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Xia F, Santacruz A, Wu D, Bertho S, Fritz E, Morales-Sosa P, McKinney S, Nowotarski SH, Rohner N. Reproductive adaptation of Astyanax mexicanus under nutrient limitation. Dev Biol 2025; 523:82-98. [PMID: 40222642 PMCID: PMC12068995 DOI: 10.1016/j.ydbio.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/15/2025]
Abstract
Reproduction is a fundamental biological process for the survival and continuity of species. Examining changes in reproductive strategies offers valuable insights into how animals have adapted their life histories to different environments. Since reproduction is one of the most energy-intensive processes in female animals, nutrient scarcity is expected to interfere with the ability to invest in gametes. Lately, a new model to study adaptation to nutrient limitation has emerged; the Mexican tetra Astyanax mexicanus. This fish species exists as two different morphs, a surface river morph and a cave-dwelling morph. The cave-dwelling morph has adapted to the dark, lower biodiversity, and nutrient-limited cave environment and consequently evolved an impressive starvation resistance. However, how reproductive strategies have adapted to nutrient limitations in this species remains poorly understood. Here, we compared breeding activities and maternal contributions between laboratory-raised surface fish and cavefish. We found that cavefish produce different clutch sizes of eggs with larger yolk compared to surface fish, indicating a greater maternal nutrient deposition in cavefish embryos. To systematically characterize yolk compositions, we used untargeted proteomics and lipidomics approaches to analyze protein and lipid profiles in 2-cell stage embryos and found an increased proportion of sphingolipids in cavefish compared to surface fish. Additionally, we generated transcriptomic profiles of surface fish and cavefish ovaries using a combination of single cell and bulk RNA sequencing to examine differences in maternal contribution. We found that genes essential for hormone regulation were upregulated in cavefish follicular somatic cells compared to surface fish. To evaluate whether these differences contribute to their reproductive abilities under natural-occurring stress, we induced breeding in starved female fish. Remarkably, cavefish maintained their ability to breed under starvation, whereas surface fish largely lost this ability. We identified insulin-like growth factor 1a receptor (igf1ra) as a potential candidate gene mediating the downregulation of ovarian development genes, potentially contributing to the starvation-resistant fertility of cavefish. Taken together, we investigated the female reproductive strategies in Astyanax mexicanus, which will provide fundamental insights into the adaptations of animals to environments with extreme nutrient deficit.
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Affiliation(s)
- Fanning Xia
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Ana Santacruz
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Di Wu
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Sylvain Bertho
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Elizabeth Fritz
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | | | - Sean McKinney
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | | | - Nicolas Rohner
- Stowers Institute for Medical Research, Kansas City, MO, USA.
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2
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van Kruining D, Losen M, Dehairs J, Swinnen JV, Waelkens E, Honing M, Martinez-Martinez P. Early plasma ceramide and sphingomyelin levels reflect APOE genotype but not familial Alzheimer's disease gene mutations in female 5xFAD mice, with brain-region specific sphingolipid alterations. Neurobiol Dis 2025; 210:106923. [PMID: 40253012 DOI: 10.1016/j.nbd.2025.106923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/16/2025] [Accepted: 04/16/2025] [Indexed: 04/21/2025] Open
Abstract
Pathophysiological changes associated with Alzheimer's disease (AD) begin decades before dementia onset, with age and APOE ε4 genotype as major risk factors [1-4]. Primary risk factors for developing AD include aging and number of copies of the apolipoprotein E (APOE) ε4 allele. Altered sphingolipid metabolism is increasingly implicated in early AD. However, the relationship between early plasma and brain sphingolipid changes-particularly in the context of APOE genotype-remains poorly defined. In this study, we analyzed plasma and brain sphingolipid profiles in transgenic AD mice carrying human APOE3 or APOE4 variants, with or without familial AD mutations (E3FAD and E4FAD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we assessed 110 sphingolipid species across four major classes (ceramides (Cers), hexosylceramides (HexCers), lactosylceramides (LacCers), and sphingomyelins (SMs)) at 2, 4, and 6 months in plasma and at 6 months in brain tissue in the cortex, hippocampus, striatum, and cerebellum. Our results demonstrate that early plasma sphingolipid alterations are largely driven by APOE genotype rather than AD pathology. Specifically, APOE4 carriers showed significant increases in SM species and reductions in Cer species compared to APOE3 carriers, independent of age or AD genotype. Brain lipid profiles showed minimal changes across genotypes after region correction. However, combined p-value analyses revealed APOE- and EFAD-dependent differences in the composition of primarily cortical sphingolipids. ROC analyses demonstrated high discriminative power of plasma sphingolipids for APOE, but not for AD genotype. These findings suggest that early plasma lipid profiles in female 5xFAD mice are more strongly influenced by APOE genotype than by overt AD pathology, potentially reflecting systemic pathways linked to APOE4-associated AD risk, while early disease-associated changes in the brain appear to be subtle and region-specific. These results underscore the importance of accounting for APOE genotype in early-stage AD lipidomic studies and in the interpretation of peripheral lipid biomarkers.
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Affiliation(s)
- Daan van Kruining
- School for Mental Health and Neuroscience, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands; Department of Pharmacology, University of Oxford, Oxford, UK.
| | - Mario Losen
- School for Mental Health and Neuroscience, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands; Department of Pharmacology, University of Oxford, Oxford, UK
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven 3000, Belgium
| | - Johannes V Swinnen
- Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven 3000, Belgium
| | - Etienne Waelkens
- Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven 3000, Belgium
| | - Maarten Honing
- Maastricht Multimodal Molecular Imaging Institute (M4I), University of Maastricht, the Netherlands
| | - Pilar Martinez-Martinez
- School for Mental Health and Neuroscience, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands; Department of Pharmacology, University of Oxford, Oxford, UK
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Guan J, Wu F, Wu S, Ren Y, Wang J, Zhu H. FTY720 alleviates D-GalN/LPS-induced acute liver failure by regulating the JNK/MAPK pathway. Int Immunopharmacol 2025; 157:114726. [PMID: 40311319 DOI: 10.1016/j.intimp.2025.114726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 04/20/2025] [Accepted: 04/22/2025] [Indexed: 05/03/2025]
Abstract
Acute liver failure (ALF) poses a considerable health and economic burden worldwide and has limited treatment options. Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive phospholipid that participates in various cellular processes by through S1P receptors (S1PRs). Previous studies have showed that the hepatic S1P levels were increased. Notably, deletion or inhibition of sphingosine kinase 1 (SphK1), the key enzyme responsible for S1P biosynthesis, could alleviate D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced ALF in mice. However, the role of the S1P receptor modulator FTY720 in ALF remains unclear. In this study, we investigated the effects of FTY720 on D-GalN/LPS-induced ALF model. Our results demonstrated that FTY720 pretreatment significantly alleviated liver injury, decreased the serum levels of alanine aminotransferase and aspartate aminotransferase, and mitigated histopathological damage in ALF model mice. Mechanistically, FTY720 could inhibit the inflammatory response and reduced apoptosis. The protective effect of FTY720 was mediated by c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signalling. A pharmacological JNK activator (anisomycin) partially counteracted these protective effects. FTY720, targeting S1PRs, is expected to be an effective therapeutic strategy for ALF.
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Affiliation(s)
- Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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4
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Wlaschek M, Maity P, Koroma AK, Geiger H, Singh K, Scharffetter-Kochanek K. Imbalanced redox dynamics induce fibroblast senescence leading to impaired stem cell pools and skin aging. Free Radic Biol Med 2025; 233:292-301. [PMID: 40154755 DOI: 10.1016/j.freeradbiomed.2025.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/05/2025] [Accepted: 03/17/2025] [Indexed: 04/01/2025]
Abstract
Skin function depends on a meticulously regulated dynamic interaction of distinct skin compartments such as the epidermis and dermis. Adaptive responses at the molecular and cellular level are essential for these interactions - and if dysregulated - drive skin aging and other pathologies. After defining the role of redox homeodynamics in physiology and aging pathology, we focus on the redox distress-dependent aging of dermal fibroblasts including their progenitors. We here discuss the prime role of senescent fibroblasts in the control of their own endogenous niche and stem cell niches for epidermal stem cells, hair follicle stem cells, adipocyte precursors and muscle stem cells. We here review that redox imbalance induced reduction in Insulin-like Growth Factor-1 drives skin aging by the depletion of stem cell pools. This IGF-1 reduction is mediated via the redox-sensitive transcription factor JunB and also by the redox-dependent changes in sphingolipid-metabolism, among others. In addition, we will discuss the changes in the extracellular matrix of the skin affecting cellular senescence and the skin integrity and function in aging. The aim is a deeper understanding of the two main redox-dependent hubs such as JunB-induced depletion of IGF-1, and the sphingolipid-mediated remodeling of the cell membrane with its impact on IGF-1, fibroblast heterogeneity, function, senescence and plasticity in skin aging.
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Affiliation(s)
- Meinhard Wlaschek
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Pallab Maity
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Albert Kallon Koroma
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Hartmut Geiger
- Aging Research Institute (arc), Ulm University, Ulm, Germany; Institute for Molecular Medicine and Stem Cell Aging, Ulm University, Ulm, Germany
| | - Karmveer Singh
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Karin Scharffetter-Kochanek
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany.
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5
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Nguyen TV, Alfarsi A, Nguyen HT, Davidson G, Lloyd NDR, Kumar A. Metabolic disruptions induced by low concentrations of DMSO in RTgill-W1 fish cells: The importance of solvent controls in in vitro studies. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2025; 283:107354. [PMID: 40209297 DOI: 10.1016/j.aquatox.2025.107354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 04/04/2025] [Accepted: 04/04/2025] [Indexed: 04/12/2025]
Abstract
Dimethyl sulfoxide (DMSO) is a widely used solvent in biological research due to its ability to enhance membrane permeability, facilitating drug delivery and molecular transport across cellular membranes. However, its effects on cellular metabolism, especially at low concentrations, remain insufficiently understood. This study investigated the metabolic disruptions induced by 0.1-10 % DMSO in the RTgill-W1 fish cell line, focusing on changes in cell viability, oxidative stress, and key metabolic pathways. Results revealed that DMSO exposure caused dose-dependent declines in cell viability at 0.5 % DMSO and increases in reactive oxygen species (ROS) at 4 % and higher, indicating elevated oxidative stress. Metabolomic profiling revealed altered levels of numerous metabolites and significant impacts on 41 metabolic pathways belonging to five major functional groups: amino acid metabolism, carbohydrate metabolism, lipid metabolism, vitamin and co-factor metabolism, and nucleotide metabolism. The effects were observed across all exposure concentrations (0.1, 0.5, 1, 4, and 8 %), with more pronounced impacts at higher concentrations. These findings highlight that DMSO, even at low concentrations (≤ 0.5 %), can have widespread effects on cellular metabolism, impacting experimental outcomes in in vitro studies. This study provides valuable insights into the biochemical impacts of DMSO on fish cell lines and emphasizes a caution in using DMSO in biological research to minimize unintended cellular effects. Additionally, it highlights the critical need to include solvent controls at matching concentrations to accurately distinguish solvent-induced effects from those caused by experimental treatments.
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Affiliation(s)
- Thao V Nguyen
- CSIRO Environment, Waite Campus, Urrbrae, South Australia 5064, Australia.
| | - Ali Alfarsi
- CSIRO Environment, Waite Campus, Urrbrae, South Australia 5064, Australia
| | - Huong Thanh Nguyen
- CSIRO Environment, Waite Campus, Urrbrae, South Australia 5064, Australia
| | - Georgia Davidson
- The Australian Wine Research Institute, PO Box 46, Glenside, SA 5065, Australia; Metabolomics Australia, PO Box 46, Glenside, SA 5065, Australia
| | - Natoiya D R Lloyd
- The Australian Wine Research Institute, PO Box 46, Glenside, SA 5065, Australia; Metabolomics Australia, PO Box 46, Glenside, SA 5065, Australia
| | - Anu Kumar
- CSIRO Environment, Waite Campus, Urrbrae, South Australia 5064, Australia.
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Uranbileg B, Hoshino Y, Ezaka M, Kurano M, Uchida K, Yatomi Y, Ito N. Metabolism of sphingolipids in a rat spinal cord stenosis model. Biochem Biophys Rep 2025; 42:102025. [PMID: 40342530 PMCID: PMC12059668 DOI: 10.1016/j.bbrep.2025.102025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 04/07/2025] [Accepted: 04/18/2025] [Indexed: 05/11/2025] Open
Abstract
Background Lumbar spinal canal stenosis (LSCS) plays a crucial role in neurogenic claudication and neuropathic pain. Recent studies suggest that changes in sphingolipid metabolism are linked to neuropathic pain. To explore the association between sphingolipids and LSCS, we measured the levels of sphingolipids and sphingolipid-associated molecules in an animal model of cauda equina compression (CEC), a typical type of LSCS. Methods By placing silicon blocks within the lumbar epidural space, CEC model were constructed in which motor disfunction had already been confirmed in our previous study. Quantitative measurements of various sphingolipids were conducted using LC-MS/MS in spinal cord and cerebrospinal fluid (CSF) samples on days 1, 7, and 28 following insertion of silicon blocks. Additionally, gene expression was analyzed in spinal cord tissue. Results In the CEC model, there was a significant increase ceramide levels in the CSF with upregulation of ceramide synthase 1 in the spinal cord tissue samples on day 1. Further, S1P levels in the CSF increased on day 7 and in the spinal cord significantly increased on day 28, and there was an increase in mRNA expression levels of sphingosine kinases (SphK)1 on days 1,7, and 28, while SphK2 on days 7 and 28. Regarding S1P receptors, there was an increase in mRNA expression levels of S1P1 on days 1,7, and 28 and S1P3 on day1. Conclusion The production and activation of the sphingolipid signaling pathway could play a pivotal role in neuropathic pain related to LSCS.
