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de Jager C, Soliman E, Theus MH. Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactions. Mol Cell Neurosci 2025; 133:104003. [PMID: 40090391 DOI: 10.1016/j.mcn.2025.104003] [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: 11/26/2024] [Revised: 03/09/2025] [Accepted: 03/11/2025] [Indexed: 03/18/2025] Open
Abstract
Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although molecular pathways have been implicated in TBI pathology, the cellular specificity of these mechanisms remains underexplored. Here, we investigate the role of endothelial cell (EC) EphA4, a receptor tyrosine kinase receptor involved in axonal guidance, in modulating cell-specific transcriptomic changes within the damaged cerebral cortex. Utilizing single-cell RNA sequencing (scRNA-seq) in an experimental TBI model, we mapped transcriptional changes across various cell types, with a focus on astrocytes and ECs. Our analysis reveals that EC-specific knockout (KO) of EphA4 triggers significant alterations in astrocyte gene expression and shifts predominate subclusters. We identified six distinct astrocyte clusters (C0-C5) in the damaged cortex including as C0-Mobp/Plp1+; C1-Slc1a3/Clu+; C2-Hbb-bs/Hba-a1/Ndrg2+; C3-GFAP/Lcn2+; C4-Gli3/Mertk+, and C5-Cox8a+. We validate a new Sox9+ cluster expressing Mertk and Gas, which mediates efferocytosis to facilitate apoptotic cell clearance and anti-inflammatory responses. Transcriptomic and CellChat analyses of EC-KO cells highlights upregulation of neuroprotective pathways, including increased amyloid precursor protein (APP) and Gas6. Key pathways predicted to be modulated in astrocytes from EC-KO mice include oxidative phosphorylation and FOXO signaling, mitochondrial dysfunction and ephrin B signaling. Concurrently, metabolic and signaling pathways in endothelial cells-such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription-indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as transcriptional networks underlying cortical tissue damage.
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Affiliation(s)
- Caroline de Jager
- Translational Biology Medicine and Health Graduate Program, Blacksburg, VA 24061, USA
| | - Eman Soliman
- Department of Biomedical Sciences and Pathobiology, Blacksburg, VA 24061, USA
| | - Michelle H Theus
- Department of Biomedical Sciences and Pathobiology, Blacksburg, VA 24061, USA; Center for Engineered Health, Virginia Tech, Blacksburg, VA 24061, USA.
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Zhao F, Shao M, Li M, Li T, Zheng Y, Sun W, Ni C, Li L. Sphingolipid metabolites involved in the pathogenesis of atherosclerosis: perspectives on sphingolipids in atherosclerosis. Cell Mol Biol Lett 2025; 30:18. [PMID: 39920588 PMCID: PMC11804087 DOI: 10.1186/s11658-024-00679-2] [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: 07/29/2024] [Accepted: 12/17/2024] [Indexed: 02/09/2025] Open
Abstract
Atherosclerosis, with its complex pathogenesis, is a leading underlying cause of many cardiovascular diseases, which are increasingly prevalent in the population. Sphingolipids play an important role in the development of atherosclerosis. Key metabolites and enzymes in sphingolipid metabolism influence the pathogenesis of atherosclerosis in a variety of ways, including inflammatory responses and oxidative stress. Thus, an investigation of sphingolipid metabolism-related metabolites and key enzymes may provide novel insights and treatment targets for atherosclerosis. This review discusses various mechanisms and research progress on the relationship between various sphingolipid metabolites, related enzymes, and atherosclerosis. Finally, we look into the future research direction of phytosphingolipids.
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Affiliation(s)
- Fufangyu Zhao
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Mingyan Shao
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Mingrui Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tianxing Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yanfei Zheng
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, 255000, Shandong, China.
| | - Cheng Ni
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Lingru Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Xiong Y, Ye Q, Liu L, Lin W, Liao Y, Gao R, Xu J, Zhang X, Chen R, Chen S, Chen Q, Wei L. The compensatory enrichment of sphingosine-1-phosphate on HDL in FSGS enhances the protective function of glomerular endothelial cells compared to MCD. Sci Rep 2025; 15:1530. [PMID: 39789110 PMCID: PMC11718056 DOI: 10.1038/s41598-025-85865-8] [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: 07/15/2024] [Accepted: 01/07/2025] [Indexed: 01/12/2025] Open
Abstract
Glomerular endothelial cells (GECs) are pivotal in developing glomerular sclerosis disorders. The advancement of focal segmental glomerulosclerosis (FSGS) is intimately tied to disruptions in lipid metabolism. Sphingosine-1-phosphate (S1P), a molecule transported by high-density lipoproteins (HDL), exhibits protective effects on vascular endothelial cells by upregulating phosphorylated endothelial nitric oxide synthase (p-eNOS) and enhancing nitric oxide (NO) production. Nevertheless, the abundance of S1P within HDL in individuals with FSGS and minimal change disease (MCD) is yet to be elucidated, and its defensive role in GECs necessitates empirical confirmation. A total of 14 FSGS patients, 16 MCD patients, and 16 healthy controls (NC) were included in the study, with FSGS and MCD confirmed by renal biopsy. After blood sample collection, HDL was isolated and categorized into intact HDL, phospholipid-depleted HDL(apo-HDL), phospholipid-remained HDL(phoHDL), and recombinant HDL (rHDL). Various HDL samples, comprising intact, apo-HDL, pho-HDL and rHDL, were co-cultivated with human renal glomerular endothelial cells (HRGECs). Western blotting was utilized to quantify p-eNOS levels and assess PI3K-AKT pathway activation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyzed S1P concentrations, while real-time quantitative PCR evaluated the expression of enzymes involved in S1P metabolism. Fluorescence labeling methods measured NO levels, and an immunofluorescence colocalization assay investigated Sphingosine-1-phosphate receptor 1 (S1PR1) expression in GECs across distinct kidney tissue groups. The HDL from FSGS patients demonstrated a significantly enhanced ability to promote p-eNOS expression and NO release in HRGECs compared to MCD patients and healthy controls. Additionally, the synthesis activity of S1P in renal tissues of FSGS patients was markedly higher than that observed in MCD patients and healthy controls, suggesting that S1P may play a crucial protective role in the progression of FSGS. Immunofluorescence staining showed that compared with MCD and NC, the expression of S1PR1 in GECs of FSGS patients was significantly decreased. Recombinant HDL with added S1P promoted the increase of p-eNOS in HRGECs. Knockdown of S1PR1 using siRNA reduced the expression of p-eNOS and NO release. The mechanism underlying the regulation of p-eNOS expression by rHDL was associated with the PI3K-AKT signaling pathway. The enhanced presence of S1P on HDL could serve as a diagnostic marker to differentiate FSGS from MCD. Incorporating S1P into HDL enhances glomerular endothelial cell function, suggesting that the S1P/S1PR pathway might offer a promising therapeutic avenue for FSGS.
