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Special Issue "Sphingolipids: Metabolic Functions and Disorders"

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 (27 September 2019).

Special Issue Editors

Prof. Dr. Burkhard Kleuser
Website
Guest Editor
Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Interests: sphingolipidomics; sphingosine 1-phosphate; S1P-receptors; insulin resistance; dendritic cells; epigenetics; nanotoxicology
Special Issues and Collections in MDPI journals
Assoc. Prof. Elisabetta Meacci
Website
Guest Editor
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Molecular and Applied Biology Research Unit, University of Florence, Florence, Italy

Special Issue Information

Dear Colleagues,

A strong case is emerging that bioactive sphingolipids, although only a minor constituent of the global lipid milieu in cells and tissues, play a central role in regulating metabolic functions. Specific bioactive sphingolipids have been identified as pathogenic mediators in metabolic disorders such as non-alcoholic fatty liver disease (NAFLD), diabetes, or cardiovascular dysfunction. Circulating mediators that are released from adipose tissue (e.g., adipokines, inflammatory cytokines) specifically modulate enzymes that are involved in sphingolipid synthesis and degradation. The accumulation of specific sphingolipid species in tissues such as the liver, muscle, heart, pancreas, and vasculature may contribute to the onset and development of metabolic diseases including insulin resistance, pancreatic β-cell failure, liver dysfunction, neuro-muscolar degeneration, cardiomyopathy, and vascular and microenviromental dysfunctions. Striking progress has been made in the last few years in elucidating the complex crosstalk between sphingolipids and the development of metabolic diseases, as scientists have figured out that pharmacological intervention or genetic ablation of enzymes controlling sphingolipid synthesis or degradation have beneficial effects in these disorders.

In the Special Issue, “Sphingolipids: Metabolic Functions and Disorders”, 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 metabolic processes.

Prof. Dr. Burkhard Kleuser
Assoc. Prof. Elisabetta Meacci
Guest Editors

Manuscript Submission Information

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Keywords

  • sphingolipids
  • ceramide
  • sphingosine
  • sphingosine 1-phosphate
  • ceramide 1-phosphate
  • glycosphingolipids
  • diabetes
  • insulin resistance
  • beta-cell failure
  • NAFLD
  • cardiovascular disease
  • metabolic dysfunction

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Published Papers (18 papers)

