International Journal of Molecular Sciences

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22 pages, 3203 KiB

Open AccessArticle

Deletion of Sphingosine Kinase 2 Attenuates Acute Kidney Injury in Mice with Hemolytic-Uremic Syndrome

by Tina Müller, Nadine Krieg, Antonia I. Lange-Polovinkin, Bianka Wissuwa, Markus H. Gräler, Sophie Dennhardt and Sina M. Coldewey

Int. J. Mol. Sci. 2024, 25(14), 7683; https://doi.org/10.3390/ijms25147683 - 12 Jul 2024

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Abstract

Typical hemolytic uremic syndrome (HUS) can occur as a severe systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli. Its pathology can be induced by Stx types, resulting in toxin-mediated damage to renal barriers, inflammation, and the development of acute kidney [...] Read more.

Typical hemolytic uremic syndrome (HUS) can occur as a severe systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli. Its pathology can be induced by Stx types, resulting in toxin-mediated damage to renal barriers, inflammation, and the development of acute kidney injury (AKI). Two sphingosine kinase (SphK) isozymes, SphK1 and SphK2, have been shown to be involved in barrier maintenance and renal inflammatory diseases. Therefore, we sought to determine their role in the pathogenesis of HUS. Experimental HUS was induced by the repeated administration of Stx2 in wild-type (WT) and SphK1 (SphK1^−/−) or SphK2 (SphK2^−/−) null mutant mice. Disease severity was evaluated by assessing clinical symptoms, renal injury and dysfunction, inflammatory status and sphingolipid levels on day 5 of HUS development. Renal inflammation and injury were found to be attenuated in the SphK2^−/− mice, but exacerbated in the SphK1^−/− mice compared to the WT mice. The divergent outcome appeared to be associated with oppositely altered sphingolipid levels. This study represents the first description of the distinct roles of SphK1^−/− and SphK2^−/− in the pathogenesis of HUS. The identification of sphingolipid metabolism as a potential target for HUS therapy represents a significant advance in the field of HUS research. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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15 pages, 3231 KiB

Open AccessArticle

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

by Sarah E. Nicholas, Sandip K. Basu, Nawajes Mandal and Dimitrios Karamichos

Int. J. Mol. Sci. 2024, 25(12), 6560; https://doi.org/10.3390/ijms25126560 - 14 Jun 2024

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Abstract

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in [...] Read more.

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I₂). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I₂; prevention groups; (4) S1P/β1; and (5) I₂/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I₂ prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I₂ prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I₂ treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I₂ as a novel therapy for corneal fibrosis. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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18 pages, 8570 KiB

Open AccessArticle

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

by Kathryn Frost, Jonathan W. Lewis, Simon W. Jones, James R. Edwards, Amy J. Naylor and Helen M. McGettrick

Int. J. Mol. Sci. 2024, 25(10), 5118; https://doi.org/10.3390/ijms25105118 - 8 May 2024

Cited by 1 | Viewed by 1115

Abstract

The deterioration of osteoblast-led bone formation and the upregulation of osteoclast-regulated bone resorption are the primary causes of bone diseases, including osteoporosis. Numerous circulating factors play a role in bone homeostasis by regulating osteoblast and osteoclast activity, including the sphingolipid—sphingosine-1-phosphate (S1P). However, to [...] Read more.

The deterioration of osteoblast-led bone formation and the upregulation of osteoclast-regulated bone resorption are the primary causes of bone diseases, including osteoporosis. Numerous circulating factors play a role in bone homeostasis by regulating osteoblast and osteoclast activity, including the sphingolipid—sphingosine-1-phosphate (S1P). However, to date no comprehensive studies have investigated the impact of S1P activity on human and murine osteoblasts and osteoclasts. We observed species-specific responses to S1P in both osteoblasts and osteoclasts, where S1P stimulated human osteoblast mineralisation and reduced human pre-osteoclast differentiation and mineral resorption, thereby favouring bone formation. The opposite was true for murine osteoblasts and osteoclasts, resulting in more mineral resorption and less mineral deposition. Species-specific differences in osteoblast responses to S1P were potentially explained by differential expression of S1P receptor 1. By contrast, human and murine osteoclasts expressed comparable levels of S1P receptors but showed differential expression patterns of the two sphingosine kinase enzymes responsible for S1P production. Ultimately, we reveal that murine models may not accurately represent how human bone cells will respond to S1P, and thus are not a suitable model for exploring S1P physiology or potential therapeutic agents. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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29 pages, 5550 KiB