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Affiliation(s)
- Yunfeng Xiong
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Qiuping Ye
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Lifang Liu
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Wanjun Lin
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Yonggen Liao
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Ruiyu Gao
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jiaming Xu
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Xinyu Zhang
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Ruoyan Chen
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Sihui Chen
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Qiaoling Chen
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China.
| | - Lixin Wei
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China.
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Adibi A, Adibi I, Javidan M. Effect of Different Treatments on Retinal Thickness Changes in Patients With Multiple Sclerosis: A Review. CNS Neurosci Ther 2025; 31:e70225. [PMID: 39853938 PMCID: PMC11759887 DOI: 10.1111/cns.70225] [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: 07/01/2024] [Revised: 01/02/2025] [Accepted: 01/08/2025] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND Multiple sclerosis (MS) is an autoimmune disorder affecting the central nervous system, with varying clinical manifestations such as optic neuritis, sensory disturbances, and brainstem syndromes. Disease progression is monitored through methods like MRI scans, disability scales, and optical coherence tomography (OCT), which can detect retinal thinning, even in the absence of optic neuritis. MS progression involves neurodegeneration, particularly trans-synaptic degeneration, which extends beyond the initial injury site. This review focuses on the impact of different MS treatments on retinal thickness as assessed by OCT. RESULTS Injectable drugs, such as interferon beta and glatiramer acetate (GA), have a relatively modest impact on retinal atrophy. Oral medications like Fingolimod, Teriflunomide, and Dimethyl fumarate also have different impacts on retinal thickness. Fingolimod has been shown to protect against retinal thinning but may lead to macular edema. DMF-treated patients had less ganglion cell-inner plexiform layer thinning than GA-treated patients but more thinning compared to natalizumab-treated patients and healthy controls. Teriflunomide's impact on retinal layers remains unexplored in human studies. Monoclonal antibodies, including Alemtuzumab, Rituximab, Ocrelizumab, and Natalizumab, had protective effects on retinal layer atrophy. Alemtuzumab-treated patients showed significantly less atrophy compared to interferon- and GA-treated patients. Rituximab initially increased atrophy rates in the first months but subsequently demonstrated potential neuroprotective effects. Ocrelizumab slowed the rate of inner nuclear layer thinning in progressive forms of the disease. Natalizumab is considered the most effective in reducing retinal layer atrophy, particularly the peripapillary retinal nerve fiber layer. CONCLUSIONS It's important to note that the effectiveness of these treatments may vary depending on MS subtype and individual factors. Future research should explore the long-term effects of these treatments on retinal layers and their correlations with overall disease progression and disability in MS patients.
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Affiliation(s)
- Armin Adibi
- Department of NeurologyIsfahan University of Medical SciencesIsfahanIran
- Neuroscience Research CenterIsfahan University of Medical SciencesIsfahanIran
| | - Iman Adibi
- Department of NeurologyIsfahan University of Medical SciencesIsfahanIran
- Neuroscience Research CenterIsfahan University of Medical SciencesIsfahanIran
| | - Milad Javidan
- Department of NeurologyIsfahan University of Medical SciencesIsfahanIran
- Neuroscience Research CenterIsfahan University of Medical SciencesIsfahanIran
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Xu Z, Yang S, Cui L. Understanding the heterogeneity and dysfunction of HDL in chronic kidney disease: insights from recent reviews. BMC Nephrol 2024; 25:400. [PMID: 39511510 PMCID: PMC11542271 DOI: 10.1186/s12882-024-03808-3] [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: 06/25/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Chronic kidney disease (CKD) is a complex disease that affects the global population's health, with dyslipidemia being one of its major complications. High density lipoprotein (HDL) is regarded as the "hero" in the bloodstream due to its role in reverse cholesterol transport, which lowers cholesterol levels in the blood and prevents atherosclerosis. However, in the complex internal environment of CKD, even this "hero" may struggle to perform its beneficial functions and could potentially become harmful. This article reviews HDL heterogeneity, HDL subclasses, functional changes in HDL during the progression of CKD, and the application of HDL in CKD treatment. This review aims to deepen understanding of lipid metabolism abnormalities in CKD patients and provide a basis for new therapeutic strategies.
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Affiliation(s)
- Zhen Xu
- Peking University Third Hospital, Beijing, China
| | - Shuo Yang
- Peking University Third Hospital, Beijing, China
| | - Liyan Cui
- Peking University Third Hospital, Beijing, China.
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Chen C, Wang J, Liu C, Hu J, Liu L. Pioneering therapies for post-infarction angiogenesis: Insight into molecular mechanisms and preclinical studies. Biomed Pharmacother 2023; 166:115306. [PMID: 37572633 DOI: 10.1016/j.biopha.2023.115306] [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: 06/16/2023] [Revised: 08/01/2023] [Accepted: 08/07/2023] [Indexed: 08/14/2023] Open
Abstract
Acute myocardial infarction (MI), despite significant progress in its treatment, remains a leading cause of chronic heart failure and cardiovascular events such as cardiac arrest. Promoting angiogenesis in the myocardial tissue after MI to restore blood flow in the ischemic and hypoxic tissue is considered an effective treatment strategy. The repair of the myocardial tissue post-MI involves a robust angiogenic response, with mechanisms involved including endothelial cell proliferation and migration, capillary growth, changes in the extracellular matrix, and stabilization of pericytes for neovascularization. In this review, we provide a detailed overview of six key pathways in angiogenesis post-MI: the PI3K/Akt/mTOR signaling pathway, the Notch signaling pathway, the Wnt/β-catenin signaling pathway, the Hippo signaling pathway, the Sonic Hedgehog signaling pathway, and the JAK/STAT signaling pathway. We also discuss novel therapeutic approaches targeting these pathways, including drug therapy, gene therapy, protein therapy, cell therapy, and extracellular vesicle therapy. A comprehensive understanding of these key pathways and their targeted therapies will aid in our understanding of the pathological and physiological mechanisms of angiogenesis after MI and the development and application of new treatment strategies.
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Affiliation(s)
- Cong Chen
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Jie Wang
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
| | - Chao Liu
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Jun Hu
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Lanchun Liu
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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Lai Y, Tian Y, You X, Du J, Huang J. Effects of sphingolipid metabolism disorders on endothelial cells. Lipids Health Dis 2022; 21:101. [PMID: 36229882 PMCID: PMC9563846 DOI: 10.1186/s12944-022-01701-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/05/2022] [Indexed: 11/10/2022] Open
Abstract
Many cardiovascular disorders, including atherosclerosis, hypertension, coronary heart disease, diabetes, etc., are characterized by endothelial cell dysfunction. Endothelial cell function is closely related to sphingolipid metabolism, and normal sphingolipid metabolism is critical for maintaining endothelial cell homeostasis. Sphingolipid metabolites or key enzymes in abnormal situation, including sphingosine, ceramide (Cer), sphingosine-1-phosphate (S1P), serine, sphingosine kinase (SPHK), ceramide kinase (Cerk), sphingosine-1-phosphate lyase (S1PL) etc., may have a protective or damaging effect on the function of endothelial cells. This review summarizes the effects of sphingolipid metabolites and key enzymes disordering in sphingolipid metabolism on endothelial cells, offering some insights into further research on the pathogenesis of cardiovascular diseases and corresponding therapeutic targets.