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Affiliation(s)
- Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoko Hoshino
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Mariko Ezaka
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kanji Uchida
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuko Ito
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan
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7
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Deng S, Kim W, Cheng K, Yang Q, Singh Y, Bae G, Bézière N, Mager L, Kommoss S, Sprengel J, Trautwein C. Identification and impact of microbiota-derived metabolites in ascites of ovarian and gastrointestinal cancer. Cancer Metab 2025; 13:21. [PMID: 40361187 PMCID: PMC12076955 DOI: 10.1186/s40170-025-00391-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Malignant ascites is a common complication of advanced ovarian cancer (OC) and gastrointestinal cancer (GI), significantly impacting metastasis, quality of life, and survival. Increased intestinal permeability can lead to blood or lymphatic infiltration and microbial translocation from the gastrointestinal or uterine tract. This study aimed to identify microbiota-derived metabolites in ascites from OC (stages II-III and IV) and GI patients, assessing their roles in tumor progression. METHODS Malignant ascites samples from 18 OC and GI patients were analyzed using a four-dimensional (4D) untargeted metabolomics approach combining reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) with trapped ion mobility spectrometry time-of-flight mass spectrometry (timsTOF-MS). Additonally, a targeted flow cytometry-based cytokine panel was used to screen for inflammatory markers. Non-endogenous, microbiota-derived metabolites were identified through the Human Microbial Metabolome Database (MiMeDB). RESULTS OC stage IV exhibited metabolic profiles similar to GI cancers, while OC stage II-III differed significantly. Stage IV OC patients exhibited higher levels of 11 typically microbiome-derived metabolites, including 1-methylhistidine, 3-hydroxyanthranilic acid, 4-pyridoxic acid, biliverdin, butyryl-L-carnitine, hydroxypropionic acid, indole, lysophosphatidylinositol 18:1 (LPI 18:1), mevalonic acid, N-acetyl-L-phenylalanine, and nudifloramide, and lower levels of 5 metabolites, including benzyl alcohol, naringenin, o-cresol, octadecanedioic acid, and phenol, compared to stage II-III. Correlation analysis revealed positive associations between IL-10 and metabolites such as glucosamine and LPCs, while MCP-1 positively correlated with benzyl alcohol and phenol. CONCLUSION 4D metabolomics revealed distinct metabolic signatures in OC and GI ascites, highlighting microbiota-derived metabolites involved in lipid metabolism and inflammation. Metabolites like 3-hydroxyanthranilic acid, indole, and naringenin may serve as markers of disease progression and underscore the microbiota's role in shaping malignant ascites and tumor biology.
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Affiliation(s)
- Sisi Deng
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
- Core Facility Metabolomics, Faculty of Medicine, University of Tübingen, Tübingen, Germany
- M3 Research Center for Microbiome, Metabolome and Malignome, Faculty of Medicine, University of Tübingen, Tübingen, Germany
| | - Wooyong Kim
- Core Facility Metabolomics, Faculty of Medicine, University of Tübingen, Tübingen, Germany
- M3 Research Center for Microbiome, Metabolome and Malignome, Faculty of Medicine, University of Tübingen, Tübingen, Germany
| | - Kefan Cheng
- Core Facility Metabolomics, Faculty of Medicine, University of Tübingen, Tübingen, Germany
- M3 Research Center for Microbiome, Metabolome and Malignome, Faculty of Medicine, University of Tübingen, Tübingen, Germany
| | - Qianlu Yang
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany
| | - Yogesh Singh
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Gyuntae Bae
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Nicolas Bézière
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence CMFI (EXC 2124) "Controlling Microbes to Fight Infections", Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Lukas Mager
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
- M3 Research Center for Microbiome, Metabolome and Malignome, Faculty of Medicine, University of Tübingen, Tübingen, Germany
- Cluster of Excellence CMFI (EXC 2124) "Controlling Microbes to Fight Infections", Eberhard Karls University of Tübingen, Tübingen, Germany
- Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Stefan Kommoss
- Department of Obstetrics and Gynecology, Diak Klinikum, Schäbisch Hall, Germany
| | - Jannik Sprengel
- Core Facility Metabolomics, Faculty of Medicine, University of Tübingen, Tübingen, Germany
- M3 Research Center for Microbiome, Metabolome and Malignome, Faculty of Medicine, University of Tübingen, Tübingen, Germany
| | - Christoph Trautwein
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany.
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
- Core Facility Metabolomics, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
- M3 Research Center for Microbiome, Metabolome and Malignome, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
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Gao L, Hao J, Hua Z, Zeng C, Li J, Zeng J. Lipidomics Atlas Tracks Alterations Associated with Deltamethrin-Induced Developmental Neurotoxicity in Embryonic Zebrafish. J Proteome Res 2025; 24:2280-2290. [PMID: 40176748 DOI: 10.1021/acs.jproteome.4c00779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
Deltamethrin (DM) is a widely used pyrethroid pesticide associated with childhood neurodevelopmental disorders. However, the specific impact of DM exposure during distinct early life stages remains unclear. Here, zebrafish embryos were exposed to DM at different stages: before (10-16 hpf), at the onset of (16-24 hpf), at the peak of (24-36 hpf) hypothalamic neurogenesis, and continuously from 10 to 120 hpf (subchronic exposure), using different dosages (1, 100, and 250 nM). Exposure to middle/high-dose DM at 24-36 and 10-120 hpf significantly reduced zebrafish locomotor activities and increased apoptotic cells in the spinal cord. As a pivotal factor in central nervous system disorder progression, altered lipid metabolism was investigated using nontargeted lipidomic analysis. DM exposure at 10-16 and 24-36 hpf led to the most significant lipidome reprogramming. Despite exhibiting a dose-dependent trend, even low-dose DM changed the lipidome. Cer 40:2;2 and PG 44:12 showed potential in identifying DM exposure effects. Significant changes in sphingolipid, cardiolipin, phosphatidylglycerol, and glycerolipid pathways were linked to DM-induced developmental neurotoxicity, indicating impaired membrane function, mitochondrial damage, and disrupted energy metabolism. Our study sheds new light on assessing early neurodevelopmental disturbances and identifying intervention targets, emphasizing sensitivity to DM during the critical early phase of neurodevelopment.
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Affiliation(s)
- Longhua Gao
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Jingwen Hao
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Zhengyi Hua
- School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Changchun Zeng
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Shenzhen 518110, China
| | - Jia Li
- Key Laboratory of Tea Biology and Resources Utilization, Ministry of Agriculture, Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China
| | - Jun Zeng
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
- Xiamen Key Laboratory of Marine Functional Food, Xiamen 361021, China
- Research Unit Analytical BioGeoChemistry, Helmholtz Munich, Neuherberg 85764, Germany
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9
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Lin H, Ma C, Cai K, Guo L, Wang X, Lv L, Zhang C, Lin J, Zhang D, Ye C, Wang T, Huang S, Han J, Zhang Z, Gao J, Zhang M, Pu Z, Li F, Guo Y, Zhou X, Qin C, Yi F, Yu X, Kong W, Jiang C, Sun JP. Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis. Science 2025; 388:eado4188. [PMID: 40080544 DOI: 10.1126/science.ado4188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 09/13/2024] [Accepted: 01/03/2025] [Indexed: 03/15/2025]
Abstract
Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify formyl peptide receptor 2 (FPR2) as a membrane receptor that specifically binds long-chain ceramides (C14 to C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis through Gi cyclic adenosine monophosphate signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with Gi trimers bound to C16:0, C18:0, and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.
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Affiliation(s)
- Hui Lin
- New Cornerstone Science Laboratory, Advanced Medical Research Institute, and NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, Shandong, China
| | - Chuanshun Ma
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Kui Cai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Lulu Guo
- New Cornerstone Science Laboratory, Advanced Medical Research Institute, and NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Membrane Receptor Drug Target Discovery and Lead Drug Screening at Shandong Province, Shandong, China
| | - Xuemei Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Lin Lv
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chao Zhang
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jun Lin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Daolai Zhang
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Chuan Ye
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Tengwei Wang
- New Cornerstone Science Laboratory, Advanced Medical Research Institute, and NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shenming Huang
- New Cornerstone Science Laboratory, Advanced Medical Research Institute, and NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jifei Han
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Zihao Zhang
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Junyan Gao
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, Shandong, China
| | - Mingxiang Zhang
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Zhao Pu
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
- Department of Biochemistry and Human Biology, University of Toronto, Toronto, Ontario, Canada
| | - Fengyang Li
- School of Pharmacy, Shandong University, Jinan, Shandong, China
| | - Yongyuan Guo
- Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiaojun Zhou
- School of Pharmacy, Shandong University, Jinan, Shandong, China
| | - Chengxue Qin
- School of Pharmacy, Shandong University, Jinan, Shandong, China
| | - Fan Yi
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xiao Yu
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
- Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Jin-Peng Sun
- New Cornerstone Science Laboratory, Advanced Medical Research Institute, and NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China
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10
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Ran Y, Guo Z, Zhang L, Li H, Zhang X, Guan X, Cui X, Chen H, Cheng M. Mitochondria‑derived peptides: Promising microproteins in cardiovascular diseases (Review). Mol Med Rep 2025; 31:127. [PMID: 40084698 PMCID: PMC11924172 DOI: 10.3892/mmr.2025.13492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/27/2025] [Indexed: 03/16/2025] Open
Abstract
Mitochondria‑derived peptides (MDPs) are a unique class of peptides encoded by short open reading frames in mitochondrial DNA, including the mitochondrial open reading frame of the 12S ribosomal RNA type‑c (MOTS‑c). Recent studies suggest that MDPs offer therapeutic benefits in various diseases, including neurodegenerative disorders and types of cancer, due to their ability to increase cellular resilience. Mitochondrial dysfunction is a key factor in the onset and progression of cardiovascular diseases (CVDs), such as atherosclerosis and heart failure, as it disrupts energy metabolism, increases oxidative stress and promotes inflammation. MDPs such as humanin and MOTS‑c have emerged as important regulators of mitochondrial health, as they show protective effects against these processes. Recent studies have shown that MDPs can restore mitochondrial function, reduce oxidative damage and alleviate inflammation, thus counteracting the pathological mechanisms that drive CVDs. Therefore, MDPs hold promise as therapeutic agents that are capable of slowing, stopping, or even reversing CVD progression and their use presents a promising strategy for future treatments. However, the clinical application of MDPs remains challenging due to their low bioavailability, poor stability and high synthesis costs. Thus, it is necessary to improve drug delivery systems to enhance the bioavailability of MDPs. Moreover, integrating basic research with clinical trials is essential to bridge the gap between experimental findings and clinical applications.
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Affiliation(s)
- Yutong Ran
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Zhiliang Guo
- Department of Spinal Surgery, The 80th Group Army Hospital of Chinese PLA, Weifang, Shandong 261021, P.R. China
| | - Lijuan Zhang
- Stroke Centre, Second People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Hong Li
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaoyun Zhang
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiumei Guan
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaodong Cui
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Hao Chen
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Min Cheng
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
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11
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Kalenta H, Kilroe SP, Romsdahl TB, Marchant ED, Maroto R, Linares JJ, Russell WK, Rasmussen BB. Constitutively active mTORC1 signaling modifies the skeletal muscle metabolome and lipidome response to exercise. J Appl Physiol (1985) 2025; 138:1173-1186. [PMID: 40215109 DOI: 10.1152/japplphysiol.00987.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/21/2025] [Accepted: 04/04/2025] [Indexed: 05/01/2025] Open
Abstract
A chronic increase in the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling is implicated in reduced longevity, altered metabolism, and mitochondrial dysfunction. Abnormal mTORC1 signaling may also be involved in the etiology of sarcopenia. To better understand the role of mTORC1 signaling in the regulation of muscle metabolism, we developed an inducible muscle-specific knockout model of DEP domain-containing 5 protein (DEPDC5 mKO), which results in constitutively active mTORC1 signaling. We hypothesized that constitutively active mTORC1 signaling in skeletal muscle would alter the metabolomic and lipidomic response to an acute bout of exercise. Wild-type (WT) and DEPDC5 muscle-specific knockout (KO) mice were studied at rest and following a 1 h bout of treadmill exercise. Acute exercise induced an increased reliance on glycolytic and pentose phosphate pathway (PPP) metabolites in the muscle of mice with hyperactive mTORC1. Lipidomic analysis showed an increase in triglycerides (TGs) in KO mice. Although exercise had a pronounced effect on muscle metabolism, the genotype effect was larger, indicating that constitutively active mTORC1 signaling exerts a dominant influence on metabolic and lipidomic regulation. We conclude that increased mTORC1 signaling shifts muscle metabolism toward greater reliance on nonoxidative energy sources in response to exercise. Understanding the mechanisms responsible for these effects may lead to the development of strategies for restoring proper mTORC1 signaling in conditions such as aging and sarcopenia.NEW & NOTEWORTHY This study demonstrates that hyperactive mTORC1 alters the muscle metabolomic and lipidomic response to exercise, with genotype having a larger effect than exercise. Knockout mice exhibited an increase in reliance on glycolysis and pentose phosphate pathway and an increase in triglyceride turnover. Wild-type mice primarily showed an increase in utilization of TCA cycle and lipid metabolism intermediates.
