabetic and hypertensive rats. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?)
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18 pages, 9631 KiB  
Article
Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications
by Gregory C. Wilson, Simone Keitsch, Matthias Soddemann, Barbara Wilker, Michael J. Edwards and Erich Gulbins
Int. J. Mol. Sci. 2023, 24(19), 14626; https://doi.org/10.3390/ijms241914626 - 27 Sep 2023
Cited by 1 | Viewed by 798
Abstract
Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be [...] Read more.
Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be defined. Here, we investigated whether tyrosine nitrosylation, which is caused by reaction of the C-atom 3 of the tyrosine phenol ring with peroxynitrate (ONOO−), plays a role in experimental MDD, because tyrosine nitrosylation may affect many cell functions altered in MDD. To this end, we induced stress through glucocorticoid application or chronic environmental unpredictable stress and determined tyrosine nitrosylation in the hippocampus through immuno-staining and ELISA. The role of catalases and peroxidases for tyrosine nitrosylation was measured using enzyme assays. We show that glucocorticoid- and chronic unpredictable environmental stress induced tyrosine nitrosylation in the hippocampus. Long-term treatment of stressed mice with the classical antidepressants amitriptyline or fluoxetine prevented tyrosine nitrosylation. Tyrosine nitrosylation was also prevented through i.v. application of anti-ceramide antibodies or recombinant ceramidase to neutralize or degrade, respectively, blood plasma ceramide that has been recently shown to induce experimental MDD. Finally, the application of phosphatidic acid, previously shown to be reduced in the hippocampus upon stress, also reverted stress-induced tyrosine nitrosylation. The inhibition of tyrosine nitrosylation by interfering with the formation of NO radicals at least partly restored normal behavior in stressed mice. These data suggest that tyrosine nitrosylation might contribute to the pathogenesis of MDD and targeting this process might contribute to the treatment of MDD. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?)
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18 pages, 12162 KiB  
Article
Reduced Sphingosine in Cystic Fibrosis Increases Susceptibility to Mycobacterium abscessus Infections
by Fabian Schnitker, Yongjie Liu, Simone Keitsch, Matthias Soddemann, Hedda Luise Verhasselt, Jan Kehrmann, Heike Grassmé, Markus Kamler, Erich Gulbins and Yuqing Wu
Int. J. Mol. Sci. 2023, 24(18), 14004; https://doi.org/10.3390/ijms241814004 - 12 Sep 2023
Viewed by 849
Abstract
Cystic fibrosis (CF) is an autosomal recessive disorder caused by the deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) and often leads to pulmonary infections caused by various pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and nontuberculous mycobacteria, particularly Mycobacterium abscessus [...] Read more.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by the deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) and often leads to pulmonary infections caused by various pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and nontuberculous mycobacteria, particularly Mycobacterium abscessus. Unfortunately, M. abscessus infections are increasing in prevalence and are associated with the rapid deterioration of CF patients. The treatment options for M. abscessus infections are limited, requiring the urgent need to comprehend infectious pathogenesis and develop new therapeutic interventions targeting affected CF patients. Here, we show that the deficiency of CFTR reduces sphingosine levels in bronchial and alveolar epithelial cells and macrophages from CF mice and humans. Decreased sphingosine contributes to the susceptibility of CF tissues to M. abscessus infection, resulting in a higher incidence of infections in CF mice. Notably, treatment of M. abscessus with sphingosine demonstrated potent bactericidal activity against the pathogen. Most importantly, restoration of sphingosine levels in CF cells, whether human or mouse, and in the lungs of CF mice, provided protection against M. abscessus infections. Our findings demonstrate that pulmonary sphingosine levels are important in controlling M. abscessus infection. These results offer a promising therapeutic avenue for CF patients with pulmonary M. abscessus infections. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?)