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Affiliation(s)
- Yali Lai
- School of Traditional Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yue Tian
- School of Traditional Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xintong You
- School of Traditional Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiangnan Du
- School of Traditional Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jianmei Huang
- School of Traditional Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
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Luo D, Guo Z, Zhao X, Wu L, Liu X, Zhang Y, Zhang Y, Deng Z, Qu X, Cui S, Wan S. Novel 5-fluorouracil sensitizers for colorectal cancer therapy: Design and synthesis of S1P receptor 2 (S1PR2) antagonists. Eur J Med Chem 2022; 227:113923. [PMID: 34688013 DOI: 10.1016/j.ejmech.2021.113923] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/05/2021] [Accepted: 10/12/2021] [Indexed: 12/21/2022]
Abstract
Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (KD = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.
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Affiliation(s)
- Dongdong Luo
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003, Qingdao, China
| | - Zhikun Guo
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China
| | - Xuecui Zhao
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003, Qingdao, China
| | - Lijuan Wu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003, Qingdao, China
| | - Xiaochun Liu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003, Qingdao, China
| | - Yingzhi Zhang
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China
| | - Yuhang Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China
| | - Zirong Deng
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003, Qingdao, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China
| | - Shuxiang Cui
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China.
| | - Shengbiao Wan
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003, Qingdao, China.
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Feng X, Du M, Zhang Y, Ding J, Wang Y, Liu P. The Role of Lymphangiogenesis in Coronary Atherosclerosis. Lymphat Res Biol 2021; 20:290-301. [PMID: 34714136 DOI: 10.1089/lrb.2021.0026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Lymphatic circulation, a one-way channel system independent of blood circulation, collects interstitial fluid in a blind-end way. Existing widely in various organs and tissues, lymphatic vessels play important roles in maintaining tissue fluid homeostasis, regulating immune function, and promoting lipid transport. Recent studies have shown clear evidence that lymphangiogenesis has a strong mutual effect on coronary atherosclerosis (AS). In this study, we focus on this topic, especially in the aspects of relevant ligand/receptor, inflammation, and adipose metabolism. For the moment, however, the role of lymphangiogenesis and remodeling in coronary AS still remains controversial. The studies of our group and accumulating published evidence show that the pathological remodeling of lymphatic vessels in coronary AS may have a negative effect, but normal functional lymphangiogenesis is probably beneficial to the regression of coronary AS. Thus, the conclusion of this review is that lymphatic vessel function rather than its quantity determines its influence in AS, which needs more evidence to support.
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Affiliation(s)
- Xiaoteng Feng
- Department of Cardiology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Min Du
- Department of Cardiology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifan Zhang
- Department of Cardiology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Ding
- Department of Cardiology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiru Wang
- Department of Cardiology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Liu
- Department of Cardiology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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11
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Darabi M, Kontush A. High-density lipoproteins (HDL): Novel function and therapeutic applications. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1867:159058. [PMID: 34624514 DOI: 10.1016/j.bbalip.2021.159058] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/16/2021] [Accepted: 08/25/2021] [Indexed: 12/30/2022]
Abstract
The failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL. Ensuing cholesterol transport to the liver with excretion into the bile may reduce cholesterol influx in the arterial wall by accelerating removal from circulation of atherogenic, cholesterol-rich TGRL remnants. Such novel function of HDL opens wide therapeutic applications to reduce CVD in statin-treated patients, which primarily involve activation of cholesterol flux upon lipolysis.
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Affiliation(s)
- Maryam Darabi
- National Institute for Health and Medical Research (INSERM), UMRS 1166 ICAN, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, Paris, France
| | - Anatol Kontush
- National Institute for Health and Medical Research (INSERM), UMRS 1166 ICAN, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, Paris, France.
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12
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The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium. Int J Mol Sci 2021; 22:ijms221810168. [PMID: 34576329 PMCID: PMC8467920 DOI: 10.3390/ijms221810168] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 12/29/2022] Open
Abstract
Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in the remodeling of the actin cytoskeleton. In the endothelium, they regulate junctional stabilization and play a crucial role in angiogenesis and endothelial barrier integrity. Multiple extracellular signals originating from different vascular processes can influence the activity of Trio and thereby the regulation of the forementioned small GTPases and actin cytoskeleton. This review elucidates how various signals regulate Trio in a distinct manner, resulting in different functional outcomes that are crucial for endothelial cell function in response to inflammation.
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Barbano L, Ziccardi L, Landi D, Nicoletti CG, Mataluni G, Falsini B, Centonze D, Marfia GA, Quaranta L, Parisi V. Assessment of Macular Function by Multifocal Electroretinogram in Patients with Multiple Sclerosis Treated with Fingolimod. Adv Ther 2021; 38:3986-3996. [PMID: 34109558 PMCID: PMC8280030 DOI: 10.1007/s12325-021-01728-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/24/2021] [Indexed: 11/24/2022]
Abstract
Introduction This study aimed to evaluate whether treatment with fingolimod (FTY) may induce functional changes on the macular pre-ganglionic retinal elements in patients affected by relapsing–remitting multiple sclerosis (RR-MS) without optic neuritis (ON). Methods This case–control observational and retrospective study assessed multifocal electroretinogram (mfERG) responses from 35 healthy controls (mean age 43.58 ± 5.76 years), 41 patients with RR-MS without ON (mean age 40.64 ± 4.83 years, MS-noFTY group), and from 21 patients with RR-MS without ON (mean age 42.38 ± 12.34 years) and treated with fingolimod (Gilenya®, Novartis Europharm, 0.5 mg/day) (MS-FTY group). MfERG N1 and P1 implicit times (ITs), and N1–P1 response amplitude densities (RADs) were measured from concentric rings (R) with increasing foveal eccentricity: 0–5° (R1), 5–10° (R2), 10–15° (R3), 15–20° (R4), 20–25° (R5). We considered R1 and R2 as “central macular areas” and R3, R4 and R5 as “more eccentric retinal areas”. In the MS-FTY group, mfERG recordings were performed between 6 and 12 months (mean 7.2 ± 1.5 months) from the start of FTY. Results In the MS-FTY group, the mean values of mfERG N1 and P1 ITs and RADs detected in both central macular areas (R1 and R2) and in more eccentric retinal areas (R3, R4 and R5) were not significantly different (p > 0.01) with respect to those of control and MS-noFTY groups. Conclusions Our mfERG results suggest that the chronic use of FTY does not induce a dysfunction of pre-ganglionic retinal elements located in the 0–25° of central retina. Since FTY does not cause any retinal functional abnormality, we suggest that FTY treatment could not produce any toxic effect on pre-ganglionic retinal elements even in the absence of macular oedema.