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Affiliation(s)
- Hanna Kalenta
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Sean P Kilroe
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Trevor B Romsdahl
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Erik D Marchant
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Rosario Maroto
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
| | - Jennifer J Linares
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
- Mass Spectrometry Facility, University of Texas Medical Branch, Galveston, Texas, United States
| | - William K Russell
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
- Mass Spectrometry Facility, University of Texas Medical Branch, Galveston, Texas, United States
| | - Blake B Rasmussen
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
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12
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Yamada C, Akkaoui J, Morozov A, Movila A. Role of Canonical and Non-Canonical Sphingolipids and their Metabolic Enzymes in Bone Health. Curr Osteoporos Rep 2025; 23:21. [PMID: 40266422 PMCID: PMC12018623 DOI: 10.1007/s11914-025-00908-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2025] [Indexed: 04/24/2025]
Abstract
PURPOSE OF REVIEW This review summarizes the recently published scientific evidence regarding the role of enzymes engaged in de novo anabolic biosynthesis, catabolic, and salvage pathways of ceramide bioactive sphingolipids in bone dynamics and skeletal health. RECENT FINDINGS Ceramides are precursors for bioactive sphingolipids, including sphingosine, sphingosine-1-phosphate, and others. Studies of bone metabolism and bone-related cells demonstrated that ceramide and sphingosine-1-phosphate control levels of bone remodeling and resorption generated by osteoblasts and osteoclasts. Multiple published studies demonstrated the critical role of enzymes in regulating the ceramide/sphingosine-1-phosphate ratio relative to bone physiology and the promotion of inflammatory osteolysis. Accordingly, emerging evidence suggests that targeting sphingolipid metabolism has the potential to alleviate inflammatory osteolysis and accelerate bone regeneration. Therefore, this study aimed to discuss current knowledge about crosstalk between sphingolipids and their metabolic enzymes within osteoclast and osteoblast coupling in bone remodeling and pathogenic osteolysis. This review highlights the complexity of de novo sphingolipid biosynthesis and knowledge gaps in bone physiology and pathology. We also discuss the importance of canonical and non-canonical mammalian and bacterial-derived sphingolipids relative to bone health.
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Affiliation(s)
- Chiaki Yamada
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN, USA
| | - Juliet Akkaoui
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Alexandr Morozov
- Institute of Zoology, Moldova State University, Chisinau, Republic of Moldova
- Medpark International Hospital, Chisinau, Republic of Moldova
| | - Alexandru Movila
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN, USA.
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13
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Hannun YA, Merrill AH, Luberto C. The Bioactive Sphingolipid Playbook. A Primer for the Uninitiated as well as Sphingolipidologists. J Lipid Res 2025:100813. [PMID: 40254066 DOI: 10.1016/j.jlr.2025.100813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/13/2025] [Accepted: 04/15/2025] [Indexed: 04/22/2025] Open
Abstract
Sphingolipids and glycosphingolipids are among the most structurally diverse and complex compounds in the mammalian metabolome. They are well known to play important roles in biological architecture, cell-cell communication and cellular regulation, and for many biological processes, multiple sphingolipids are involved. Thus, it is not surprising that untargeted genetic/transcriptomic/pharmacologic/metabolomic screens have uncovered changes in sphingolipids and sphingolipid genes/proteins while studying physiological and pathological processes. Consequently, with increasing frequency, both targeted and untargeted mass spectrometry methodologies are being used to conduct sphingolipidomic analyses. Interpretation of such large data sets and design of follow-up experiments can be daunting for investigators with limited expertise with sphingolipids (and sometimes even for someone well-versed in sphingolipidology). Therefore, this review gives an overview of essential elements of sphingolipid structure and analysis, metabolism, functions, and roles in disease, and discusses some of the items to consider when interpreting lipidomics data and designing follow-up investigations.
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Affiliation(s)
- Yusuf A Hannun
- Departments of Biochemistry, Medicine, and the Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
| | - Alfred H Merrill
- School of Biological Sciences and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
| | - Chiara Luberto
- Department of Physiology and Biophysics, and the Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
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14
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Varghese M, Thekkelnaycke R, Soni T, Zhang J, Maddipati K, Singer K. Sex differences in the lipid profiles of visceral adipose tissue with obesity and gonadectomy. J Lipid Res 2025; 66:100803. [PMID: 40245983 DOI: 10.1016/j.jlr.2025.100803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 03/05/2025] [Accepted: 04/10/2025] [Indexed: 04/19/2025] Open
Abstract
In obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral versus subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and postmenopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharolipids and prenol lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic, and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction identified higher omega-6 to omega-3 free fatty acid profile in males and differences in PUFAs-derived prostaglandins, thromboxanes, and leukotrienes. Both obese male and female GWAT stromal vascular fraction showed increased levels of arachidonic acid-derived oxylipins compared to their lean counterparts. Bulk RNA-seq of sorted GWAT AT macrophages highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA-derived mediators with diet and GX emphasize sex differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.
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Affiliation(s)
- Mita Varghese
- Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rajendiran Thekkelnaycke
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA
| | - Tanu Soni
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA
| | - Jiayu Zhang
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA
| | | | - Kanakadurga Singer
- Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
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15
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Vianello E, Beltrami AP, Aleksova A, Janjusevic M, Fluca AL, Corsi Romanelli MM, La Sala L, Dozio E. The Advanced Glycation End-Products (AGE)-Receptor for AGE System (RAGE): An Inflammatory Pathway Linking Obesity and Cardiovascular Diseases. Int J Mol Sci 2025; 26:3707. [PMID: 40332316 PMCID: PMC12028226 DOI: 10.3390/ijms26083707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/31/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
The AGE (advanced glycation end-products)-RAGE (receptor for AGE) system is a pro-inflammatory pathway that contributes to the pathogenesis of obesity and obesity-related cardiovascular disorders (CVD). Circulating AGE and the soluble form of RAGE (sRAGE) has been suggested as a potential biomarker of CVD related to obesity. In this study, we aim to (1) summarize the current knowledge about the role of obesity in the onset and progression of CVD, (2) discuss the role of the AGE-RAGE system as a pathway promoting obesity and linking obesity to CVD, and (3) highlight available strategies for reducing AGE-RAGE system activation and the associated beneficial effects.
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Affiliation(s)
- Elena Vianello
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- Experimental Laboratory for Research on Organ Damage Biomarkers, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
| | - Antonio P. Beltrami
- Department of Medicine, Università degli Studi di Udine, 33100 Udine, Italy;
- Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy
| | - Aneta Aleksova
- Department of Medical Surgical and Health Sciences, Università degli Studi di Trieste, 34129 Trieste, Italy; (A.A.); (M.J.); (A.L.F.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34100 Trieste, Italy
| | - Milijana Janjusevic
- Department of Medical Surgical and Health Sciences, Università degli Studi di Trieste, 34129 Trieste, Italy; (A.A.); (M.J.); (A.L.F.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34100 Trieste, Italy
| | - Alessandra L. Fluca
- Department of Medical Surgical and Health Sciences, Università degli Studi di Trieste, 34129 Trieste, Italy; (A.A.); (M.J.); (A.L.F.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34100 Trieste, Italy
| | - Massimiliano M. Corsi Romanelli
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- Department of Clinical and Experimental Pathology, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
| | - Lucia La Sala
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- IRCCS Multimedica, 20138 Milan, Italy
| | - Elena Dozio
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- Experimental Laboratory for Research on Organ Damage Biomarkers, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
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16
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Brunmaier LAE, Ozdemir T, Walker TW. Angiogenesis: Biological Mechanisms and In Vitro Models. Ann Biomed Eng 2025:10.1007/s10439-025-03721-2. [PMID: 40210793 DOI: 10.1007/s10439-025-03721-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/12/2025]
Abstract
The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.
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Affiliation(s)
- Laura A E Brunmaier
- Nanoscience and Biomedical Engineering Department, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA
| | - Tugba Ozdemir
- Nanoscience and Biomedical Engineering Department, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA
| | - Travis W Walker
- Karen M. Swindler Department of Chemical and Biological Engineering, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA.
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17
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Liu C, Guo Y, Dong Y, Qu Z, Mu Y, Liu B, Wang F, Li Y. Study on the synthesis, characterization, and antitumor mechanism investigation of QZQ-01115 via targeting sphingosine kinase 2. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167829. [PMID: 40216369 DOI: 10.1016/j.bbadis.2025.167829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/23/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025]
Abstract
Sphingosine kinase 2 (SphK2) is an oncogenic enzyme that plays an essential role in the development of oral squamous cell carcinoma (OSCC). Therefore, development of SphK2 inhibitors is of great significance for the treatment of OSCC. In this study, we synthesized a series of thiazolidinediones and screened compounds with good inhibitory activity against CAL-27 using cytotoxicity assay. The compounds were further investigated in vitro using a series of in vitro experiments such as Western blot and qPCR were used to investigate the in vivo anti-tumor mechanisms, and in vivo investigation was applied by using a nude mouse ectopic tumor model. The results showed that four new compounds were successfully synthesized, and among which the compound named QZQ-01115 showed the best inhibitory activity against CAL-27 at the concentration of 5.84 ± 0.042 μM. Further mechanistic studies showed that QZQ-01115 could inhibit the proliferation, migration and invasion of CAL-27 cells at a concentration of 4 μM-6 μM. QZQ-01115 affected the PI3K/AKT signaling pathway by influencing the levels of S1P and ceramides in CAL-27, which in turn affected the mTOR/p70S6K, resulting in the blockage of protein synthesis and the blockage of cell cycle at the G0/G0 level. Apoptosis was promoted by down-regulating Bcl-2 and up-regulating Bax. The in vivo results showed that QZQ-01115 reduced the volume and weight of xenograft tumors in nude mice. The induction of apoptosis by QZQ-01115 was further determined by HE staining and immunohistochemical analysis. These results suggest that QZQ-01115 may be a potential candidate for the treatment of OSCC.
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Affiliation(s)
- Caiyu Liu
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Yaxin Guo
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Yutong Dong
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Zhiqiang Qu
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Yanling Mu
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; National Key Laboratory of Advanced Drug Delivery System, Jinan 250117, China
| | - Bo Liu
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
| | - Fuwen Wang
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; National Key Laboratory of Advanced Drug Delivery System, Jinan 250117, China.
| | - Yan Li
- School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; National Key Laboratory of Advanced Drug Delivery System, Jinan 250117, China.
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18
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Xu D, Dai X, He Q, Mei Z, Zhou Y, Zhao J, Xiong N. Elucidating molecular lipid perturbations in trigeminal neuralgia using cerebrospinal fluid lipidomics. Sci Rep 2025; 15:11777. [PMID: 40189602 PMCID: PMC11973149 DOI: 10.1038/s41598-025-89755-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 02/07/2025] [Indexed: 04/09/2025] Open
Abstract
Trigeminal neuralgia (TN) is a neuropathic facial pain disorder characterized by severe stabbing pain along the trigeminal nerve. While its pathogenesis remains unclear, nerve demyelination and inflammation are likely involved. Current research has primarily focused on various blood-based omics approaches, which do not fully capture the lipid alterations occurring during TN progression in brain. In contrast, our study is the first to investigate cerebrospinal fluid (CSF) lipidomic profiles in TN patients, aiming to elucidate potential disease mechanisms. CSF samples were collected from 22 TN patients and 18 healthy controls, followed by untargeted lipidomic analysis using high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. A pipeline for lipid identification and relative quantification, combined with statistical analysis, revealed 188 lipid species across 21 classes. We found significant upregulation of Cer-NPs, LPCs, PCs, TGs, and OxTGs in TN patients, while stigmasterol hexoside was downregulated. Moderate correlations were observed between lipid species and clinical parameters. These findings highlight considerable CSF lipidome alterations in TN, suggesting roles for nerve demyelination, neuroinflammation, and pain sensitization in its pathogenesis. Our study provides novel insights into lipid targets that may offer therapeutic potential for managing TN.
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Affiliation(s)
- Dongyuan Xu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan, 430071, China
| | - Xuan Dai
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan, 430071, China
| | - Qianwen He
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
| | - Zhimin Mei
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan, 430071, China
| | - Yixuan Zhou
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan, 430071, China
| | - Jingwei Zhao
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan, 430071, China
| | - Nanxiang Xiong
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan, 430071, China.
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Dai CL, Bian XW, Yao XH. Identification of Six Cerebrospinal Fluid Metabolites Causally Associated with Anorexia Nervosa Risk: A Mendelian Randomization Analysis. Int J Mol Sci 2025; 26:3248. [PMID: 40244111 PMCID: PMC11989412 DOI: 10.3390/ijms26073248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Anorexia nervosa (AN) is a severe psychiatric disorder characterized by substantial heritability and a high mortality rate among psychiatric disorders. While cerebrospinal fluid (CSF) metabolomics has emerged as a novel approach to investigating central nervous system pathologies, its specific causal relationship with anorexia nervosa remains to be fully elucidated. Using genome-wide association study (GWAS) summary statistics for human CSF metabolites and AN information from publicly available datasets, we performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method as the primary approach, complemented by sensitivity analyses. Through a comprehensive analysis of 338 CSF metabolites, we identified six metabolites with significant causal relationships with AN risk. 1-stearoyl-2-linoleoyl-gpc (18:0/18:2) (OR = 1.09, 95% CI 1.00-1.18) and alpha-tocopherol (OR = 1.36, 95% CI 1.00-1.83) showed positive associations, increasing AN risk. Conversely, sphingomyelin (d18:1/20:0, d16:1/22:0) (OR = 0.86, 95% CI 0.77-0.95), 2,3-dihydroxy-2-methylbutyrate (OR = 0.92, 95% CI 0.86-0.98), N-acetylhistidine (OR = 0.92, 95% CI 0.86-0.98), and oxalate (ethanedioate) (OR = 0.83, 95% CI 0.73-0.94) had protective effects, reducing AN risk. Sensitivity analyses showed no evidence of horizontal pleiotropy or heterogeneity in the MR results. An MR directionality test and a Steiger filtering test confirmed the absence of reverse causality, thereby substantiating the robustness of our findings. These findings suggest that these CSF metabolites could serve as potential biomarkers for early AN detection and highlight novel therapeutic targets, potentially improving diagnosis and intervention strategies for this challenging disorder.