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Research

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Open AccessArticle
Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts
Int. J. Mol. Sci. 2020, 21(6), 2064; https://doi.org/10.3390/ijms21062064 - 17 Mar 2020
Abstract
The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung [...] Read more.
The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β- or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β- or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
β-Galactosylceramidase Deficiency Causes Bone Marrow Vascular Defects in an Animal Model of Krabbe Disease
Int. J. Mol. Sci. 2020, 21(1), 251; https://doi.org/10.3390/ijms21010251 - 30 Dec 2019
Abstract
Krabbe disease (KD) is an autosomal recessive sphingolipidosis caused by the deficiency of the lysosomal hydrolase β-galactosylceramidase (GALC). Oligodendroglia degeneration and demyelination of the nervous system lead to neurological dysfunctions which are usually lethal by two years of age. At present, the only [...] Read more.
Krabbe disease (KD) is an autosomal recessive sphingolipidosis caused by the deficiency of the lysosomal hydrolase β-galactosylceramidase (GALC). Oligodendroglia degeneration and demyelination of the nervous system lead to neurological dysfunctions which are usually lethal by two years of age. At present, the only clinical treatment with any proven efficacy is hematopoietic stem-cell transplantation, which is more effective when administered in the neonatal period to presymptomatic recipients. Bone marrow (BM) sinusoidal endothelial cells (SECs) play a pivotal role in stem cell engraftment and reconstitution of hematopoiesis. Previous observations had shown significant alterations of microvascular endothelial cells in the brain of KD patients and in Galc mutant twitcher mice, an authentic model of the disease. In the present study, we investigated the vascular component of the BM in the femurs of symptomatic homozygous twitcher mice at postnatal day P36. Histological, immunohistochemical, and two-photon microscopy imaging analyses revealed the presence of significant alterations of the diaphyseal BM vasculature, characterized by enlarged, discontinuous, and hemorrhagic SECs that express the endothelial marker vascular endothelial growth factor receptor-2 (VEGFR2) but lack platelet/endothelial cell adhesion molecule-1 (CD31) expression. In addition, computer-aided image analysis indicates that twitcher CD31/VEGFR2+ SECs show a significant increase in lumen size and in the number and size of endothelial gaps compared to BM SECs of wild type littermates. These results suggest that morphofunctional defects in the BM vascular niche may contribute to the limited therapeutic efficacy of hematopoietic stem-cell transplantation in KD patients at symptomatic stages of the disease. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling
Int. J. Mol. Sci. 2019, 20(24), 6361; https://doi.org/10.3390/ijms20246361 - 17 Dec 2019
Abstract
Sphingosine-1-phosphate (S1P) has been implicated recently in the physiology and pathology of the cardiovascular system including regulation of vascular tone. Pilot experiments showed that the vasoconstrictor effect of S1P was enhanced markedly in the presence of phenylephrine (PE). Based on this observation, we [...] Read more.
Sphingosine-1-phosphate (S1P) has been implicated recently in the physiology and pathology of the cardiovascular system including regulation of vascular tone. Pilot experiments showed that the vasoconstrictor effect of S1P was enhanced markedly in the presence of phenylephrine (PE). Based on this observation, we hypothesized that S1P might modulate α1-adrenergic vasoactivity. In murine aortas, a 20-minute exposure to S1P but not to its vehicle increased the Emax and decreased the EC50 of PE-induced contractions indicating a hyperreactivity to α1-adrenergic stimulation. The potentiating effect of S1P disappeared in S1P2 but not in S1P3 receptor-deficient vessels. In addition, smooth muscle specific conditional deletion of G12/13 proteins or pharmacological inhibition of the Rho-associated protein kinase (ROCK) by Y-27632 or fasudil abolished the effect of S1P on α1-adrenergic vasoconstriction. Unexpectedly, PE-induced contractions remained enhanced markedly as late as three hours after S1P-exposure in wild-type (WT) and S1P3 KO but not in S1P2 KO vessels. In conclusion, the S1P–S1P2–G12/13–ROCK signaling pathway appears to have a major influence on α1-adrenergic vasoactivity. This cooperativity might lead to sustained vasoconstriction when increased sympathetic tone is accompanied by increased S1P production as it occurs during acute coronary syndrome and stroke. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Acid Sphingomyelinase Deficiency Ameliorates Farber Disease
Int. J. Mol. Sci. 2019, 20(24), 6253; https://doi.org/10.3390/ijms20246253 - 11 Dec 2019
Abstract
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model [...] Read more.
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation
Int. J. Mol. Sci. 2019, 20(24), 6237; https://doi.org/10.3390/ijms20246237 - 11 Dec 2019
Abstract
Background: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia–reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim [...] Read more.
Background: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia–reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation. Methods: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways. Results: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index. Conclusions: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics