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Affiliation(s)
| | | | - Doriana Landi
- Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy
| | - Carolina Gabri Nicoletti
- Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy
| | - Giorgia Mataluni
- Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy
| | - Benedetto Falsini
- Ophthalmology Department, IRCCS Fondazione Policlinico Universitario A. Gemelli, Catholic University, Rome, Italy
| | - Diego Centonze
- Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy
- Unit of Neurology, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy
| | - Girolama Alessandra Marfia
- Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy
- Unit of Neurology, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy
| | - Luciano Quaranta
- Department of Surgical and Clinical, Diagnostic and Pediatric Sciences, Section of Ophthalmology, University of Pavia, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.
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Thakkar H, Vincent V, Sen A, Singh A, Roy A. Changing Perspectives on HDL: From Simple Quantity Measurements to Functional Quality Assessment. J Lipids 2021; 2021:5585521. [PMID: 33996157 PMCID: PMC8096543 DOI: 10.1155/2021/5585521] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/10/2021] [Accepted: 04/19/2021] [Indexed: 12/29/2022] Open
Abstract
High-density lipoprotein (HDL) comprises a heterogeneous group of particles differing in size, density, and composition. HDL cholesterol (HDL-C) levels have long been suggested to indicate cardiovascular risk, inferred from multiple epidemiological studies. The failure of HDL-C targeted interventions and genetic studies has raised doubts on the atheroprotective role of HDL-C. The current consensus is that HDL-C is neither a biomarker nor a causative agent of cardiovascular disorders. With better understanding of the complex nature of HDL which comprises a large number of proteins and lipids with unique functions, recent focus has shifted from HDL quantity to HDL quality in terms of atheroprotective functions. The current research is focused on developing laboratory assays to assess HDL functions for cardiovascular risk prediction. Also, HDL mimetics designed based on the key determinants of HDL functions are being investigated to modify cardiovascular risk. Improving HDL functions by altering its composition is the key area of future research in HDL biology to reduce cardiovascular risk.
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Affiliation(s)
- Himani Thakkar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Vinnyfred Vincent
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Atanu Sen
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Archna Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Ambuj Roy
- Department of Cardiology, All India Institute of Medical Sciences, New Delhi 110029, India
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15
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Claesson-Welsh L, Dejana E, McDonald DM. Permeability of the Endothelial Barrier: Identifying and Reconciling Controversies. Trends Mol Med 2020; 27:314-331. [PMID: 33309601 DOI: 10.1016/j.molmed.2020.11.006] [Citation(s) in RCA: 346] [Impact Index Per Article: 69.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022]
Abstract
Leakage from blood vessels into tissues is governed by mechanisms that control endothelial barrier function to maintain homeostasis. Dysregulated endothelial permeability contributes to many conditions and can influence disease morbidity and treatment. Diverse approaches used to study endothelial permeability have yielded a wealth of valuable insights. Yet, ongoing questions, technical challenges, and unresolved controversies relating to the mechanisms and relative contributions of barrier regulation, transendothelial sieving, and transport of fluid, solutes, and particulates complicate interpretations in the context of vascular physiology and pathophysiology. Here, we describe recent in vivo findings and other advances in understanding endothelial barrier function with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease.
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Affiliation(s)
- Lena Claesson-Welsh
- Uppsala University, Rudbeck, SciLifeLab and Beijer Laboratories, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
| | - Elisabetta Dejana
- Uppsala University, Rudbeck, SciLifeLab and Beijer Laboratories, Department of Immunology, Genetics and Pathology, Uppsala, Sweden; IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
| | - Donald M McDonald
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
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16
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Faqar-Uz-Zaman WF, Schmidt KG, Thomas D, Pfeilschifter JM, Radeke HH, Schwiebs A. S1P Lyase siRNA Dampens Malignancy of DLD-1 Colorectal Cancer Cells. Lipids 2020; 56:155-166. [PMID: 32971566 DOI: 10.1002/lipd.12282] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 07/30/2020] [Accepted: 08/19/2020] [Indexed: 12/23/2022]
Abstract
Sphingosine-1-phosphate lyase 1 (S1P lyase or SGPL1) is an essential sphingosine-1-phosphate-degrading enzyme. Its manipulation favors onset and progression of colorectal cancer and others in vivo. Thus, SGPL1 is an important modulator of cancer initiation. However, in established cancer, the impact of retrospective SGPL1 modulation is elusive. Herein, we analyzed how SGPL1 siRNA affects malignancy of the human colorectal cancer cells DLD-1 and found that in parallel to the reduction of SGPL1 expression levels, migration, invasion, and differentiation status changed. Diminished SGPL1 expression was accompanied with reduced cell migration and cell invasion in scratch assays and transwell assays, whereas metabolic activity and proliferation was not altered. Decreased migration was attended by increased cell-cell-adhesion through upregulation of E-cadherin and formation of cadherin-actin complexes. Spreading cell islets showed lower vimentin abundance in border cells. Furthermore, SGPL1 siRNA treatment induced expression of epithelial cell differentiation markers, such as intestinal alkaline phosphatase and cytokeratin 20. Hence, interference with SGPL1 expression augmented a partial redifferentiation of colorectal cancer cells toward normal colon epithelial cells. Our investigation showed that SGPL1 siRNA influenced tumorigenic activity of established colorectal cancer cells. We therefore suggest SGPL1 as a target for lowering malignant potential of already existing cancer.
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Affiliation(s)
- Wajiha Farha Faqar-Uz-Zaman
- Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe University, Frankfurt am Main, Germany
| | - Katrin G Schmidt
- Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe University, Frankfurt am Main, Germany
| | - Dominique Thomas
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Hospital of the Goethe University, Frankfurt am Main, Germany
| | - Josef M Pfeilschifter
- Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe University, Frankfurt am Main, Germany
| | - Heinfried H Radeke
- Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe University, Frankfurt am Main, Germany
| | - Anja Schwiebs
- Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe University, Frankfurt am Main, Germany
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17
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Meilhac O, Tanaka S, Couret D. High-Density Lipoproteins Are Bug Scavengers. Biomolecules 2020; 10:biom10040598. [PMID: 32290632 PMCID: PMC7226336 DOI: 10.3390/biom10040598] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 12/11/2022] Open
Abstract
Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol transporter could be challenged. All lipoproteins are reported to bind and potentially neutralize bacterial lipopolysaccharides (LPS); this is particularly true for HDL particles. In addition, HDL levels are drastically decreased under infectious conditions such as sepsis, suggesting a potential role in the clearance of bacterial material and, particularly, LPS. Moreover, "omics" technologies have unveiled significant changes in HDL composition in different inflammatory states, ranging from acute inflammation occurring during septic shock to low-grade inflammation associated with moderate endotoxemia such as periodontal disease or obesity. In this review, we will discuss HDL modifications associated with exposure to pathogens including bacteria, viruses and parasites, with a special focus on sepsis and the potential of HDL therapy in this context. Low-grade inflammation associated with atherosclerosis, periodontitis or metabolic syndrome may also highlight the protective role of HDLs in theses pathologies by other mechanisms than the reverse transport of cholesterol.