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Affiliation(s)
- Cheng-Liang Dai
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiu-Wu Bian
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Hong Yao
- Institute of Pathology, Third Military Medical University (Army Medical University), and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China
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20
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Liu H, Chen S, Xiang H, Xiao J, Zhao S, Zhang X, Shu Z, Zhang J, Ouyang J, Liu Q, Quan Q, Fan J, Gao P, Zheng X, Chen AF, Lu H. S1PR3 in hippocampal neurons improves synaptic plasticity and decreases depressive behavior via downregulation of RhoA/ROCK1. Prog Neuropsychopharmacol Biol Psychiatry 2025; 137:111256. [PMID: 39828081 DOI: 10.1016/j.pnpbp.2025.111256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 10/30/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
The study investigates how Sphingosine-1-phosphate receptor 3 (S1PR3) and the Chronic Unpredictable Mild Stress (CUMS) affects depression-like behaviors. The S1P/S1PR3 signaling pathway is known to play a role in mood regulation, but it is not yet fully understood how it is connected to depression. This study looks to further explore this topic. To investigate the effect of CUMS on S1PR3 expression in hippocampus neurons and the synaptic plasticity, we observed animals' behavior with Sucrose Preference Test (SPT), Forced Swim Test (FST) and Open Field Test (OFT). Combining molecular and histological analysis, we investigated the S1PR3 expression, the change in synapse density, and synaptic structure change in the hippocampus. The CUMS caused a significant decrease in the S1PR3 expression, the density of the synaptic spine and synaptic ultrastructure change in mice. On the other hand, over-expression of S1PR3 by adeno-associated virus (AAV) in hippocampal neurons alleviated the depressive-like behaviors and synaptic deficits observed in stress-susceptible animals. Furthermore, the depressive-like phenotype and synaptic impairments were normalized by the expression of RhoA, implicating the RhoA/ROCK1 pathway in S1PR3 actions. Collectively, our findings provide strong evidence that S1PR3 plays a key role in hippocampal synaptic plasticity and depression and that modulation of S1PR3/RhoA/ROCK1 signaling may offer a novel therapeutic strategy for MDD. This study not only underscores the therapeutic potential of S1PR3 but also provides novel insights into the molecular mechanisms underlying depression.
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Affiliation(s)
- Huiqin Liu
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China
| | - Hong Xiang
- Center for Experimental Medicine, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jie Xiao
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Shaoli Zhao
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiao Zhang
- Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China
| | - Zhihao Shu
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jing Zhang
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jie Ouyang
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Quanjun Liu
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Qisheng Quan
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jianing Fan
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Peng Gao
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xinru Zheng
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Alex F Chen
- Center for Experimental Medicine, The Third Xiangya Hospital of Central South University, Changsha, China; Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongwei Lu
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China.
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21
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Sivanandham S, Sivanandham R, Xu C, Symmonds J, Sette P, He T, Funderburg N, Abdel-Mohsen M, Landay A, Apetrei C, Pandrea I. Plasma lipidomic alterations during pathogenic SIV infection with and without antiretroviral therapy. Front Immunol 2025; 16:1475160. [PMID: 40129985 PMCID: PMC11931036 DOI: 10.3389/fimmu.2025.1475160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 02/05/2025] [Indexed: 03/26/2025] Open
Abstract
Introduction Lipid profiles change in human immunodeficiency virus (HIV) infection and correlate with inflammation. Lipidomic alterations are impacted by multiple non-HIV-related behavioral risk factors; thus, use of animal models in which these behavioral factors are controlled may inform on the specific lipid changes induced by simian immunodeficiency virus (SIV) infection and/or antiretroviral therapy (ART). Methods Using ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy, we assessed and compared (ANOVA) longitudinal lipid changes in naïve and ART-treated SIV-infected pigtailed macaques (PTMs). Key parameters of infection (IL-6, TNFa, D-dimer, CRP and CD4+ T cell counts) were correlated (Spearman) with lipid concentrations at critical time points of infection and treatment. Results Sphingomyelins (SM) and lactosylceramides (LCER) increased during acute infection, returning to baseline during chronic infection; Hexosylceramides (HCER) increased throughout infection, being normalized with prolonged ART; Phosphatidylinositols (PI) and lysophosphatidylcholines (LPC) decreased with SIV infection and did not return to normal with ART; Phosphatidylethanolamines (PE), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC) were unchanged by SIV infection, yet significantly decreased throughout ART. Specific lipid species (SLS) were also substantially modified by SIV and/or ART in most lipid classes. In conclusion, using a metabolically controlled model, we identified specific lipidomics signatures of SIV infection and/or ART, some of which were similar to people living with HIV (PWH). Many SLS were identical to those involved in development of organ dysfunctions encountered in virally suppressed individuals. Lipid changes also correlated with markers of disease progression, inflammation and coagulation. Discussion Our data suggest that lipidomic profile alterations contribute to residual systemic inflammation and comorbidities seen in HIV/SIV infections and therefore may be used as biomarkers of SIV/HIV comorbidities. Further exploration into the benefits of interventions targeting dyslipidemia is needed for the prevention HIV-related comorbidities.
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Affiliation(s)
- Sindhuja Sivanandham
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ranjit Sivanandham
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Cuiling Xu
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jen Symmonds
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Paola Sette
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Tianyu He
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Nicholas Funderburg
- Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH, United States
| | - Mohamed Abdel-Mohsen
- Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA, United States
| | - Alan Landay
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Cristian Apetrei
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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22
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Jang Y. Bioactive Compounds Targeting Dihydroceramide and Their Therapeutic Potential in Cancer Treatment. Cancers (Basel) 2025; 17:909. [PMID: 40075756 PMCID: PMC11898591 DOI: 10.3390/cancers17050909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/23/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Dihydroceramide (dhCer) was previously considered an inactive precursor of ceramide, a well-known sphingoid base involved in regulating apoptosis and cell death. However, recent studies have shown that dhCer plays a crucial role in various important cellular responses. In this review, we summarize the latest findings on the biological functions of dhCer and the enzymes involved in its biosynthesis. We specifically focus on the emerging evidence implicating dhCer in cancer, as well as its role in regulating key processes such as cell cycle arrest, autophagy, apoptosis, ER stress, and oxidative stress. Furthermore, we discuss bioactive compounds that can modulate dhCer levels in cancer cells, highlighting their potential therapeutic applications in counteracting cancer progression. This review emphasizes the growing recognition of dhCer as a bioactive sphingolipid metabolite with significant potential for cancer therapy.
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Affiliation(s)
- Yumi Jang
- Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea; ; Tel.: +82-52-259-2374
- Basic-Clinical Convergence Research Institute, University of Ulsan, Ulsan 44610, Republic of Korea
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23
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Xiong Y, Li W, Jin S, Wan S, Wu S. Inflammation in glomerular diseases. Front Immunol 2025; 16:1526285. [PMID: 40103820 PMCID: PMC11913671 DOI: 10.3389/fimmu.2025.1526285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/12/2025] [Indexed: 03/20/2025] Open
Abstract
The structural and functional integrity of glomerular cells is critical for maintaining normal kidney function. Glomerular diseases, which involve chronic histological damage to the kidney, are related to injury to glomerular cells such as endothelial cells, mesangial cells (MCs), and podocytes. When faced with pathogenic conditions, these cells release pro-inflammatory cytokines such as chemokines, inflammatory factors, and adhesion factors. These substances interact with glomerular cells through specific inflammatory pathways, resulting in damage to the structure and function of the glomeruli, ultimately causing glomerular disease. Although the role of inflammation in chronic kidney diseases is well known, the specific molecular pathways that result in glomerular diseases remain largely unclear. For a long time, it has been believed that only immune cells can secrete inflammatory factors. Therefore, targeted therapies against immune cells were considered the first choice for treating inflammation in glomerular disease. However, emerging research indicates that non-immune cells such as glomerular endothelial cells, MCs, and podocytes can also play a role in renal inflammation by releasing inflammatory factors. Similarly, targeted therapies against glomerular cells should be considered. This review aims to uncover glomerular diseases related to inflammation and pathways in glomerular inflammation, and for the first time summarized that non-immune cells in the glomerulus can participate in glomerular inflammatory damage by secreting inflammatory factors, providing valuable references for future strategies to prevent and treat glomerular diseases. More importantly, we emphasized targeted glomerular cell therapy, which may be a key direction for the future treatment of glomerular diseases.
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Affiliation(s)
- Yongqing Xiong
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Wei Li
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Songzhi Jin
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Shujing Wan
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Suzhen Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
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24
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Chen D, Bi X, Feng Q, Sun Y. Supplementation with Lentil ( Lens culinaris) Hull Soluble Dietary Fiber Ameliorates Sodium Dextran Sulfate-Induced Colitis and Behavioral Deficits via the Gut-Brain Axis. Foods 2025; 14:870. [PMID: 40077572 PMCID: PMC11898428 DOI: 10.3390/foods14050870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 02/21/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
In this study, the impact of lentil hull soluble dietary fibers (SDFs) on colitis and behavioral deficits in mice was assessed. Structural characterizations of SDFs confirmed that cellulase-modified soluble dietary fiber exhibited better physicochemical properties: more porous microstructure; similar polysaccharide structure; more stable particle size distribution; higher crystallinity; better adsorption capacity; and lower viscosity. Additionally, we explored its potential cognitive benefits via the gut-brain axis by behavioral tests, histopathology, 16S rRNA sequencing, gas chromatography and metabolomics analysis. The results showed that SDFs significantly improved inflammatory symptoms in colon and brain and cognitive behaviors. LSDF had better efficacy than HSDF. LSDF intervention decreased the harmful bacteria abundance (Bacteroides, Flexispira and Escherichia, etc.) and increased beneficial bacteria abundance (Aggregatibacter and Helicobacter, etc.). LSDF also affected brain metabolites through the sphingolipid metabolism. Spearman correlation analysis showed that there was a positive correlation between harmful bacteria with inflammatory factors (LPS, IL-1β, IL-6, and TNF-α, etc.) and sphingolipid metabolites, while beneficial bacteria were positively correlated with brain-derived neurotrophic factor (BDNF), IL-10, and cognitive behavior. This study highlights the value of SDFs in future diet-based therapeutic strategies targeting gut-brain interactions.
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Affiliation(s)
- Dongying Chen
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China;
| | - Xin Bi
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China;
| | - Qian Feng
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Yong Sun
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China;
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25
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Xuan X, Huang Z, Kong Z, Li R, Li J, Huang H. GENETIC INSIGHTS INTO SEPSIS: MENDELIAN RANDOMIZATION ANALYSIS OF CEREBROSPINAL FLUID METABOLITES. Shock 2025; 63:379-384. [PMID: 39454631 DOI: 10.1097/shk.0000000000002494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2024]
Abstract
ABSTRACT Background: Sepsis, a life-threatening response to infection leading to systemic inflammation and organ dysfunction, has been hypothesized to be influenced by metabolic alterations in cerebrospinal fluid (CSF). Despite extensive research, the specific metabolic pathways contributing to sepsis remain unclear. This study aims to elucidate the causal relationships between CSF metabolites and sepsis risk using Mendelian randomization (MR), offering insights that could lead to novel therapeutic strategies. Methods: We conducted a two-sample MR analysis using genetic variants as instrumental variables (IVs) to investigate 338 CSF metabolites identified through a genome-wide association study. Data on sepsis-related outcomes were extracted from the genome-wide association study catalog encompassing 486,484 individuals of European descent. IVs were rigorously selected based on stringent genetic association and linkage disequilibrium criteria. Statistical analyses, including inverse variance weighting (IVW) and weighted median methods, were performed using the "TwoSampleMR" package in R software, supplemented by comprehensive sensitivity analyses to ensure the robustness of our findings. Results: Our analysis identified 19 CSF metabolites causally associated with sepsis risk. Notably, metabolites such as 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) and 2-hydroxyglutarate showed significant negative correlations with sepsis risk. The reverse MR analysis further revealed that sepsis could negatively impact certain CSF metabolite levels, particularly ribonate, suggesting a bidirectional relationship. These relationships were substantiated by rigorous statistical testing and sensitivity analyses confirming the absence of horizontal pleiotropy and the stability of our results across various MR methods. Conclusions: This study demonstrates significant causal associations between specific CSF metabolites and the risk of developing sepsis, highlighting the potential for these metabolites to serve as biomarkers or therapeutic targets. The bidirectional nature of these findings also suggests that sepsis itself may alter metabolic profiles, offering further avenues for intervention.