Int. J. Mol. Sci. 2019, 20(22), 5598; https://doi.org/10.3390/ijms20225598 - 09 Nov 2019
Abstract
Diesel exhaust particles (DEPs) are known pathogenic pollutants that constitute a significant quantity of air pollution. Given the ubiquitous presence of macrophages throughout the body, including the lungs, as well as their critical role in tissue and organismal metabolic function, we sought to [...] Read more.
Diesel exhaust particles (DEPs) are known pathogenic pollutants that constitute a significant quantity of air pollution. Given the ubiquitous presence of macrophages throughout the body, including the lungs, as well as their critical role in tissue and organismal metabolic function, we sought to determine the effect of DEP exposure on macrophage mitochondrial function. Following daily DEP exposure in mice, pulmonary macrophages were isolated for mitochondrial analyses, revealing reduced respiration rates and dramatically elevated H2O2 levels. Serum ceramides and inflammatory cytokines were increased. To determine the degree to which the changes in mitochondrial function in macrophages were not dependent on any cross-cell communication, primary pulmonary murine macrophages were used to replicate the DEP exposure in a cell culture model. We observed similar changes as seen in pulmonary macrophages, namely diminished mitochondrial respiration, but increased H2O2 production. Interestingly, when treated with myriocin to inhibit ceramide biosynthesis, these DEP-induced mitochondrial changes were mitigated. Altogether, these data suggest that DEP exposure may compromise macrophage mitochondrial and whole-body function via pathologic alterations in macrophage ceramide metabolism. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Sphingosine 1-Phosphate Receptor Blockade Affects Pro-Inflammatory Bone Marrow-Derived Macrophages and Relieves Mouse Fatty Liver Injury
Int. J. Mol. Sci. 2019, 20(19), 4695; https://doi.org/10.3390/ijms20194695 - 22 Sep 2019
Cited by 1
Abstract
Fatty liver injury is characterized by liver fat accumulation and results in serious health problems worldwide. There is no effective treatment that reverses fatty liver injury besides etiological therapy. Inflammation is an important macrophage-involving pathological process of liver injury. Here, we investigated the [...] Read more.
Fatty liver injury is characterized by liver fat accumulation and results in serious health problems worldwide. There is no effective treatment that reverses fatty liver injury besides etiological therapy. Inflammation is an important macrophage-involving pathological process of liver injury. Here, we investigated the role of sphingosine 1-phosphate receptors (S1PRs) in fatty liver injury and explored whether S1PR2/3 blockade could cure fatty liver injury. A methionine-choline-deficient and a high-fat (MCDHF) diet was used to induce fatty liver injury, and the number of macrophages was evaluated by flow cytometry. Gene expressions were detected using RT-qPCR and cytometric bead array. In MCDHF-diet-fed mice, pro-inflammatory factor expressions were upregulated by fatty liver injury. The S1P level and S1PR2/3 expressions were significantly elevated. Moreover, increased S1P level and S1PR2/3 mRNA expressions were positively correlated with pro-inflammatory factor expressions in the liver. Furthermore, the number of pro-inflammatory macrophages (iMφ) increased in injured liver, and they were mainly bone-marrow-derived macrophages. In vivo, S1PR2/3 blockade decreased the amount of iMφ and inflammation and attenuated liver injury and fibrosis, although liver fat accumulation was unchanged. These data strongly suggest that anti-inflammatory treatment by blocking the S1P/S1PR2/3 axis attenuates fatty liver injury, which might serve as a potential target for fatty liver injury. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Hyperbaric Oxygen Treatment Ameliorates Hearing Loss and Auditory Cortex Injury in Noise Exposed Mice by Repressing Local Ceramide Accumulation
Int. J. Mol. Sci. 2019, 20(19), 4675; https://doi.org/10.3390/ijms20194675 - 20 Sep 2019
Cited by 1
Abstract
Noise-induced hearing loss (NIHL) relates closely to auditory cortex (AC) injury, so countermeasures aiming at the AC recovery would be of benefit. In this work, the effect of hyperbaric oxygen treatment on NIHL was elucidated, which was imposed on mice before (HBOP), during [...] Read more.
Noise-induced hearing loss (NIHL) relates closely to auditory cortex (AC) injury, so countermeasures aiming at the AC recovery would be of benefit. In this work, the effect of hyperbaric oxygen treatment on NIHL was elucidated, which was imposed on mice before (HBOP), during (HBOD) or after (HBOA) noise exposure. Morphology of neurons was assayed by hematoxylin-eosin or Nissl staining. Ceramide (Cer) level was measured through immunohistochemistry analysis. Apoptotic neurons were counted using transferase-mediated dUTP nick end labeling (TUNEL) staining. We demonstrated that the intense, broad band noise raised the threshold of auditory brainstem response, evoked neuronal degeneration or apoptosis and triggered the Cer accumulation in AC, all of which were restored significantly by HBOP, but not HBOD or HBOA. Cer over-generation reversed the advantages of HBOP significantly, while its curtailment recapitulated the effect. Next, noise exposure raised the superoxide or malondialdehyde (MDA) production which was blocked by HBOP or Cer repression. Oxidative control not only attenuated the hearing loss or neurodegeneration but, in turn, reduced the Cer formation significantly. In summary, mutual regulation between Cer and oxidative stress underlies the HBOP’s curative effect on hearing loss and neuronal damage in noise-exposed mice. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Activation of the Sphingosine 1 Phosphate–Rho Pathway in Pterygium and in Ultraviolet-Irradiated Normal Conjunctiva