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13 pages, 1155 KiB  
Article
The Interplay between Bioactive Sphingolipids in the Psoriatic Skin and the Severity of the Disease
by Mateusz Matwiejuk, Hanna Mysliwiec, Bartłomiej Lukaszuk, Marta Lewoc, Hend Malla, Piotr Mysliwiec, Jacek Dadan, Adrian Chabowski and Iwona Flisiak
Int. J. Mol. Sci. 2023, 24(14), 11336; https://doi.org/10.3390/ijms241411336 - 12 Jul 2023
Cited by 3 | Viewed by 1004
Abstract
Psoriasis is a complex chronic immunologically mediated disease that may involve skin, nails, and joints. It is characterized by hyperproliferation, deregulated differentiation, and impaired apoptosis of keratinocytes. Sphingolipids, namely ceramide, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate, are signal molecules that may regulate cell growth, [...] Read more.
Psoriasis is a complex chronic immunologically mediated disease that may involve skin, nails, and joints. It is characterized by hyperproliferation, deregulated differentiation, and impaired apoptosis of keratinocytes. Sphingolipids, namely ceramide, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate, are signal molecules that may regulate cell growth, immune reactions, and apoptosis. Fifteen patients with psoriasis and seventeen healthy persons were enrolled in the study. Skin samples were taken from psoriatic lesions and non-lesional areas. Tissue concentration of ceramides, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate was measured by liquid chromatography. We assessed that all levels of ceramides, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate were higher in lesioned psoriatic skin than in non-affected skin. The profile of bioactive lipids in the lesional skin of patients with psoriasis differed significantly from non-involved psoriatic skin and skin in healthy subjects. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?)
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23 pages, 5932 KiB  
Article
The Presence of Periodontitis Exacerbates Non-Alcoholic Fatty Liver Disease via Sphingolipid Metabolism-Associated Insulin Resistance and Hepatic Inflammation in Mice with Metabolic Syndrome
by Zhongyang Lu, Yanchun Li, Nityananda Chowdhury, Hong Yu, Wing-Kin Syn, Maria Lopes-Virella, Özlem Yilmaz and Yan Huang
Int. J. Mol. Sci. 2023, 24(9), 8322; https://doi.org/10.3390/ijms24098322 - 05 May 2023
Cited by 3 | Viewed by 1699
Abstract
Clinical studies have shown that periodontitis is associated with non-alcoholic fatty liver disease (NAFLD). However, it remains unclear if periodontitis contributes to the progression of NAFLD. In this study, we generated a mouse model with high-fat diet (HFD)-induced metabolic syndrome (MetS) and NAFLD [...] Read more.
Clinical studies have shown that periodontitis is associated with non-alcoholic fatty liver disease (NAFLD). However, it remains unclear if periodontitis contributes to the progression of NAFLD. In this study, we generated a mouse model with high-fat diet (HFD)-induced metabolic syndrome (MetS) and NAFLD and oral P. gingivalis inoculation-induced periodontitis. Results showed that the presence of periodontitis increased insulin resistance and hepatic inflammation and exacerbated the progression of NAFLD. To determine the role of sphingolipid metabolism in the association between NAFLD and periodontitis, we also treated mice with imipramine, an inhibitor of acid sphingomyelinase (ASMase), and demonstrated that imipramine treatment significantly alleviated insulin resistance and hepatic inflammation, and improved NAFLD. Studies performed in vitro showed that lipopolysaccharide (LPS) and palmitic acid (PA), a major saturated fatty acid associated with MetS and NAFLD, synergistically increased the production of ceramide, a bioactive sphingolipid involved in NAFLD progression in macrophages but imipramine effectively reversed the ceramide production stimulated by LPS and PA. Taken together, this study showed for the first time that the presence of periodontitis contributed to the progression of NAFLD, likely due to alterations in sphingolipid metabolism that led to exacerbated insulin resistance and hepatic inflammation. This study also showed that targeting ASMase with imipramine improves NAFLD by reducing insulin resistance and hepatic inflammation. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutic Opportunities of Sphingolipids: Where Are We?)
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