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Affiliation(s)
- Xin Xuan
- Department of Emergency Medicine, Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, Guangdong, China
| | - Zhihao Huang
- Department of Otorhinolaryngology, Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, Guangdong, China
| | - Zhiqian Kong
- Department of Emergency Medicine, Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, Guangdong, China
| | - Ruoyu Li
- Department of Intensive Care Unit, Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, Guangdong, China
| | - Jianfeng Li
- Department of Emergency Medicine, Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, Guangdong, China
| | - Haiyan Huang
- Department of Internal Medicine of Chinese Medicine, Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, Guangdong, China
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Wan J, Hu Z, Zhu H, Li J, Zheng Z, Deng Z, Lu J, Chen Y, Chen GL, Zeng B, Zhang J, Duan J. The essential role of sphingolipids in TRPC5 ion channel localization and functionality within lipid rafts. Pharmacol Res 2025; 213:107648. [PMID: 39923924 DOI: 10.1016/j.phrs.2025.107648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/06/2025] [Accepted: 02/05/2025] [Indexed: 02/11/2025]
Abstract
Sphingolipids are critical components of cellular membranes that play a pivotal role in modulating ion channel function by forming lipid rafts that stabilize and localize these channels. These lipids regulate membrane fluidity and protein-lipid interactions, directly influencing ion channel activity, trafficking, and signaling pathways essential for maintaining cellular homeostasis. Despite their fundamental role, the impact of sphingolipids on ion channel functionality, particularly within the nervous system, remains insufficiently understood. This study addresses this gap by examining the influence of sphingolipids on transient receptor potential canonical 5 (TRPC5), a key brain ion channel involved in sensory transduction and linked to conditions such as obesity, anxiety, and postpartum depression when disrupted. In this study, we demonstrate that TRPC5 is localized within lipid rafts. Inhibition of sphingolipid synthesis through myrioncin (Myr), the sphingomyelin synthase 2 inhibitor Ly93, or D,L-erythro-PDMP hydrochloride (PMDP) significantly disrupts TRPC5 localization at the plasma membrane. Treatment with lipid raft disruptors methyl-β-cyclodextrin (MCD) or sphingomyelin phosphodiesterase 3 (SMPD3), in conjunction with sphingolipid synthesis inhibitors, led to decreased TRPC5-mediated calcium flux and currents. This highlights the critical importance of TRPC5 localization in lipid rafts for its functionality. Furthermore, LC-MS/MS-based sphingolipidomics has shown that a balanced sphingolipid profile is crucial for channel function. Alterations in sphingolipid metabolism, especially the deficiency of sphingomyelin and glycosphingolipids, may primarily disrupt lipid raft structure. Interactions between amino acid residues with phenyl ring side chains and lipids at the inner and outer plasma membrane edges serve as 'fixators', anchoring TRPC5 channels within lipid rafts. Given the structural similarities among TRP channels, we propose that sphingolipid metabolic homeostasis may universally influence TRP channel activity, potentially explaining diverse neurological disorder phenotypes associated with sphingolipid metabolism disruptions.
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Affiliation(s)
- Junliang Wan
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Zhenying Hu
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Huaiyi Zhu
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Jingyi Li
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Ziyuan Zheng
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Zhitao Deng
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Junyan Lu
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Yu Chen
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China
| | - Gui-Lan Chen
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Bo Zeng
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Jin Zhang
- School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330031, China
| | - Jingjing Duan
- Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi 330031, China.
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Zhang H, Li Y, Li L. Blood metabolites reflect the effect of gut microbiota on differentiated thyroid cancer: a Mendelian randomization analysis. BMC Cancer 2025; 25:368. [PMID: 40022019 PMCID: PMC11869591 DOI: 10.1186/s12885-025-13598-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 01/27/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Studies have linked gut microbiome and differentiated thyroid cancer (DTC). However, their causal relationships and potential mediating factors have not been well defined. Our study investigated the causal relationships between the gut microbiome, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), as well as the mediating effect of potential blood metabolites, using genetic approaches. METHODS Leveraging the summary statistics of gut microbial taxa, blood metabolites, PTC and FTC from the largest genome-wide association studies (GWAS) to date, we applied the bidirectional and mediation Mendelian randomization (MR) design. The multivariable MR approach based on Bayesian model averaging (MR-BMA) was used to prioritize the most likely causal taxa. Furthermore, metabolic pathway analysis was performed via the web-based Metaconflict 4.0. RESULTS After sensitivity analyses, we identified 4 taxa, 19 blood metabolites, and 5 gut bacterial pathways were causally associated with PTC. Similarly, 3 taxa, 31 blood metabolites, and 3 gut bacterial pathways were found to be causally associated with FTC, with 2 blood metabolites exhibiting bidirectional causal relationships. Metabolic pathway analysis revealed 8 significant pathways in PTC and FTC. MR-BMA analysis pinpointed species Bifidobacterium longum as the primary causal taxon for PTC and genus Bacteroides for FTC. The mediation MR analysis showed that sphingomyelin (d18:2/23:0, d18:1/23:1, d17:1/24:1) and 2-hydroxysebacate mediated the causal effects of specific gut microbiota on PTC and FTC, respectively. CONCLUSION The study suggested a causal relationship between several gut microbial taxa and DTC, and that specific blood metabolites might mediate this relationship.
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Affiliation(s)
- Hanfei Zhang
- Department of Nuclear Medicine, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, China
| | - Yuhao Li
- Department of Nuclear Medicine, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, China
| | - Lin Li
- Department of Nuclear Medicine, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, China.
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Le Goff W, Bourron O, Materne C, Galier S, Phan F, Tan-Chen S, Guillas I, Hartemann A, Salem JE, Redheuil A, Foufelle F, Le Stunff H, Hajduch E, Guerin M. Inverse relationship between circulating sphingosine-1-phosphate and precursor species and coronary artery calcification score in type 2 diabetes. Cardiovasc Diabetol 2025; 24:85. [PMID: 39984928 PMCID: PMC11846453 DOI: 10.1186/s12933-025-02624-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/31/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Sphingosine 1-phosphate (S1P) is a key mediator of lipid signaling with strong immunomodulatory and anti-inflammatory effects. Circulating S1P levels including S1P in high-density lipoproteins (HDL) were demonstrated to be inversely associated with cardiovascular diseases (CVD). However, no studies are available regarding a potential implication of S1P on the risk of CVD in type 2 diabetes (T2D). The objective of this study is to determine if the increased CVD risk in T2D may involve an alteration of circulating S1P species as well as their precursors. METHODS A total of 168 and 31 patients with T2D (154 men and 45 women) with available Coronary artery calcification (CAC) score from the DIACART and CERABIAB cohorts, respectively, were included in the study. Quantification of S1P species and their precursors was carried out by LC-MS/MS in plasma and isolated HDL. CAC score was modeled as a binary variable (0/1 below or equal/above 100) using CAC < 100 for reference. S1P species or precursors were modeled as binary variables dichotomized at the median (0/1: below or equal/above the median). The relationships between S1P species and CAC score modeled as a binary variable (below or equal/above 100) was evaluated by linear regression analyses. In vitro experiments were conducted to evaluate the contribution of HDL-S1P content on anti-inflammatory properties of HDL particles. RESULTS Multivariate analysis revealed that plasma S1P levels, especially d18:1-S1P, and sphingosine in HDL were inversely associated with the high risk of CVD (CAC > 100) in patients with T2D. Clustering of HDL according to their concentration in S1P species and their precursors revealed that S1P-impoverished HDL is a major feature of patients with a CAC > 100. In vitro analysis of monocyte adhesion and inflammation in human umbilical vein endothelial cells as well as inflammatory phenotype of human macrophages demonstrated that low HDL-S1P exhibited impaired anti-inflammatory properties in comparison to high HDL-S1P. CONCLUSION This study unraveled that circulating S1P and their precursors are biomarkers of coronary atherosclerosis in T2D, which may underlie the lower abundance of S1P and anti-inflammatory activities of HDL. Trial registration ClinicalTrials.gov number, NCT02431234.
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Affiliation(s)
- Wilfried Le Goff
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Olivier Bourron
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
- Diabetology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Clément Materne
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Sophie Galier
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Franck Phan
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
- Diabetology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Sophie Tan-Chen
- Centre de Recherche Des Cordeliers, INSERM, Sorbonne Université, Paris, France
| | - Isabelle Guillas
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Agnès Hartemann
- Diabetology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Joe-Elie Salem
- AP-HP, INSERM, CIC-1901, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Alban Redheuil
- Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, ICT Cardiovascular and Thoracic Imaging Unit, Assistance Publique‑Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Fabienne Foufelle
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Hervé Le Stunff
- CNRS UMR 9197, Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, Saclay, France.
| | - Eric Hajduch
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France.
| | - Maryse Guerin
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France.
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Oeztuerk M, Herebian D, Dipali K, Hentschel A, Rademacher N, Kraft F, Horvath R, Distelmaier F, Meuth SG, Ruck T, Schara-Schmidt U, Roos A. Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5. Front Mol Neurosci 2025; 18:1548255. [PMID: 40051915 PMCID: PMC11882581 DOI: 10.3389/fnmol.2025.1548255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/29/2025] [Indexed: 03/09/2025] Open
Abstract
Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions. This study employs a multi-omics approach to investigate the biochemical impact of AFG3L2 mutations in immortalized lymphoblastoid cell lines derived from a patient with biallelic variants leading to spastic ataxia (SPAX5). Our proteomic analysis revealed AFG3L2 impairment, with significant dysregulation of proteins critical for mitochondrial function, cytoskeletal integrity, and cellular metabolism. Specifically, disruptions were observed in mitochondrial dynamics and calcium homeostasis, alongside downregulation of key proteins like COX11, a copper chaperone for complex IV assembly, and NFU1, an iron-sulfur cluster protein linked to spastic paraparesis and infection-related worsening. Lipidomic analysis highlighted substantial alterations in lipid composition, with significant decreases in sphingomyelins, phosphatidylethanolamine, and phosphatidylcholine, reflecting disruptions in lipid metabolism and membrane integrity. Metabolomic profiling did not reveal any significant findings. Our comprehensive investigation into loss of functional AFG3L2 elucidates a pathophysiology extending beyond mitochondrial proteostasis, implicating a wide array of cellular processes. The findings reveal substantial cellular disturbances at multiple levels, contributing to neurodegeneration through disrupted mitochondrial respiratory chain, calcium homeostasis, cytoskeletal integrity, and altered lipid homeostasis. This study underscores the complexity of SPAX5 pathophysiology and the importance of multi-omics approaches in developing effective strategies to address the impact of loss of functional AFG3L2. Our data also highlight the value of immortalized lymphoblastoid cells as a tool for pre-clinical testing and research, offering a detailed biochemical fingerprint that enhances our understanding of SPAX5 and identifies potential areas for further investigation.
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Affiliation(s)
- Menekse Oeztuerk
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
- Department of Neurology, BG-University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
- Heimer Institute for Muscle Research, BG-University Hospital Bergmannsheil, Bochum, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Kale Dipali
- Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V., Dortmund, Germany
| | - Andreas Hentschel
- Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V., Dortmund, Germany
| | - Nina Rademacher
- Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany
| | - Florian Kraft
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany
| | - Rita Horvath
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Felix Distelmaier
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Sven G. Meuth
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Tobias Ruck
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
- Department of Neurology, BG-University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
- Heimer Institute for Muscle Research, BG-University Hospital Bergmannsheil, Bochum, Germany
| | - Ulrike Schara-Schmidt
- Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany
| | - Andreas Roos
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
- Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany
- Brain and Mind Research Institute, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
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Chen Q, Shan D. Letter to the Editor From Chen and Shan: "Moderate-Intensity Combined Training Induces Lipidomic Changes in Individuals With Obesity and Type 2 Diabetes". J Clin Endocrinol Metab 2025; 110:e911. [PMID: 39351773 DOI: 10.1210/clinem/dgae684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Indexed: 02/19/2025]
Affiliation(s)
- Qingyan Chen
- The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
- Zhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Department of Geriatrics, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang 310006, China
| | - Dan Shan
- Clinical Science Institute, University Hospital Galway, Newcastle Road, Galway, H91 YR71, Ireland
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Xia F, Santacruz A, Wu D, Bertho S, Fritz E, Morales-Sosa P, McKinney S, Nowotarski SH, Rohner N. Reproductive Adaptation of Astyanax mexicanus Under Nutrient Limitation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.13.638191. [PMID: 40027826 PMCID: PMC11870393 DOI: 10.1101/2025.02.13.638191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Reproduction is a fundamental biological process for the survival and continuity of species. Examining changes in reproductive strategies offers valuable insights into how animals have adapted their life histories to different environments. Since reproduction is one of the most energy-intensive processes in female animals, nutrient scarcity is expected to interfere with the ability to invest in gametes. Lately, a new model to study adaptation to nutrient limitation has emerged; the Mexican tetra Astyanax mexicanus . This fish species exists as two different morphs, a surface river morph and a cave-dwelling morph. The cave-dwelling morph has adapted to the dark, biodiversity, and nutrient-limited cave environment and consequently evolved an impressive starvation resistance. However, how reproductive strategies have adapted to nutrient limitations in this species remains poorly understood. Here, we compared breeding activities and maternal contributions between laboratory-raised surface fish and cavefish. We found that cavefish produce different clutch sizes of eggs with larger yolk compared to surface fish, indicating a greater maternal nutrient deposition in cavefish embryos. To systematically characterize yolk compositions, we used untargeted proteomics and lipidomics approaches to analyze protein and lipid profiles in 2-cell stage embryos and found an increased proportion of sphingolipids in cavefish compared to surface fish. Additionally, we generated transcriptomic profiles of surface fish and cavefish ovaries using a combination of single cell and bulk RNA sequencing to examine differences in maternal contribution. We found that genes essential for hormone regulation were upregulated in cavefish follicular somatic cells compared to surface fish. To evaluate whether these differences contribute to their reproductive abilities under natural-occurring stress, we induced breeding in starved female fish. Remarkably, cavefish maintained their ability to breed under starvation, whereas surface fish largely lost this ability. We identified insulin-like growth factor 1a receptor ( igf1ra ) as a potential candidate gene mediating the downregulation of ovarian development genes, potentially contributing to the starvation-resistant fertility of cavefish. Taken together, we investigated the female reproductive strategies in Astyanax mexicanus , which will provide fundamental insights into the adaptations of animals to environments with extreme nutrient deficit.