Int. J. Mol. Sci. 2019, 20(19), 4670; https://doi.org/10.3390/ijms20194670 - 20 Sep 2019
Cited by 1
Abstract
Sphingosine 1 phosphate (S1P) is a bioactive lipid that regulates cellular activity, including proliferation, cytoskeletal organization, migration, and fibrosis. In this study, the potential relevance of S1P–Rho signaling in pterygium formation and the effects of ultraviolet (UV) irradiation on activation of the S1P/S1P [...] Read more.
Sphingosine 1 phosphate (S1P) is a bioactive lipid that regulates cellular activity, including proliferation, cytoskeletal organization, migration, and fibrosis. In this study, the potential relevance of S1P–Rho signaling in pterygium formation and the effects of ultraviolet (UV) irradiation on activation of the S1P/S1P receptor axis and fibrotic responses were investigated in vitro. Expressions of the S1P2, S1P4, and S1P5 receptors were significantly higher in pterygium tissue than in normal conjunctiva, and the concentration of S1P was significantly elevated in the lysate of normal conjunctival fibroblast cell (NCFC) irradiated with UV (UV-NCFCs). RhoA activity was significantly upregulated in pterygium fibroblast cells (PFCs) and UV-NCFCs, and myosin phosphatase–Rho interacting protein (MRIP) was upregulated, and myosin phosphatase target subunit 1 (MYPT1) was downregulated in PFCs. Fibrogenic changes were significantly upregulated in both PFCs and UV-NCFCs compared to NCFCs. We found that the activation of the S1P receptor–Rho cascade was observed in pterygium tissue. Additionally, in vitro examination showed S1P–rho activation and fibrogenic changes in PFCs and UV-NCFCs. S1P elevation and the resulting upregulation of the downstream Rho signaling pathway may be important in pterygium formation; this pathway offers a potential therapeutic target for suppressing pterygium generation. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Light Stress-Induced Increase of Sphingosine 1-Phosphate in Photoreceptors and Its Relevance to Retinal Degeneration
Int. J. Mol. Sci. 2019, 20(15), 3670; https://doi.org/10.3390/ijms20153670 - 26 Jul 2019
Abstract
Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity [...] Read more.
Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity in a photoreceptor cell line (661W cells) was significantly increased by exposure to light. The enhancement of SphK1 expression was dependent on illumination, and all-trans-retinal significantly promoted SphK1 expression. S1P treatment reduced protein kinase B (Akt) phosphorylation and increased the protein expression of cleaved caspase-3, and induced photoreceptor cell apoptosis. In vivo, light exposure enhanced the expression of SphK1 in the outer segments of photoreceptors. Intravitreal injection of a SphK inhibitor significantly suppressed the thinning of the outer nuclear layer and ameliorated the attenuation of the amplitudes of a-waves and b-waves of electroretinograms during light-induced retinal degeneration. These findings imply that light exposure induces the synthesis of S1P in photoreceptors by upregulating SphK1, which is facilitated by all-trans-retinal, causing retinal degeneration. Inhibition of this enhancement may be a therapeutic target of outer retinal degeneration, including age-related macular degeneration. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessArticle
Cardiodynamic Interactions between Two S1P1 Receptor Modulators in an Experimental Clinical Setting: Different Pharmacokinetic Properties as an Opportunity to Mitigate First-Dose Heart Rate Effects
Int. J. Mol. Sci. 2019, 20(13), 3232; https://doi.org/10.3390/ijms20133232 - 01 Jul 2019
Cited by 1
Abstract
A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required [...] Read more.
A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required for compounds with a long t1/2 due to the less pronounced first-dose-related negative chronotropic effects. Based on this conceptual framework, this mechanistic study investigated whether first-dose HR effects of ponesimod (t1/2 ~32 h) can be mitigated by prior administration of cenerimod (t1/2 ~415 h). Healthy subjects (n = 12) were randomly assigned to active or placebo (2:1 ratio). Active treatment consisted of a single dose of 10 mg ponesimod on Day 1, 18, and 37 and multiple-dose administration of 2 mg once daily cenerimod (Day 9–36). Placebos of cenerimod and ponesimod were used as reference treatment. Cardiodynamic parameters were derived from 24 h Holter electrocardiogram (ECG) assessments on Day 1, 9, 10, 18, 36, and 37. Ponesimod (10 mg) alone triggered a transient mean decrease from baseline in hourly mean HR of 17 bpm. In contrast, decreases of 5.0 and 4.8 bpm were observed when ponesimod was given at near half steady-state (Day 18) or steady-state (Day 37) cenerimod, respectively. Hourly mean HR decreased after first administration of cenerimod and placebo was 7.4 and 4.0 bpm, respectively. Treatment with ponesimod and cenerimod alone or in combination was safe and tolerated. First-dose-related negative chronotropic effects of ponesimod were less pronounced when administered after initiation of cenerimod suggesting mitigation of this class-related liability. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Review