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Affiliation(s)
- Olivier Meilhac
- Université de la Réunion, Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), F-97490 Sainte-Clotilde, France; (S.T.); (D.C.)
- CHU de La Réunion, Centre d’Investigations Clinique 1410, 97410 Saint-Pierre, France
- Correspondence: ; Tel.: +33-262-93-88-11
| | - Sébastien Tanaka
- Université de la Réunion, Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), F-97490 Sainte-Clotilde, France; (S.T.); (D.C.)
- AP-HP, Service d’Anesthésie-Réanimation, CHU Bichat-Claude Bernard, 75018 Paris, France
| | - David Couret
- Université de la Réunion, Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), F-97490 Sainte-Clotilde, France; (S.T.); (D.C.)
- CHU de La Réunion, Neurocritical Care Unit, 97410 Saint-Pierre, France
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18
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Riboni L, Abdel Hadi L, Navone SE, Guarnaccia L, Campanella R, Marfia G. Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks. Cells 2020; 9:E337. [PMID: 32024090 PMCID: PMC7072483 DOI: 10.3390/cells9020337] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 02/07/2023] Open
Abstract
As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment.
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Affiliation(s)
- Laura Riboni
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy
| | - Loubna Abdel Hadi
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy
| | - Stefania Elena Navone
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy (L.G.)
| | - Laura Guarnaccia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy (L.G.)
- Department of Clinical Sciences and Community Health, University of Milan, 20100 Milan, Italy
| | - Rolando Campanella
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy (L.G.)
| | - Giovanni Marfia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy (L.G.)
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19
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Danese S, Furfaro F, Vetrano S. Targeting S1P in Inflammatory Bowel Disease: New Avenues for Modulating Intestinal Leukocyte Migration. J Crohns Colitis 2018; 12:S678-S686. [PMID: 28961752 DOI: 10.1093/ecco-jcc/jjx107] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Sphingosine 1 phosphate [S1P] is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors [S1PRs]. Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, the S1P/S1PR1 axis has been identified as key regulator for lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocyte migration into the mucosa in inflammatory bowel disease [IBD]. This review briefly summarises the current evidence coming from clinical studies, and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease.
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Affiliation(s)
- Silvio Danese
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Federica Furfaro
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Stefania Vetrano
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
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20
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Abdel Hadi L, Anelli V, Guarnaccia L, Navone S, Beretta M, Moccia F, Tringali C, Urechie V, Campanella R, Marfia G, Riboni L. A bidirectional crosstalk between glioblastoma and brain endothelial cells potentiates the angiogenic and proliferative signaling of sphingosine-1-phosphate in the glioblastoma microenvironment. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:1179-1192. [PMID: 30056170 DOI: 10.1016/j.bbalip.2018.07.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 06/21/2018] [Accepted: 07/21/2018] [Indexed: 12/24/2022]
Abstract
Glioblastoma is one of the most malignant, angiogenic, and incurable tumors in humans. The aberrant communication between glioblastoma cells and tumor microenvironment represents one of the major factors regulating glioblastoma malignancy and angiogenic properties. Emerging evidence implicates sphingosine-1-phosphate signaling in the pathobiology of glioblastoma and angiogenesis, but its role in glioblastoma-endothelial crosstalk remains largely unknown. In this study, we sought to determine whether the crosstalk between glioblastoma cells and brain endothelial cells regulates sphingosine-1-phosphate signaling in the tumor microenvironment. Using human glioblastoma and brain endothelial cell lines, as well as primary brain endothelial cells derived from human glioblastoma, we report that glioblastoma-co-culture promotes the expression, activity, and plasma membrane enrichment of sphingosine kinase 2 in brain endothelial cells, leading to increased cellular level of sphingosine-1-phosphate, and significant potentiation of its secretion. In turn, extracellular sphingosine-1-phosphate stimulates glioblastoma cell proliferation, and brain endothelial cells migration and angiogenesis. We also show that, after co-culture, glioblastoma cells exhibit enhanced expression of S1P1 and S1P3, the sphingosine-1-phosphate receptors that are of paramount importance for cell growth and invasivity. Collectively, our results envision glioblastoma-endothelial crosstalk as a multi-compartmental strategy to enforce pro-tumoral sphingosine-1-phosphate signaling in the glioblastoma microenvironment.
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Affiliation(s)
- Loubna Abdel Hadi
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Italy
| | - Viviana Anelli
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Italy
| | - Laura Guarnaccia
- Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milan, Laboratory of Experimental Neurosurgery and Cell Therapy, University of Milan, Italy
| | - Stefania Navone
- Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milan, Laboratory of Experimental Neurosurgery and Cell Therapy, University of Milan, Italy
| | - Matteo Beretta
- Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milan, Laboratory of Experimental Neurosurgery and Cell Therapy, University of Milan, Italy
| | - Francesco Moccia
- Laboratory of General Physiology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy
| | - Cristina Tringali
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Italy
| | - Vasile Urechie
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Italy
| | - Rolando Campanella
- Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milan, Laboratory of Experimental Neurosurgery and Cell Therapy, University of Milan, Italy
| | - Giovanni Marfia
- Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milan, Laboratory of Experimental Neurosurgery and Cell Therapy, University of Milan, Italy
| | - Laura Riboni
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Italy.
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21
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FTY720 restores endothelial cell permeability induced by malaria sera. Sci Rep 2018; 8:10959. [PMID: 30026484 PMCID: PMC6053398 DOI: 10.1038/s41598-018-28536-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023] Open
Abstract
Increased endothelial cell (EC) permeability in severe Plasmodium falciparum malaria contributes to major complications of severe malaria. This study explored EC permeability in malaria, and evaluated the potential use of FTY720 to restore EC permeability. ECs were incubated with sera from malaria patients (P. vivax, uncomplicated and complicated P. falciparum malaria). Cellular permeability was investigated using a fluorescein isothiocyanate (FITC)-dextran permeability assay. FTY720, an analogue of sphingosine-1-phosphate (S1P), was tested for its potential action in maintaining EC integrity. ECs incubated with sera from malaria patients with complicated P. falciparum showed higher fluorescein leakage compared with ECs incubated with sera from P. vivax (p < 0.001) and uncomplicated P. falciparum (p < 0.001). ECs pretreated with FTY720 before incubation with malaria sera had significantly decreased fluorescein leakage compared with no FTY720 treatment. In addition, FTY720 treatment significantly reduced fluorescein leakage for both uncomplicated (at 45 min) (p = 0.015), and complicated P. falciparum malaria (15 min) (p = 0.043). The permeability increase induced by complicated P. falciparum sera was significantly reversed and prevented by FTY720 in vitro. FTY720 may have clinical applications to protect against endothelial barrier dysfunction in severe P. falciparum malaria.