Open AccessArticle

Development of Genetically Encoded Fluorescent KSR1-Based Probes to Track Ceramides during Phagocytosis

by Vladimir Girik, Larissa van Ek, Isabelle Dentand Quadri, Maral Azam, María Cruz Cobo, Marion Mandavit, Isabelle Riezman, Howard Riezman, Anne-Claude Gavin and Paula Nunes-Hasler

Int. J. Mol. Sci. 2024, 25(5), 2996; https://doi.org/10.3390/ijms25052996 - 5 Mar 2024

Viewed by 1746

Abstract

Ceramides regulate phagocytosis; however, their exact function remains poorly understood. Here, we sought (1) to develop genetically encoded fluorescent tools for imaging ceramides, and (2) to use them to examine ceramide dynamics during phagocytosis. Fourteen enhanced green fluorescent protein (EGFP) fusion constructs based [...] Read more.

Ceramides regulate phagocytosis; however, their exact function remains poorly understood. Here, we sought (1) to develop genetically encoded fluorescent tools for imaging ceramides, and (2) to use them to examine ceramide dynamics during phagocytosis. Fourteen enhanced green fluorescent protein (EGFP) fusion constructs based on four known ceramide-binding domains were generated and screened. While most constructs localized to the nucleus or cytosol, three based on the CA3 ceramide-binding domain of kinase suppressor of ras 1 (KSR1) localized to the plasma membrane or autolysosomes. C-terminally tagged CA3 with a vector-based (C-KSR) or glycine-serine linker (C-KSR-GS) responded sensitively and similarly to ceramide depletion and accumulation using a panel of ceramide modifying drugs, whereas N-terminally tagged CA3 (N-KSR) responded differently to a subset of treatments. Lipidomic and liposome microarray analysis suggested that, instead, N-KSR may preferentially bind glucosyl-ceramide. Additionally, the three probes showed distinct dynamics during phagocytosis. Despite partial autolysosomal degradation, C-KSR and C-KSR-GS accumulated at the plasma membrane during phagocytosis, whereas N-KSR did not. Moreover, the weak recruitment of C-KSR-GS to the endoplasmic reticulum and phagosomes was enhanced through overexpression of the endoplasmic reticulum proteins stromal interaction molecule 1 (STIM1) and Sec22b, and was more salient in dendritic cells. The data suggest these novel probes can be used to analyze sphingolipid dynamics and function in living cells. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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17 pages, 2216 KiB

Open AccessArticle

Sphingomyelin Metabolism Modifies Luminal A Breast Cancer Cell Line under a High Dose of Vitamin C

by Michela Codini, Federico Fiorani, Martina Mandarano, Samuela Cataldi, Cataldo Arcuri, Alessandra Mirarchi, Maria Rachele Ceccarini, Tommaso Beccari, Toshihide Kobayashi, Nario Tomishige, Angelo Sidoni and Elisabetta Albi

Int. J. Mol. Sci. 2023, 24(24), 17263; https://doi.org/10.3390/ijms242417263 - 8 Dec 2023

Cited by 2 | Viewed by 1432

Abstract

The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin [...] Read more.