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Open AccessReview
Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover
Int. J. Mol. Sci. 2020, 21(1), 40; https://doi.org/10.3390/ijms21010040 - 19 Dec 2019
Cited by 2
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the main causes of chronic liver disease worldwide. NAFLD comprises a group of conditions characterized by the accumulation of hepatic lipids that can eventually lead to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the main causes of chronic liver disease worldwide. NAFLD comprises a group of conditions characterized by the accumulation of hepatic lipids that can eventually lead to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), the fifth most common cancer type with a poor survival rate. In this context, several works have pointed out perturbations in lipid metabolism and, particularly, changes in bioactive sphingolipids, as a hallmark of NAFLD and derived HCC. In the present work, we have reviewed existing literature about sphingolipids and the development of NAFLD and NAFLD-derived HCC. During metabolic syndrome, considered a risk factor for steatosis development, an increase in ceramide and sphigosine-1-phosphate (S1P) have been reported. Likewise, other reports have highlighted that increased sphingomyelin and ceramide content is observed during steatosis and NASH. Ceramide also plays a role in liver fibrosis and cirrhosis, acting synergistically with S1P. Finally, during HCC, metabolic fluxes are redirected to reduce cellular ceramide levels whilst increasing S1P to support tumor growth. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessReview
S1P/S1P Receptor Signaling in Neuromuscolar Disorders
Int. J. Mol. Sci. 2019, 20(24), 6364; https://doi.org/10.3390/ijms20246364 - 17 Dec 2019
Cited by 1
Abstract
The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears [...] Read more.
The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot–Marie–Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessReview
Colon Cancer and Perturbations of the Sphingolipid Metabolism
Int. J. Mol. Sci. 2019, 20(23), 6051; https://doi.org/10.3390/ijms20236051 - 30 Nov 2019
Cited by 1
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessReview
Sphingolipids in Obesity and Correlated Co-Morbidities: The Contribution of Gender, Age and Environment
Int. J. Mol. Sci. 2019, 20(23), 5901; https://doi.org/10.3390/ijms20235901 - 24 Nov 2019
Abstract
This paper reviews our present knowledge on the contribution of ceramide (Cer), sphingomyelin (SM), dihydroceramide (DhCer) and sphingosine-1-phosphate (S1P) in obesity and related co-morbidities. Specifically, in this paper, we address the role of acyl chain composition in bodily fluids for monitoring obesity in [...] Read more.
This paper reviews our present knowledge on the contribution of ceramide (Cer), sphingomyelin (SM), dihydroceramide (DhCer) and sphingosine-1-phosphate (S1P) in obesity and related co-morbidities. Specifically, in this paper, we address the role of acyl chain composition in bodily fluids for monitoring obesity in males and females, in aging persons and in situations of environmental hypoxia adaptation. After a brief introduction on sphingolipid synthesis and compartmentalization, the node of detection methods has been critically revised as the node of the use of animal models. The latter do not recapitulate the human condition, making it difficult to compare levels of sphingolipids found in animal tissues and human bodily fluids, and thus, to find definitive conclusions. In human subjects, the search for putative biomarkers has to be performed on easily accessible material, such as serum. The serum “sphingolipidome” profile indicates that attention should be focused on specific acyl chains associated with obesity, per se, since total Cer and SM levels coupled with dyslipidemia and vitamin D deficiency can be confounding factors. Furthermore, exposure to hypoxia indicates a relationship between dyslipidemia, obesity, oxygen level and aerobic/anaerobic metabolism, thus, opening new research avenues in the role of sphingolipids. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessReview
Sphingosine 1-Phosphate (S1P)/ S1P Receptor Signaling and Mechanotransduction: Implications for Intrinsic Tissue Repair/Regeneration
Int. J. Mol. Sci. 2019, 20(22), 5545; https://doi.org/10.3390/ijms20225545 - 07 Nov 2019
Cited by 4
Abstract