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22
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Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment. Cancers (Basel) 2018; 10:cancers10070227. [PMID: 29987226 PMCID: PMC6071084 DOI: 10.3390/cancers10070227] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/03/2018] [Accepted: 07/05/2018] [Indexed: 12/12/2022] Open
Abstract
As one of the important cancer hallmarks, metabolism reprogramming, including lipid metabolism alterations, occurs in tumor cells and the tumor microenvironment (TME). It plays an important role in tumorigenesis, progression, and metastasis. Lipids, and several lysophospholipids in particular, are elevated in the blood, ascites, and/or epithelial ovarian cancer (EOC) tissues, making them not only useful biomarkers, but also potential therapeutic targets. While the roles and signaling of these lipids in tumor cells are extensively studied, there is a significant gap in our understanding of their regulations and functions in the context of the microenvironment. This review focuses on the recent study development in several oncolipids, including lysophosphatidic acid and sphingosine-1-phosphate, with emphasis on TME in ovarian cancer.
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23
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Kajani S, Curley S, McGillicuddy FC. Unravelling HDL-Looking beyond the Cholesterol Surface to the Quality Within. Int J Mol Sci 2018; 19:ijms19071971. [PMID: 29986413 PMCID: PMC6073561 DOI: 10.3390/ijms19071971] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/03/2018] [Accepted: 07/04/2018] [Indexed: 12/11/2022] Open
Abstract
High-density lipoprotein (HDL) particles have experienced a turbulent decade of falling from grace with widespread demotion from the most-sought-after therapeutic target to reverse cardiovascular disease (CVD), to mere biomarker status. HDL is slowly emerging from these dark times due to the HDL flux hypothesis wherein measures of HDL cholesterol efflux capacity (CEC) are better predictors of reduced CVD risk than static HDL-cholesterol (HDL-C) levels. HDL particles are emulsions of metabolites, lipids, protein, and microRNA (miR) built on the backbone of Apolipoprotein A1 (ApoA1) that are growing in their complexity due to the higher sensitivity of the respective “omic” technologies. Our understanding of particle composition has increased dramatically within this era and has exposed how our understanding of these particles to date has been oversimplified. Elucidation of the HDL proteome coupled with the identification of specific miRs on HDL have highlighted the “hormonal” characteristics of HDL in that it carries and delivers messages systemically. HDL can dock to most peripheral cells via its receptors, including SR-B1, ABCA1, and ABCG1, which may be a critical step for facilitating HDL-to-cell communication. The composition of HDL particles is, in turn, altered in numerous disease states including diabetes, auto-immune disease, and CVD. The consequence of changes in composition, however, on subsequent biological activities of HDL is currently poorly understood and this is an important avenue for the field to explore in the future. Improving HDL particle quality as opposed to HDL quantity may, in turn, prove a more beneficial investment to reduce CVD risk.
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Affiliation(s)
- Sarina Kajani
- Cardiometabolic Research Group, Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, 4 Dublin, Ireland.
| | - Sean Curley
- Cardiometabolic Research Group, Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, 4 Dublin, Ireland.
| | - Fiona C McGillicuddy
- Cardiometabolic Research Group, Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, 4 Dublin, Ireland.
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Vaisar T, Couzens E, Hwang A, Russell M, Barlow CE, DeFina LF, Hoofnagle AN, Kim F. Type 2 diabetes is associated with loss of HDL endothelium protective functions. PLoS One 2018; 13:e0192616. [PMID: 29543843 PMCID: PMC5854245 DOI: 10.1371/journal.pone.0192616] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 01/27/2018] [Indexed: 11/18/2022] Open
Abstract
Aims/Hypothesis One of the hallmarks of diabetes is impaired endothelial function. Previous studies showed that HDL can exert protective effects on endothelium stimulating NO production and protecting from inflammation and suggested that HDL in obese people with diabetes and dyslipidemia may have lower endothelial protective function. We aimed to investigate whether type 2 diabetes impairs HDL endothelium protective functions in people with otherwise normal lipid profile. Methods In a case-control study (n = 41 per group) nested in the Cooper Center Longitudinal Study we tested the ability of HDL to protect endothelium by stimulating endothelial nitric oxide synthase activity and suppressing NFκB-mediated inflammatory response in endothelial cells. In parallel we measured HDL protein composition, sphinogosine-1-phosphate and P-selectin. Results Despite similar levels of plasma HDL-C the HDL in individuals with type 2 diabetes lost almost 40% of its ability to stimulate eNOS activity (P<0.001) and 20% of its ability to suppress TNFα-dependent NFκB-mediated inflammatory response in endothelial cells (P<0.001) compared to non-T2D controls despite similar BMI and lipid profile (HDL-C, LDL-C, TC, TG). Significantly, the ability of HDL to stimulate eNOS activity was negatively associated with plasma levels of P-selectin, an established marker of endothelial dysfunction (r = −0.32, P<0.001). Furthermore, sphingosine-1-phosphate (S1P) levels were decreased in diabetic plasma (P = 0.017) and correlated with HDL-mediated eNOS activation. Conclusions/Interpretations Collectively, our data suggest that HDL in individuals with type 2 diabetes loses its ability to maintain proper endothelial function independent of HDL-C, perhaps due to loss of S1P, and may contribute to development of diabetic complications.
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Affiliation(s)
- Tomáš Vaisar
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Erica Couzens
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Arnold Hwang
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Michael Russell
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | | | - Laura F DeFina
- The Cooper Institute, Dallas, Texas, United States of America
| | - Andrew N Hoofnagle
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
| | - Francis Kim
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington, United States of America
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Shirakabe K, Higashiyama M, Furuhashi H, Takajo T, Maruta K, Okada Y, Kurihara C, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Saruta M, Hokari R. Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine-1-phosphate lyase inhibitor. J Gastroenterol Hepatol 2018; 33:1608-1616. [PMID: 29336057 DOI: 10.1111/jgh.14092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 12/18/2017] [Accepted: 12/29/2017] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Sphingosine-1-phosphate (S1P) receptor 1, a therapeutic target of the S1P1 agonist FTY720, plays a crucial role in lymphocyte migration and is expressed in several cells including naïve T lymphocytes and endothelial cells. 2-Acetyl-4-tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase, exhibits immunomodulatory activity through increasing the S1P concentration in the secondary lymphoid organs, but its effects on colitis remain unclear. This study aimed to clarify how THI affects colitis and migration of naïve T lymphocytes in Peyer's patches (PPs). METHODS The effect of THI on gut immunity was investigated by analyzing the dextran sulfate sodium (DSS)-induced murine colitis model, lymphocyte components in thoracic duct lymphocytes (TDLs), and microscopic movement of TDLs in PPs. RESULTS 2-Acetyl-4-tetrahydroxybutyl imidazole ameliorated DSS-induced colitis histologically by causing a significant decrease in colonic lymphocyte infiltration and expression of mucosal pro-inflammatory cytokines. THI suppressed the inflow of naïve T lymphocytes into the thoracic duct. Microscopic observation of PPs in control animals revealed that many TDLs egressed to the stroma and migrated to lymph capillaries after attaching to the high endothelial venules (HEVs). THI or FTY720 treatment in recipient animals blocked lymphocyte egression from the HEVs to the stroma. CONCLUSIONS This is the first study to clarify the ameliorating effects of THI on DSS-induced colitis. Microscopic observations demonstrated the involvement of HEVs in the egression of S1P-dependent gut-tropic T lymphocytes to lymph capillaries. This S1P lyase inhibitor might become a novel immunosuppressant for inflammatory bowel disease therapy by blocking infiltration of lymphocytes through HEVs into the stroma in PPs.