The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin metabolism in the changes induced by vitamin C in breast cancer cells. The MCF7 cell line reproducing luminal A breast cancer and the MDA-MB-231 cell line reproducing triple-negative breast cancer were used. Cell phenotype was tested by estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 expression, and proliferation index percentage. Sphingomyelin was localized by an EGFP-NT-Lys fluorescent probe. Sphingomyelin metabolism was analyzed by RT-PCR, Western blotting and UFLC-MS/MS. The results showed that a high dose of vitamin C produced reduced cell viability, modulated cell cycle related genes, and changed the cell phenotype with estrogen receptor downregulation in MCF7 cell. In these cells, the catabolism of sphingomyelin was promoted with a large increase in ceramide content. No changes in viability and molecular expression were observed in MB231 cells. In conclusion, a high dose of vitamin C induces changes in the luminal A cell line involving sphingomyelin metabolism. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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22 pages, 5291 KiB

Open AccessArticle

Ceramide Is Involved in Temozolomide Resistance in Human Glioblastoma U87MG Overexpressing EGFR

by Rosaria Bassi, Michele Dei Cas, Cristina Tringali, Federica Compostella, Rita Paroni and Paola Giussani

Int. J. Mol. Sci. 2023, 24(20), 15394; https://doi.org/10.3390/ijms242015394 - 20 Oct 2023

Cited by 1 | Viewed by 1534

Abstract

Glioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able [...] Read more.

Glioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able to induce antiproliferative and apoptotic responses in different types of tumors including GBM, most of which overexpress the epidermal growth factor receptor variant III (EGFRvIII). In this paper, we investigated whether Cer metabolism is altered in the U87MG human glioma cell line overexpressing EGFRvIII (EGFR+ cells) to elucidate their possible interplay in the mechanisms regulating GBM survival properties and the response to the alkylating agent temozolomide (TMZ). Notably, we demonstrated that a low dose of TMZ significantly increases Cer levels in U87MG cells but slightly in EGFR+ cells (sensitive and resistant to TMZ, respectively). Moreover, the inhibition of the synthesis of complex sphingolipids made EGFR+ cells sensitive to TMZ, thus involving Cer accumulation/removal in TMZ resistance of GBM cells. This suggests that the enhanced resistance of EGFR+ cells to TMZ is dependent on Cer metabolism. Altogether, our results indicate that EGFRvIII expression confers a TMZ-resistance phenotype to U87MG glioma cells by counteracting Cer increase. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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Review

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34 pages, 1521 KiB

Open AccessReview

Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications

by Samar M. Hammad and Maria F. Lopes-Virella

Int. J. Mol. Sci. 2023, 24(18), 14015; https://doi.org/10.3390/ijms241814015 - 13 Sep 2023

Cited by 9 | Viewed by 2564

Abstract

Sphingolipids play an important role in the development of diabetes, both type 1 and type 2 diabetes, as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most [...] Read more.

Sphingolipids play an important role in the development of diabetes, both type 1 and type 2 diabetes, as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most of the emphasis has been on the possible mechanisms by which sphingolipids, mainly ceramides, contribute to the development of diabetes. Research on circulating levels of the different classes of sphingolipids in serum and in lipoproteins and their importance as biomarkers to predict not only the development of diabetes but also of its complications has only recently emerged and it is still in its infancy. This review summarizes the previously published literature concerning sphingolipid-mediated mechanisms involved in the development of diabetes and its complications, focusing on how circulating plasma sphingolipid levels and the relative content carried by the different lipoproteins may impact their role as possible biomarkers both in the development of diabetes and mainly in the development of diabetic complications. Further studies in this field may open new therapeutic avenues to prevent or arrest/reduce both the development of diabetes and progression of its complications. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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16 pages, 1514 KiB

Open AccessReview

Circulating Sphingolipids and Glucose Homeostasis: An Update

by Sarah Ali-Berrada, Jeanne Guitton, Sophie Tan-Chen, Anna Gyulkhandanyan, Eric Hajduch and Hervé Le Stunff

Int. J. Mol. Sci. 2023, 24(16), 12720; https://doi.org/10.3390/ijms241612720 - 12 Aug 2023

Cited by 9 | Viewed by 2188

Abstract

Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance [...] Read more.

Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)

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