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Mahmud I, Chan WK, Yannell K, Simmermaker C, Van de Bittner G, Wu L, Chan D, Mohsin SB, Liu Y, Sausen J, Weinstein JN, Lorenzi PL. Single-sample, multi-omic mass spectrometry for investigating mechanisms of drug toxicity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.13.638125. [PMID: 40027784 PMCID: PMC11870395 DOI: 10.1101/2025.02.13.638125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Poor therapeutic index is a principal cause of drug attrition during development. A case in point is L-asparaginase (ASNase), an enzyme-drug approved for treatment of pediatric acute lymphoblastic leukemia (ALL) but too toxic for adults. To elucidate potentially targetable mechanisms for mitigation of ASNase toxicity, we performed multi-omic profiling of the response to sub-toxic and toxic doses of ASNase in mice. We collected whole blood samples longitudinally, processed them to plasma, and extracted metabolites, lipids, and proteins from a single 20-µL plasma sample. We analyzed the extracts using multiple reaction monitoring (MRM) of 500+ water soluble metabolites, 750+ lipids, and 375 peptides on a triple quadrupole LC-MS/MS platform. Metabolites, lipids, and peptides that were modulated in a dose-dependent manner appeared to converge on antioxidation, inflammation, autophagy, and cell death pathways, prompting the hypothesis that inhibiting those pathways might decrease ASNase toxicity while preserving anticancer activity. Overall, we provide here a streamlined, three-in-one LC-MS/MS workflow for targeted metabolomics, lipidomics, and proteomics and demonstrate its ability to generate new insights into mechanisms of drug toxicity.
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Hagn G, Cho A, Zila N, Sterniczky B, Jantschitsch C, Dong D, Bileck A, Koren M, Paulitschke P, Mohr T, Knobler R, Weninger WP, Gerner C, Paulitschke V. Extracorporeal photopheresis induces the release of anti-inflammatory fatty acids and oxylipins and suppresses pro-inflammatory sphingosine-1-phosphate. Inflamm Res 2025; 74:40. [PMID: 39945859 PMCID: PMC11825557 DOI: 10.1007/s00011-025-02007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 01/09/2025] [Accepted: 02/07/2025] [Indexed: 02/16/2025] Open
Abstract
AIMS Extracorporeal photopheresis (ECP) is a UVA-based phototherapy of whole blood and well established as a first line or combination therapy for the treatment of cutaneous T-cell lymphoma, systemic sclerosis, graft-versus-host disease and is used to control organ transplant rejection. While the proapoptotic activity on activated T-cells is evident, the clinical efficacy of this treatment also appears to be based on other yet unknown mechanisms. In this study, we aimed to identify novel mechanisms of ECP regardless of the patient's background situation. MAIN METHODS To better understand the immediate consequences of ECP, we analyzed blood plasma of patients with different ECP indications immediately before and after treatment with regard to proteins and lipid mediators. KEY FINDINGS While proteome profiling identified substantial inter-individual differences in the protein composition, no significant alteration was detectable upon treatment. In contrast, several fatty acids and lipid mediators were found to be significantly altered by ECP. Remarkably, upregulated lipid mediators including polyunsaturated fatty acids, 12-HEPE and 13-OxoODE have been described to be anti-inflammatory, while the downregulated molecules sphingosine-1-phosphate (S1P) and stearic acid are potent pro-inflammatory mediators. A selective sphingosine-1-phosphate-1 receptor (S1P1) modulator AUY954, which decreases S1P1 and experimentally reduces transplant rejection in vivo, showed greater anti-proliferative activity in human lung fibroblasts from COPD patients compared to normal lung fibroblasts, confirming that this pathway may be important in ECP and its mode of action. SIGNIFICANCE AND OUTLOOK In conclusion, we suggest that the ECP-induced changes in lipid mediators may contribute to the remarkable anti-inflammatory effects of the treatment. Depending on their lipid status, patients may benefit from novel treatment regimens combining ECP with lipid modulators. This could be used for the prevention of transplant organ rejection, the treatment of acute or chronic GvHD or transplant organ rejection and the long-term treatment of various skin diseases. This study uncovers novel mechanisms of ECP, that can be used to establish clinically relevant lipid profiles of patients to support patient stratification, predictive or prognostic purposes and thus personalized medical care in the framework of PPPM practice. A combination with S1P modulators may therefore have beneficial effects.
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Affiliation(s)
- Gerhard Hagn
- Department of Analytical Chemistry, University of Vienna, Währinger Street 38, 1090, Vienna, Austria
| | - Ara Cho
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Nina Zila
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Department Health Sciences, Section Biomedical Science, University of Applied Sciences FH Campus Wien, Vienna, Austria
| | - Barbara Sterniczky
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Christian Jantschitsch
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Dexin Dong
- Department of Analytical Chemistry, University of Vienna, Währinger Street 38, 1090, Vienna, Austria
| | - Andrea Bileck
- Department of Analytical Chemistry, University of Vienna, Währinger Street 38, 1090, Vienna, Austria
- Joint Metabolome Facility, University and Medical University of Vienna, Vienna, Austria
| | | | | | - Thomas Mohr
- Department of Analytical Chemistry, University of Vienna, Währinger Street 38, 1090, Vienna, Austria
| | - Robert Knobler
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Wolfgang Peter Weninger
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Christopher Gerner
- Department of Analytical Chemistry, University of Vienna, Währinger Street 38, 1090, Vienna, Austria.
- Joint Metabolome Facility, University and Medical University of Vienna, Vienna, Austria.
| | - Verena Paulitschke
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
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Cao X, Wu X, Zhao L, Zheng J, Jin X, Hao X, Winderickx J, Liu S, Chen L, Liu B. Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids. eLife 2025; 12:RP92180. [PMID: 39927758 PMCID: PMC11810108 DOI: 10.7554/elife.92180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025] Open
Abstract
Due to proteostasis stress induced by aging or disease, misfolded proteins can form toxic intermediate species of aggregates and eventually mature into less toxic inclusion bodies (IBs). Here, using a yeast imaging-based screen, we identified 84 potential synphilin-1 (SY1) IB regulators and isolated the conserved sphingolipid metabolic components in the most enriched groups. Furthermore, we show that, in both yeast cells and mammalian cells, SY1 IBs are associated with mitochondria. Pharmacological inhibition of the sphingolipid metabolism pathway or knockout of its key genes results in a delayed IB maturation and increased SY1 cytotoxicity. We postulate that SY1 IB matures by association with the mitochondrion membrane, and that sphingolipids stimulate the maturation via their membrane-modulating function and thereby protecting cells from SY1 cytotoxicity. Our findings identify a conserved cellular component essential for IB maturation and suggest a mechanism by which cells may detoxify the pathogenic protein aggregates through forming mitochondrion-associated IBs.
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Affiliation(s)
- Xiuling Cao
- State Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityHangzhouChina
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Xiang Wu
- State Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityHangzhouChina
| | - Lei Zhao
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Ju Zheng
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
- Functional Biology, KU LeuvenLeuvenBelgium
| | - Xuejiao Jin
- State Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityHangzhouChina
| | - Xinxin Hao
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | | | - Shenkui Liu
- State Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityHangzhouChina
| | - Lihua Chen
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
- Guangzhou National Laboratory, GuangzhouGuangdongChina
| | - Beidong Liu
- State Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityHangzhouChina
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
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Rahman MA, Datta S, Lakkakula H, Koka S, Boini KM. Acid Sphingomyelinase and Ceramide Signaling Pathway Mediates Nicotine-Induced NLRP3 Inflammasome Activation and Podocyte Injury. Biomedicines 2025; 13:416. [PMID: 40002829 PMCID: PMC11852453 DOI: 10.3390/biomedicines13020416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/23/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Recent studies have shown that Nlrp3 inflammasome activation is importantly involved in podocyte dysfunction induced by nicotine. The present study was designed to test whether acid sphingomyelinase (Asm) and ceramide signaling play a role in mediating nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte damage. Methods and Results: Nicotine treatment significantly increased the Asm expression and ceramide production compared to control cells. However, prior treatment with amitriptyline, an Asm inhibitor significantly attenuated the nicotine-induced Asm expression and ceramide production. Confocal microscopic and biochemical analyses showed that nicotine treatment increased the colocalization of NLRP3 with Asc, Nlrp3 vs. caspase-1, IL-1β production, caspase-1 activity, and desmin expression in podocytes compared to control cells. Pretreatment with amitriptyline abolished the nicotine-induced colocalization of NLRP3 with Asc, Nlrp3 with caspase-1, IL-1β production, caspase-1 activity and desmin expression. Immunofluorescence analyses showed that nicotine treatment significantly decreased the podocin expression compared to control cells. However, prior treatment with amitriptyline attenuated the nicotine-induced podocin reduction. In addition, nicotine treatment significantly increased the cell permeability, O2 production, and apoptosis compared to control cells. However, prior treatment with amitriptyline significantly attenuated the nicotine-induced cell permeability, O2 production and apoptosis in podocytes. Conclusions: Asm is one of the important mediators of nicotine-induced inflammasome activation and podocyte injury. Asm may be a therapeutic target for the treatment or prevention of glomerulosclerosis associated with smoking.
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Affiliation(s)
- Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Martin Luther King Blvd, Houston, TX 77204, USA (H.L.)
| | - Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Martin Luther King Blvd, Houston, TX 77204, USA (H.L.)
| | - Harini Lakkakula
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Martin Luther King Blvd, Houston, TX 77204, USA (H.L.)
- Novi High School, Novi, MI 48375, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A & M University, Kingsville, TX 78363, USA
| | - Krishna M. Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Martin Luther King Blvd, Houston, TX 77204, USA (H.L.)
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Ouyang Z, Tan Z, Ali U, Zhang Y, Li B, Yao X, Yang B, Guo L. Ceramide-1-phosphate enhances defense responses against Sclerotinia sclerotiorum in Brassica napus. PLANT PHYSIOLOGY 2025; 197:kiae649. [PMID: 39928582 DOI: 10.1093/plphys/kiae649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 10/27/2024] [Indexed: 02/12/2025]
Abstract
Sclerotinia stem rot caused by Sclerotinia sclerotiorum is one of the most severe diseases affecting the growth and production of Brassica napus. Sphingolipid metabolism plays a crucial role in plant response to pathogens. In this study, we show that ceramide kinase (CERK) is significantly induced during S. sclerotiorum infection to produce higher levels of ceramide-1-phosphate (C1P) in B. napus. The balance between ceramide (Cer) and C1P affects plant resistance to S. sclerotiorum, with CERK mutant lines exhibiting greater susceptibility to S. sclerotiorum and CERK overexpression lines showing enhanced resistance to this pathogen. Moreover, we identified candidate C1P-binding proteins by proteomic analysis and determined that C1P binds to and promotes the activity of a Gly-Asp-Ser-Leu lipase protein involved in B. napus resistance to S. sclerotiorum infection. In conclusion, our results indicate that C1P plays a key role in S. sclerotiorum resistance through metabolic regulation and signal transduction in B. napus.
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Affiliation(s)
- Zhewen Ouyang
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China
| | - Zengdong Tan
- Yazhouwan National Laboratory, Sanya 572025, China
| | - Usman Ali
- State Key Laboratory of Wheat and Maize Crop Science, Henan Agricultural University, Zhengzhou 450046, China
| | - Ying Zhang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
- The Provincial Key Lab of Plant Pathology of Hubei Province, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Bo Li
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
- The Provincial Key Lab of Plant Pathology of Hubei Province, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Xuan Yao
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China
- Yazhouwan National Laboratory, Sanya 572025, China
| | - Bao Yang
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China
- Department of Biology, University of Missouri, St. Louis, MO 63121, USA
- Donald Danforth Plant Science Center, St. Louis, MO 63132, USA
| | - Liang Guo
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China
- Yazhouwan National Laboratory, Sanya 572025, China
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Yin K, Ding L, Li X, Zhang Y, Song S, Cao L, Deng R, Li M, Li Z, Xia Q, Zhao D, Li X, Wang Z. Causal role of plasma liposome in diabetic retinopathy: mendelian randomization (MR) study. Diabetol Metab Syndr 2025; 17:47. [PMID: 39920782 PMCID: PMC11803952 DOI: 10.1186/s13098-025-01612-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 01/24/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Research indicates that there may be an association between plasma lipidome levels and the incidence of diabetic retinopathy (DR) in patients. However, the potential causality of this relationship is yet to be determined. To investigate this matter further, we employed a two-sample Mendelian randomization (MR) analysis to comprehensively assess the causality between lipidome levels and DR. METHODS Summary statistics for lipid levels and DR were obtained from the Genome-Wide Association Studies (GWAS) Catalog database and the FinnGen Consortium, respectively. We conducted a two-sample MR analysis, and statistical analysis were performed using the inverse variance weighted (IVW) with the addition of the MR-Egger, weighted median (WM), constrained maximum likelihood and model averaging (cML-MA) to test for causal associations between lipid levels and DR. Heterogeneity was checked using Cochran's Q statistic. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) global test and the MR-Egger regression were used to detect horizontal pleiotropy. The robustness of our findings was assessed using leave-one-out and funnel plots. To further assess the reliability of the results, linkage disequilibrium score regressions, colocalization analysis and reverse MR analysis were also performed. RESULTS Analysis of the pooled MR results and after correction for the false discovery rate (FDR) revealed that five lipid levels were associated with DR risk. Phosphatidylcholine (16:0_16:0) levels [OR = 0.869 (0.810 to 0.933), Pfdr = 0.006], phosphatidylcholine (16:0_20:2) levels [OR = 0.893 (0.834 to 0.956), Pfdr = 0.043] and phosphatidylethanolamine (18:0_20:4) levels [OR = 0.906 (0.863 to 0.951), Pfdr = 0.006] were protective against DR, whereas sphingomyelin (d36:1) levels [OR = 1.120 (1.061 to 1.183), Pfdr = 0.006], and sphingomyelin (d40:1) levels [OR = 1.081 (1.031 to 1.134), Pfdr = 0.043] were associated with a greater risk of DR. Further sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy. CONCLUSION In summary, genetic evidence suggests a causal relationship between the levels of specific lipid levels and DR. These findings may provide valuable insights into the causal relationships between lipid levels and DR, potentially informing future prevention and treatment strategies.