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Affiliation(s)
- Kazuhiko Shirakabe
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Masaaki Higashiyama
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Hirotaka Furuhashi
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Takeshi Takajo
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Koji Maruta
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Yoshikiyo Okada
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Chie Kurihara
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Chikako Watanabe
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Shunsuke Komoto
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Kengo Tomita
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Shigeaki Nagao
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Soichiro Miura
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
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26
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Vitamin D attenuates sphingosine-1-phosphate (S1P)-mediated inhibition of extravillous trophoblast migration. Placenta 2017; 60:1-8. [PMID: 29208234 PMCID: PMC5754325 DOI: 10.1016/j.placenta.2017.09.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 09/17/2017] [Accepted: 09/21/2017] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Failure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE). In other systems, the sphingolipid, sphingosine-1-phosphate (S1P), controls cell migration therefore this study determined its effect on extravillous trophoblast (EVT) function. METHODS A transwell migration system was used to assess the behaviour of three trophoblast cell lines, Swan-71, SGHPL-4, and JEG3, and primary human trophoblasts in the presence or absence of S1P, S1P pathway inhibitors and 1,25(OH)2D3. QPCR and immunolocalisation were used to demonstrate EVT S1P receptor expression. RESULTS EVTs express S1P receptors 1, 2 and 3. S1P inhibited EVT migration. This effect was abolished in the presence of the specific S1PR2 inhibitor, JTE-013 (p < 0.05 versus S1P alone) whereas treatment with the S1R1/3 inhibitor, FTY720, had no effect. In other cell types S1PR2 is regulated by vitamin D; here we found that treatment with 1,25(OH)2D3 for 48 or 72 h reduces S1PR2 (4-fold; <0.05), but not R1 and R3, expression. Moreover, S1P did not inhibit the migration of cells exposed to 1,25(OH)2D3 (p < 0.05). DISCUSSION This study demonstrates that although EVT express three S1P receptor isoforms, S1P predominantly signals through S1PR2/Gα12/13 to activate Rho and thereby acts as potent inhibitor of EVT migration. Importantly, expression of S1PR2, and therefore S1P function, can be down-regulated by vitamin D. Our data suggest that vitamin D deficiency, which is known to be associated with PE, may contribute to the impaired trophoblast migration that underlies this condition.
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27
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Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and potential therapeutic target for bone repair. Pharmacol Res 2017; 125:232-245. [PMID: 28855094 DOI: 10.1016/j.phrs.2017.08.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 08/22/2017] [Accepted: 08/23/2017] [Indexed: 12/30/2022]
Abstract
The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis-related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P's role in promoting angiogenesis is well-established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico-chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair.
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28
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Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 2017; 20:409-426. [PMID: 28660302 DOI: 10.1007/s10456-017-9562-9] [Citation(s) in RCA: 998] [Impact Index Per Article: 124.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 06/21/2017] [Indexed: 12/27/2022]
Abstract
Tumor blood vessels are a key target for cancer therapeutic management. Tumor cells secrete high levels of pro-angiogenic factors which contribute to the creation of an abnormal vascular network characterized by disorganized, immature and permeable blood vessels, resulting in poorly perfused tumors. The hypoxic microenvironment created by impaired tumor perfusion can promote the selection of more invasive and aggressive tumor cells and can also impede the tumor-killing action of immune cells. Furthermore, abnormal tumor perfusion also reduces the diffusion of chemotherapeutic drugs and radiotherapy efficiency. To fight against this defective phenotype, the normalization of the tumor vasculature has emerged as a new therapeutic strategy. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. In this review, we investigate the mechanisms involved in tumor angiogenesis and describe strategies used to achieve vascular normalization.
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29
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Rodriguez-Cuenca S, Pellegrinelli V, Campbell M, Oresic M, Vidal-Puig A. Sphingolipids and glycerophospholipids - The "ying and yang" of lipotoxicity in metabolic diseases. Prog Lipid Res 2017; 66:14-29. [PMID: 28104532 DOI: 10.1016/j.plipres.2017.01.002] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 11/30/2016] [Accepted: 01/05/2017] [Indexed: 12/14/2022]
Abstract
Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of "ying/yang" interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.
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Affiliation(s)
- S Rodriguez-Cuenca
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK.
| | - V Pellegrinelli
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK
| | - M Campbell
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK
| | - M Oresic
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI -20520 Turku, Finland
| | - A Vidal-Puig
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK.
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High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression. Atherosclerosis 2017; 257:29-37. [DOI: 10.1016/j.atherosclerosis.2016.12.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 11/22/2016] [Accepted: 12/08/2016] [Indexed: 01/11/2023]
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31
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Ruiz M, Frej C, Holmér A, Guo LJ, Tran S, Dahlbäck B. High-Density Lipoprotein-Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1. Arterioscler Thromb Vasc Biol 2016; 37:118-129. [PMID: 27879252 DOI: 10.1161/atvbaha.116.308435] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 11/08/2016] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Plasma high-density lipoproteins (HDL) are potent antiatherogenic and anti-inflammatory particles. However, HDL particles are highly heterogenic in composition, and different HDL-mediated functions can be ascribed to different subclasses of HDL. Only a small HDL population contains apolipoprotein M (ApoM), which is the main plasma carrier of the bioactive lipid mediator sphingosine-1-phosphate (S1P). Vascular inflammation is modulated by S1P, but both pro- and anti-inflammatory roles have been ascribed to S1P. The goal of this study is to elucidate the role of ApoM and S1P in endothelial anti-inflammatory events related to HDL. APPROACH AND RESULTS Aortic or brain human primary endothelial cells were challenged with tumor necrosis factor-α (TNF-α) as inflammatory stimuli. The presence of recombinant ApoM-bound S1P or ApoM-containing HDL reduced the abundance of adhesion molecules in the cell surface, whereas ApoM and ApoM-lacking HDL did not. Specifically, ApoM-bound S1P decreased vascular adhesion molecule-1 (VCAM-1) and E-selectin surface abundance but not intercellular adhesion molecule-1. Albumin, which is an alternative S1P carrier, was less efficient in inhibiting VCAM-1 than ApoM-bound S1P. The activation of the S1P receptor 1 was sufficient and required to promote anti-inflammation. Moreover, ApoM-bound S1P induced the rearrangement of the expression of S1P-related genes to counteract TNF-α. Functionally, HDL/ApoM/S1P limited monocyte adhesion to the endothelium and maintained endothelial barrier integrity under inflammatory conditions. CONCLUSIONS ApoM-bound S1P is a key component of HDL and is responsible for several HDL-associated protective functions in the endothelium, including regulation of adhesion molecule abundance, leukocyte-endothelial adhesion, and endothelial barrier.