Tissue damage, irrespective from the underlying etiology, destroys tissue structure and, eventually, function. In attempt to achieve a morpho-functional recover of the damaged tissue, reparative/regenerative processes start in those tissues endowed with regenerative potential, mainly mediated by activated resident stem cells. These cells [...] Read more.
Tissue damage, irrespective from the underlying etiology, destroys tissue structure and, eventually, function. In attempt to achieve a morpho-functional recover of the damaged tissue, reparative/regenerative processes start in those tissues endowed with regenerative potential, mainly mediated by activated resident stem cells. These cells reside in a specialized niche that includes different components, cells and surrounding extracellular matrix (ECM), which, reciprocally interacting with stem cells, direct their cell behavior. Evidence suggests that ECM stiffness represents an instructive signal for the activation of stem cells sensing it by various mechanosensors, able to transduce mechanical cues into gene/protein expression responses. The actin cytoskeleton network dynamic acts as key mechanotransducer of ECM signal. The identification of signaling pathways influencing stem cell mechanobiology may offer therapeutic perspectives in the regenerative medicine field. Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) signaling, acting as modulator of ECM, ECM-cytoskeleton linking proteins and cytoskeleton dynamics appears a promising candidate. This review focuses on the current knowledge on the contribution of S1P/S1PR signaling in the control of mechanotransduction in stem/progenitor cells. The potential contribution of S1P/S1PR signaling in the mechanobiology of skeletal muscle stem cells will be argued based on the intriguing findings on S1P/S1PR action in this mechanically dynamic tissue. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessReview
Ceramide and Sphingosine Regulation of Myelinogenesis: Targeting Serine Palmitoyltransferase Using microRNA in Multiple Sclerosis
Int. J. Mol. Sci. 2019, 20(20), 5031; https://doi.org/10.3390/ijms20205031 - 11 Oct 2019
Abstract
Ceramide and sphingosine display a unique profile during brain development, indicating their critical role in myelinogenesis. Employing advanced technology such as gas chromatography–mass spectrometry, high performance liquid chromatography, and immunocytochemistry, along with cell culture and molecular biology, we have found an accumulation of [...] Read more.
Ceramide and sphingosine display a unique profile during brain development, indicating their critical role in myelinogenesis. Employing advanced technology such as gas chromatography–mass spectrometry, high performance liquid chromatography, and immunocytochemistry, along with cell culture and molecular biology, we have found an accumulation of sphingosine in brain tissues of patients with multiple sclerosis (MS) and in the spinal cord of rats induced with experimental autoimmune encephalomyelitis. The elevated sphingosine leads to oligodendrocyte death and fosters demyelination. Ceramide elevation by serine palmitoyltransferse (SPT) activation was the primary source of the sphingosine elevation as myriocin, an inhibitor of SPT, prevented sphingosine elevation and protected oligodendrocytes. Supporting this view, fingolimod, a drug used for MS therapy, reduced ceramide generation, thus offering partial protection to oligodendrocytes. Sphingolipid synthesis and degradation in normal development is regulated by a series of microRNAs (miRNAs), and hence, accumulation of sphingosine in MS may be prevented by employing miRNA technology. This review will discuss the current knowledge of ceramide and sphingosine metabolism (synthesis and breakdown), and how their biosynthesis can be regulated by miRNA, which can be used as a therapeutic approach for MS. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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Open AccessReview
The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism
Int. J. Mol. Sci. 2019, 20(13), 3304; https://doi.org/10.3390/ijms20133304 - 05 Jul 2019
Cited by 3
Abstract
Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is [...] Read more.
Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies. Full article
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
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