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Affiliation(s)
- Kai Yin
- College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Lu Ding
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efcacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Xueyan Li
- College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Yuqi Zhang
- Third Clinical Hospital, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Siyu Song
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efcacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Liyuan Cao
- College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Ruixue Deng
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Min Li
- College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Zirui Li
- College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Qinjing Xia
- College of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Daqing Zhao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efcacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China
| | - Xiangyan Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efcacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China.
| | - Zeyu Wang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China.
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efcacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China.
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Gherlone F, Jojić K, Huang Y, Hoefgen S, Valiante V, Janevska S. The palmitoyl-CoA ligase Fum16 is part of a Fusarium verticillioides fumonisin subcluster involved in self-protection. mBio 2025; 16:e0268124. [PMID: 39704544 PMCID: PMC11796371 DOI: 10.1128/mbio.02681-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/02/2024] [Indexed: 12/21/2024] Open
Abstract
Fusarium verticillioides produces the mycotoxin fumonisin B1 (FB1), which disrupts sphingolipid biosynthesis by inhibiting ceramide synthase and affects the health of plants, animals, and humans. The means by which F. verticillioides protects itself from its own mycotoxin are not completely understood. Some fumonisin (FUM) cluster genes do not contribute to the biosynthesis of the compound, but their function has remained enigmatic. Recently, we showed that FUM17, FUM18, and FUM19 encode two ceramide synthases and an ATP-binding cassette transporter, respectively, which play a role in antagonizing the toxicity mediated by FB1. In the present work, we uncovered functions of two adjacent genes, FUM15 and FUM16. Using homologous and heterologous expression systems, in F. verticillioides and Saccharomyces cerevisiae, respectively, we provide evidence that both contribute to protection against FB1. Our data indicate a potential role for the P450 monooxygenase Fum15 in the modification and detoxification of FB1 since the deletion and overexpression of the respective gene affected extracellular FB1 levels in both hosts. Furthermore, relative quantification of ceramide intermediates and an in vitro enzyme assay revealed that Fum16 is a functional palmitoyl-CoA ligase. It co-localizes together with the ceramide synthase Fum18 to the endoplasmic reticulum, where they contribute to sphingolipid biosynthesis. Thereby, FUM15-19 constitute a subcluster within the FUM biosynthetic gene cluster dedicated to the fungal self-protection against FB1.IMPORTANCEThe study identifies a five-gene FUM subcluster (FUM15-19) in Fusarium verticillioides involved in self-protection against FB1. FUM16 (palmitoyl-CoA ligase), FUM17, and FUM18 (ceramide synthases) enzymatically supplement ceramide biosynthesis, while FUM19 (ATP-binding cassette transporter) acts as a repressor of the FUM cluster. The evolutionary conservation of FUM15 (P450 monooxygenase) in Fusarium and Aspergillus FUM clusters is discussed, and its effect on extracellular FB1 levels in both native (F. verticillioides) and heterologous (Saccharomyces cerevisiae) hosts is highlighted. These findings enhance our understanding of mycotoxin self-protection mechanisms and could inform strategies for predicting biological activity of unknown secondary metabolites, managing mycotoxin contamination, and developing resistant crop cultivars.
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Affiliation(s)
- Fabio Gherlone
- (Epi-)Genetic Regulation of Fungal Virulence, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Katarina Jojić
- Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Ying Huang
- Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Sandra Hoefgen
- Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Vito Valiante
- Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Slavica Janevska
- (Epi-)Genetic Regulation of Fungal Virulence, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (Leibniz-HKI), Jena, Germany
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Chen B, Pathak R, Subekti A, Cheng X, Singh S, Ostermeyer-Fay AG, Hannun YA, Luberto C, Canals D. Critical Evaluation of Sphingolipids Detection by MALDI-MSI. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.04.636486. [PMID: 39975012 PMCID: PMC11838543 DOI: 10.1101/2025.02.04.636486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
The increasing interest in the role of sphingolipids in (patho)physiology has led to the demand for visualization of these lipids within tissue samples (both from animal models and patient specimens) using techniques such as matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). While increasingly adopted, detection of sphingolipids with MALDI-MSI is challenging due to: i) the significant structural variations of sphingolipid molecules, ii) the potential breakdown of the more complex molecules into structurally simpler species which may confound the analysis, and iii) the great difference in levels among sphingolipid classes and subspecies, with the low-abundant ones often being close to the detection limit. In this study, we adopted a multi-pronged approach to establish a robust pipeline for the detection of sphingolipids by MALDI-MSI and to establish best practices and limitations of this technology. First, we evaluated the more commonly adopted methods [2,5-Dihydroxyacetophenon (DHA) or 2,5-Dihydroxybenzoic acid (DHB) matrix in positive ion mode and 1,5-Diaminonaphthalene (DAN) matrix in negative ion mode] using MALDI-MS on reference standards. These standards were used at ratios similar to their relative levels in biological samples to evaluate signal artifacts originating from fragmentation of more complex sphingolipids and impacting low level species. Next, by applying the most appropriate protocol for each sphingolipid class, MALDI-MSI signals were validated in cell culture by modulating specific sphingolipid species using sphingolipid enzymes and inhibitors. Finally, the optimized parameters were utilized on breast cancer tissue from the PyMT mouse model. We report the optimal signal for sphingomyelin (SM) and, for the first time, Sph in DHB positive ion mode (in cells and PyMT tissue), and the validated detection of ceramides and glycosphingolipids in DAN negative ion mode. We document the extensive fragmentation of SM into sphingosine-1-phosphate (S1P) and even more so into ceramide-1-phosphate (C1P) using DAN in negative ion mode and its effect in generating an artifactual C1P tissue signal; we also report the lack of detectable signal for S1P and C1P in biological samples (cells and tissue) using the more suitable DHB positive ion mode protocol.
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Shan S, Hoffman JM. Serine metabolism in aging and age-related diseases. GeroScience 2025; 47:611-630. [PMID: 39585647 PMCID: PMC11872823 DOI: 10.1007/s11357-024-01444-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 11/13/2024] [Indexed: 11/26/2024] Open
Abstract
Non-essential amino acids are often overlooked in biomedical research; however, they are crucial components of organismal metabolism. One such metabolite that is integral to physiological function is serine. Serine acts as a pivotal link connecting glycolysis with one-carbon and lipid metabolism, as well as with pyruvate and glutathione syntheses. Interestingly, increasing evidence suggests that serine metabolism may impact the aging process, and supplementation with serine may confer benefits in safeguarding against aging and age-related disorders. This review synthesizes recent insights into the regulation of serine metabolism during aging and its potential to promote healthy lifespan and mitigate a spectrum of age-related diseases.
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Affiliation(s)
- Shengshuai Shan
- Department of Biological Sciences, Augusta University, Augusta, GA, 30912, USA.
| | - Jessica M Hoffman
- Department of Biological Sciences, Augusta University, Augusta, GA, 30912, USA.
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Zhang YH, Xie R, Dai CS, Gao HW, Zhou G, Qi TT, Wang WY, Wang H, Cui YM. Thyroid hormone receptor-beta agonist HSK31679 alleviates MASLD by modulating gut microbial sphingolipids. J Hepatol 2025; 82:189-202. [PMID: 39181210 DOI: 10.1016/j.jhep.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND & AIMS As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), the thyroid hormone receptor-β (THR-β) agonist MGL-3196 (resmetirom) has garnered much attention as a liver-directed, bioactive oral drug. However, studies on MGL-3196 have also identified remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation remains to be elucidated. METHODS We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied to a randomized, double-blind, placebo-controlled multiple ascending dose cohort receiving HSK31679 treatment (n = 32) or placebo (n = 8), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures. RESULTS HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the multiple ascending dose cohort of HSK31679, the relative abundance of B. thetaiotaomicron was significantly enriched, impairing glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In contrast to the non-inferior effect of MGL-3196 and HSK31679 on MASH resolution in GFBTΔGCS mice, HSK31679 led to superior benefit on steatohepatitis in GFBTWT mice, due to its steric hindrance of R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160 mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α+ dendritic cells and MINCLE+ macrophages. CONCLUSIONS This study provided novel insights into the gut microbiota that are key to the efficacy of HSK31679 treatment, revealing microbial GCS as a potential predictive biomarker in MASH, as well as a new target for further microbiota-based treatment strategies for MASH. IMPACT AND IMPLICATIONS Remarkable heterogeneity in individual clinical efficacy of thyroid hormone receptor-β agonists and their interferences with the microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mouse models and a randomized, double-blind, multiple-dose cohort study, we identified microbial glucosylceramide synthase as a key mechanistic node in the resolution of metabolic dysfunction-associated steatohepatitis. Microbial glucosylceramide synthase activity could be a predictive biomarker of response to HSK31679 treatment or a new target for microbiota-based therapeutics in metabolic dysfunction-associated steatohepatitis.
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Affiliation(s)
- Yu-Hang Zhang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100191, China; Department of Pharmacy, Peking University First Hospital, Beijing, 100034, China
| | - Ran Xie
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100191, China; Department of Pharmacy, Peking University First Hospital, Beijing, 100034, China
| | - Chen-Shu Dai
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100191, China; Department of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, China
| | - Hong-Wei Gao
- Biomarker Technologies Corporation, Beijing, 101300, China
| | - Gan Zhou
- Department of Pharmacy, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Tian-Tian Qi
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100191, China
| | - Wen-Yu Wang
- Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
| | - Yi-Min Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100191, China; Department of Pharmacy, Peking University First Hospital, Beijing, 100034, China.
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Zhang T, Qian Y, Mo L, Dong X, Xue Q, Zheng N, Qi Y, Jiang Y. Chronic ethanol exposure induces cardiac fibroblast transdifferentiation via ceramide accumulation and oxidative stress. Toxicol Mech Methods 2025; 35:113-124. [PMID: 39143746 DOI: 10.1080/15376516.2024.2388762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/10/2024] [Accepted: 07/31/2024] [Indexed: 08/16/2024]
Abstract
AIMS Excessive alcohol consumption is associated with cardiac dysfunction and the development of myocardial fibrosis. In this study, we aimed to investigate the direct impacts of ethanol on myocardial fibroblasts and elucidate the underlying mechanism responsible for chronic ethanol-induced myocardial fibrosis. METHODS Rat primary cardiac fibroblasts exposed to ethanol for 24 h and C57BL/6J mice fed on Lieber-DeCarli diet to establish an ethanol intoxication model in vitro and in vivo, respectively. Histological analyses, molecular biology techniques, and analytical chemistry methods were then conducted. RESULTS AND CONCLUSION In vivo and vitro experiments revealed that chronic ethanol exposure induced increased myocardial fibrosis and augmented the transdifferentiation of myocardial fibroblasts. Simultaneously, it elicited an upregulation in the production of long-chain and very-long-chain ceramides in cardiac fibroblasts. The excessive accumulation of ceramide leads to elevated levels of intracellular oxidative stress, culminating in the activation of TGF-β-SMAD3 signaling and the development of fibrosis. Intervention of these pathways with pharmacological inhibitors in vitro or in vivo inhibited fibrosis. In conclusion, ethanol increased ceramides and reactive oxygen species (ROS) in cardiac fibroblasts, resulting in the activation of TGF-β-SMAD3 signaling, transdifferentiation of fibroblasts, and myocardial fibrosis.
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Affiliation(s)
- Tianyi Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yile Qian
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lingjie Mo
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaoru Dong
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Qiupeng Xue
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Nianchang Zheng
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yanyu Qi
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yan Jiang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
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Serafini S, O’Flaherty C. Sphingolipids modulate redox signalling during human sperm capacitation. Hum Reprod 2025; 40:210-225. [PMID: 39658334 PMCID: PMC11788196 DOI: 10.1093/humrep/deae268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/30/2024] [Indexed: 12/12/2024] Open
Abstract
STUDY QUESTION What role do sphingolipids have in mediating human sperm capacitation? SUMMARY ANSWER Sphingosine 1-phosphate (S1P) mediates the acquisition of fertilizing competency in human spermatozoa by engaging with its Gi-coupled receptor S1PR1 and promoting production of reactive oxygen species such as nitric oxide and superoxide anion. WHAT IS KNOWN ALREADY Bioactive sphingolipids, such as S1P, are fundamental for regulating numerous physiological domains and processes, such as cell membranes and signalling, cell death and proliferation, cell migration and invasiveness, inflammation, and central nervous system development. STUDY DESIGN, SIZE, DURATION Semen samples were obtained from a cohort of 10 healthy non-smoking volunteers (18-30 years old) to investigate the role of S1P in sperm. PARTICIPANTS/MATERIALS, SETTING, METHODS Percoll-selected human spermatozoa were incubated at 37°C for 3.5 h in BWW media with or without foetal cord serum ultrafiltrate (FCSu), sphingosine (Sph), or ceramide (Cer). Spermatozoa were also incubated with or without pharmacological inhibitors of sphingolipid metabolism. Protein tyrosine phosphorylation was determined by immunoblotting. The acrosome reaction was determined by PSA-FTIC labelling of the acrosome and analysed using fluorescence microscopy. Intracellular nitric oxide (NO•) production was determined using a DAF-2DA probe. Immunocytochemistry was performed to localize and assess the functional relationship of key components of lipid signalling in spermatozoa. Sperm viability and motility of the samples were evaluated by the hypo-osmotic swelling (HOS) test and computer-aided sperm analysis (CASA). Statistical differences between groups were determined using ANOVA and Tukey's test. Normal distribution of the data and variance homogeneity were assessed using Shapiro-Wilk and Levene's test, respectively. A difference was considered significant when the P-value was ≤0.05. MAIN RESULTS AND THE ROLE OF CHANCE S1P mediates the acquisition of fertilizing competency in human spermatozoa by engaging with its Gi-coupled receptor S1PR1. We found that S1PR1 redistributes to the post-acrosomal region upon induction of capacitation. S1P signalling promotes the activation of the PI3K-AKT pathway, leading to NO• production during sperm capacitation. L-NAME, an nitric oxide synthase inhibitor, impaired the Sph- and Cer-dependent capacitation. Additionally, Sph and Cer promote superoxide anion (O2•-) production, and the extracellular addition of superoxide dismutase (SOD) prevented Sph- and Cer-dependent capacitation, suggesting that Sph and Cer stimulate O2•- production during sperm capacitation. Protein kinase type R (PKR), ceramide kinase (CERK), and protein kinase C (PKC) are responsible for translocating and activating sphingosine kinase 1 (SphK1), which is necessary to promote S1P production for sperm capacitation. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The utilization and actions of sphingolipids may differ in spermatozoa of different species. WIDER IMPLICATIONS OF THE FINDINGS Sphingolipid metabolites such as Sph, Cer, S1P, and ceramide 1-phosphate (C1P) play a crucial role in inducing human sperm capacitation. Our research has provided new insights into fundamental sphingolipid processes in human sperm, including the importance of C1P in translocating and activating SphK1 as well as the S1P signalling to regulate the PI3K/AKT/NOS pathway to generate NO• for sperm capacitation. We are the first to identify the presence of PKR in human spermatozoa and its role in the phosphorylation activities of SphK1 with the subsequent activation of S1P signalling. Furthermore, our study has identified that S1PR1 and S1PR3 are involved in capacitation and the acrosome reaction, respectively. These findings shed light on a novel mechanism by which sphingolipids drive capacitation in human sperm and pave the way for further exploration of the role of bioactive sphingolipid metabolites in this process. Lastly, our studies lay the foundation for examining the lipid profile of infertile males, as potential discrepancies can affect the functional capacity of spermatozoa to reach fertilizing potential. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Canadian Institutes of Health Research (CIHR), grant number PJT-165962 to C.O.F. S.S. was awarded a Research Institute-MUHC Desjardins Studentship. There are no competing interests to report.
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Affiliation(s)
- Steven Serafini
- Experimental Medicine Division, Department of Medicine, McGill University, Montréal, QC, Canada
- Urology Division, Department of Surgery, McGill University, Montréal, QC, Canada
- The Research Institute, McGill University Health Centre, Montréal, QC, Canada
| | - Cristian O’Flaherty
- Experimental Medicine Division, Department of Medicine, McGill University, Montréal, QC, Canada
- Urology Division, Department of Surgery, McGill University, Montréal, QC, Canada
- The Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
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Korbelik M, Heger M, Girotti AW. Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain. J Lipid Res 2025; 66:100729. [PMID: 39675508 PMCID: PMC11911859 DOI: 10.1016/j.jlr.2024.100729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 11/19/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024] Open
Abstract
Hydroperoxides of unsaturated membrane lipids (LOOHs) are the most abundant non-radical intermediates generated by photodynamic therapy (PDT) of soft tissues such as tumors and have far longer average lifetimes than singlet oxygen or oxygen radicals formed during initial photodynamic action. LOOH-initiated post-irradiation damage to remaining membrane lipids (chain peroxidation) or to membrane-associated proteins remains largely unrecognized. Such after-light processes could occur during clinical oncological PDT, but this is not well-perceived by practitioners of this therapy. In general, the pivotal influence of lipids in tumor responses to PDT needs to be better appreciated. Of related importance is the fact that most malignant tumors have dramatically different lipid metabolism compared with healthy tissues, and this too is often ignored. The response of tumors to PDT appears especially vulnerable to manipulations within the tumor lipid microenvironment. This can be exploited for therapeutic gain with PDT, as exemplified here by the combined treatment with the antitumor lipid edelfosine.
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Affiliation(s)
- Mladen Korbelik
- Department of Integrative Oncology, BC Cancer, Vancouver, BC, Canada
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, P. R. China; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
| | - Albert W Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
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Hong X, Wang S, Zhang Q, Li L, Liu H, Yang H, Wu D, Liu X, Shen T. Bisphenol A exacerbates colorectal cancer progression through enhancing ceramide synthesis. Toxicology 2025; 511:154054. [PMID: 39809339 DOI: 10.1016/j.tox.2025.154054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Bisphenol A (BPA) is a typical environmental endocrine disruptor which have been broadly confirmed to be associated with malignant tumors, including colorectal cancer (CRC). Lipid metabolism reprogramming performed important biological effects in cancer progression. While the role of lipid metabolism in CRC progression upon BPA exposure remain elusive. Here, we found that BPA exposure enhanced de novo ceramide synthesis in vitro, along with upregulated ceramide synthase in high-BPA tumor tissue of CRC patients. Simultaneously, we demonstrated that BPA exposure exacerbated tumor biological behavior and epithelial mesenchymal transition (EMT), concurrent with elevated EMT expression of CRC tissue in high BPA group. Subsequently, the inhibition of ceramide synthase and pharmacological stimulation experiments revealed that ceramide accumulation activated EMT and exacerbated CRC progression, including Cer (d18:1/16:0) and Cer (d18:1/24:1). Collectively our findings elucidated the pathogenesis of ceramide accumulation escalating tumor progression under environmental BPA exposure, providing a strong basis for further investigation of dysregulated ceramide metabolism to boost tumor development and avoid metastatic relapse.
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Affiliation(s)
- Xu Hong
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Sheng Wang
- Center for Scientific Research of Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Qing Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Lanlan Li
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Hang Liu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Hongxu Yang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Danyang Wu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Xingcun Liu
- Department of Gastrointestinal surgery, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230032, PR China
| | - Tong Shen
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, PR China.
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Jang Y, Rajbhandari P. Neurotensin signaling in fat modulates food intake. Cell Res 2025; 35:85-86. [PMID: 39748048 PMCID: PMC11770060 DOI: 10.1038/s41422-024-01048-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Affiliation(s)
- YoungUk Jang
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Prashant Rajbhandari
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Ouro A, Castro-Mosquera M, Rodríguez-Arrizabalaga M, Debasa-Mouce M, Custodia A, Aramburu-Núñez M, Romaus-Sanjurjo D, Casas J, Lema I, Castillo J, Leira R, Sobrino T. Elevated Serum Levels of Acid Sphingomyelinase in Female Patients with Episodic and Chronic Migraine. Antioxidants (Basel) 2025; 14:159. [PMID: 40002346 PMCID: PMC11851676 DOI: 10.3390/antiox14020159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/20/2025] [Accepted: 01/27/2025] [Indexed: 02/27/2025] Open
Abstract
Migraine is one of the most common neurological disorders and the second most disabling human condition. The molecular mechanisms of migraine have been linked to neuropeptide release, endothelial dysfunction, oxidative stress and inflammatory processes. Acid sphingomyelinase (aSMase) is a secreted enzyme that leads to sphingomyelin degradation to produce ceramide. Its activity has been associated with several molecular processes involved in migraine. Therefore, this cross-sectional study aims to study the potential role of aSMase in patients with episodic and chronic migraine. In this cross-sectional pilot study, serum samples from female healthy controls (n = 23), episodic migraine (EM) patients (n = 31), and chronic migraine (CM) patients (n = 28) were studied. The total serum levels of aSMase were determined by ELISA. In addition, the serum levels of sphingomyelin (SM), dihydro-sphingomyelin (dhSM), ceramide (Cer), and dihydro-ceramide (dhCer) were determined by mass spectrometry as biomarkers involved in the main molecular pathways associated with aSMase. aSMase serum levels were found significantly elevated in both EM (3.62 ± 1.25 ng/mL) and CM (3.07 ± 0.95 ng/mL) compared with controls (1.58 ± 0.72 ng/mL) (p < 0.0001). ROC analysis showed an area under the curve (AUC) of 0.94 (95% CI: 0.89-0.99, p < 0.0001) and 0.90 (95% CI: 0.81-0.99, p < 0.0001) for EM and CM compared to controls, respectively. Regarding other biomarkers associated with aSMase's pathways, total SM serum levels were significantly decreased in both EM (173,534 ± 39,096 pmol/mL, p < 0.01) and CM (158,459 ± 40,010 pmol/mL, p < 0.0001) compared to the control subjects (219,721 ± 36,950 pmol/mL). Elevated serum levels of aSMase were found in EM and CM patients compared to the control subjects. The decreased SM levels found in both EM and CM indicate that aSMase activity plays a role in migraine. Therefore, aSMase may constitute a new therapeutic target in migraine that should be further investigated.
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Affiliation(s)
- Alberto Ouro
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Mónica Castro-Mosquera
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
| | - Mariña Rodríguez-Arrizabalaga
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
| | - Manuel Debasa-Mouce
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
| | - Antía Custodia
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Marta Aramburu-Núñez
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Daniel Romaus-Sanjurjo
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Josefina Casas
- Research Unit on BioActive Molecules, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain;
- Liver and Digestive Diseases Networking Biomedical Research Centre (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Isabel Lema
- Corneal Neurodegeneration Group (RENOIR), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Department of Surgery and Medical-Surgical Specialties, Faculty of Optics and Optometry, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- Instituto Galego de Oftalmoloxía (INGO), Hospital Provincial de Conxo, 15706 Santiago de Compostela, Spain
| | - José Castillo
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
| | - Rogelio Leira
- Department of Neurology, Hospital Clínico Universitario, Universidad de Santiago de Compostela, 15705 Santiago de Compostela, Spain;
| | - Tomás Sobrino
- NeuroAging Group Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (M.C.-M.); (M.R.-A.); (M.D.-M.); (A.C.); (M.A.-N.); (D.R.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Rufail ML, Bassi R, Giussani P. Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets. Int J Mol Sci 2025; 26:1056. [PMID: 39940821 PMCID: PMC11817292 DOI: 10.3390/ijms26031056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer biology revolves around understanding how cells undergo uncontrolled proliferation leading to the formation of malignant tumors. Key aspects include self-sufficiency in growth signals, the lack of response to signals of growth inhibition, the evasion of apoptosis, sustained angiogenesis, the evasion of immune response, the capacity to invade and metastasize, and alterations in cellular metabolism. A vast amount of research, which is exponentially growing, over the past few decades highlights the role of sphingolipids in cancer. They act not only as structural membrane components but also as bioactive molecules that regulate cell fate in different physio-pathological conditions. In cancer, sphingolipid metabolism is dysregulated, contributing to tumor progression, metastasis, and drug resistance. In this review, we outline the impact of sphingosine-1-phosphate (S1P) as a key bioactive sphingolipid in cancer. We give an overview of its metabolism summarizing the role of S1P as an intracellular and extracellular mediator through specific plasma membrane receptors in different cancers. We also describe previous findings on how the disruption in the balance between S1P and ceramide (Cer) is common in cancer cells and can contribute to tumorigenesis and resistance to chemotherapy. We finally consider the potential of targeting the metabolic pathways of S1P as well as its receptors and transporters as a promising therapeutic approach in cancer treatments.
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Affiliation(s)
- Miguel L. Rufail
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Rosaria Bassi
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA Segrate, Via Fratelli Cervi, 93, 20054 Segrate, Italy
| | - Paola Giussani
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA Segrate, Via Fratelli Cervi, 93, 20054 Segrate, Italy
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Kasumov T. Sphingolipids Demystify Prediabetic Risk. J Clin Endocrinol Metab 2025; 110:e540-e541. [PMID: 38856104 PMCID: PMC11747671 DOI: 10.1210/clinem/dgae274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Indexed: 06/11/2024]
Affiliation(s)
- Takhar Kasumov
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
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50
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Kalecký K, Buitrago L, Alarcon JM, Singh A, Bottiglieri T, Kaddurah-Daouk R, Hernández AI. Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.17.633452. [PMID: 39868189 PMCID: PMC11761635 DOI: 10.1101/2025.01.17.633452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.
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Affiliation(s)
- Karel Kalecký
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Luna Buitrago
- Neural and Behavioral Sciences Program, School of Graduate Studies, Department of Neurology/Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Juan Marcos Alarcon
- Neural and Behavioral Sciences Program, School of Graduate Studies, The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Pathology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Abanish Singh
- Department of Psychiatry and Behavioral Sciences; and Department of Medicine, Duke University School of Medicine, Durham, Durham, NC, USA
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioural Sciences, Duke University, Durham, NC, USA
- Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
- Department of Medicine, Duke University, Durham, NC, USA
| | - Alejandro Iván Hernández
- Neural and Behavioral Sciences Program, School of Graduate Studies, The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Pathology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
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