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Affiliation(s)
- Mario Ruiz
- From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
| | - Cecilia Frej
- From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Andreas Holmér
- From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Li J Guo
- From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Sinh Tran
- From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Björn Dahlbäck
- From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
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32
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Vito CD, Hadi LA, Navone SE, Marfia G, Campanella R, Mancuso ME, Riboni L. Platelet-derived sphingosine-1-phosphate and inflammation: from basic mechanisms to clinical implications. Platelets 2016; 27:393-401. [PMID: 26950429 DOI: 10.3109/09537104.2016.1144179] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Beyond key functions in hemostasis and thrombosis, platelets are recognized as key players of inflammation, an underlying feature of a variety of diseases. In this regard, platelets act as a circulating source of several pro- and anti-inflammatory molecules, which are secreted from their intracellular stores upon activation. Among them, mounting evidence highlights a crucial role of sphingosine-1-phosphate (S1P), a multifunctional sphingoid mediator. S1P-induced pleiotropic effects include those crucial in inflammatory processes, such as the maintenance of the endothelial barrier integrity, and leukocyte activation and recruitment at the injured site. This review outlines the peculiar features and molecular mechanisms that allow platelets for acting as a unique factory that produces and stores S1P in large quantities. A particular emphasis is placed on the autocrine and paracrine roles of S1P derived from the "inflamed" platelets, highlighting the role of its cross-talk with endothelial and blood cells involved in inflammation, and the mechanisms of its contribution to the development and progression of inflammatory diseases. Finally, potential clinical implications of platelet-derived S1P as diagnostic tool of inflammatory severity, and as therapeutic target in inflammation are discussed.
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Affiliation(s)
- Clara Di Vito
- a Department of Medical Biotechnology and Translational Medicine, LITA-Segrate , University of Milan , Milan , Italy
| | - Loubna Abdel Hadi
- a Department of Medical Biotechnology and Translational Medicine, LITA-Segrate , University of Milan , Milan , Italy
| | - Stefania Elena Navone
- b Neurosurgery Unit, Laboratory of Experimental Neurosurgery and Cell Therapy, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico , University of Milan , Milan , Italy
| | - Giovanni Marfia
- b Neurosurgery Unit, Laboratory of Experimental Neurosurgery and Cell Therapy, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico , University of Milan , Milan , Italy
| | - Rolando Campanella
- c Division of Neurosurgery, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico , University of Milan , Milan , Italy
| | - Maria Elisa Mancuso
- d Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico , Milan , Italy
| | - Laura Riboni
- a Department of Medical Biotechnology and Translational Medicine, LITA-Segrate , University of Milan , Milan , Italy
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Jernigan PL, Makley AT, Hoehn RS, Edwards MJ, Pritts TA. The role of sphingolipids in endothelial barrier function. Biol Chem 2016; 396:681-91. [PMID: 25867999 DOI: 10.1515/hsz-2014-0305] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 04/08/2015] [Indexed: 12/31/2022]
Abstract
Sphingolipids are a ubiquitous family of essential lipids with an increasingly understood role as biologically active mediators in numerous physiologic and pathologic processes. Two particular sphingolipid species, sphingosine-1-phosphate and ceramide, and their metabolites interact both directly and indirectly with endothelial cells to regulate vascular permeability. Sphingosine-1-phosphate generally augments endothelial integrity while ceramide tends to promote vascular leak, and a tight balance between the two is necessary to maintain normal physiologic function. The mechanisms by which sphingolipids regulate endothelial barrier function are complex and occur through multiple different pathways, and disruptions or imbalances in these pathways have been implicated in a number of specific disease processes. With improved understanding of sphingolipid biology, endothelial function, and the interactions between the two, several targets for therapeutic intervention have emerged and there is immense potential for further advancement in this field.
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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Laurenzana A, Cencetti F, Serratì S, Bruno G, Japtok L, Bianchini F, Torre E, Fibbi G, Del Rosso M, Bruni P, Donati C. Endothelial sphingosine kinase/SPNS2 axis is critical for vessel-like formation by human mesoangioblasts. J Mol Med (Berl) 2015; 93:1145-57. [PMID: 25952146 DOI: 10.1007/s00109-015-1292-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 04/10/2015] [Accepted: 04/15/2015] [Indexed: 10/23/2022]
Abstract
UNLABELLED The interaction between endothelial cells and pericytes is crucial for the stabilization of newly formed vessels in angiogenesis. The comprehension of the mechanisms regulating pericyte recruitment might open therapeutical perspectives on vascular-related pathologies. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that derives from sphingomyelin catabolism and regulates biological functions in cell survival, proliferation, and differentiation. In this study, we aimed to identify the role of S1P axis in the intercellular communication between human mesenchymal progenitor mesoangioblasts (MAB) and endothelial cells (human microvascular endothelial cells (H-MVEC)) in the formation of capillary-like structures. We demonstrated that the S1P biosynthetic pathway brought about by sphingosine kinases (SK) SK1 and SK2 as well as spinster homolog 2 (SPNS2) transporter in H-MVEC is crucial for MAB migration measured by Boyden chambers and for the formation and stabilization of capillary-like structures in a 3D Matrigel culture. Moreover, the conditioned medium (CM) harvested from H-MVEC, where SK1, SK2, and SPNS2 were down-regulated, exerted a significantly diminished effect on MAB capillary morphogenesis and migration. Notably, we demonstrated that S1P1 and S1P3 receptors were positively involved in CM-induced capillary-like formation and migration, while S1P2 exerted a negative role on CM-induced migratory action of MAB. Finally, SK inhibition as well as MAB S1P1 and S1P3 down-regulation impaired H-MVEC-MAB cross-talk significantly reducing in vivo angiogenesis evaluated by Matrigel plug assay. These findings individuate novel targets for the employment of MAB in vascular-related pathologic conditions. KEY MESSAGE • Down-regulation of SK1/2 in H-MVEC impaired vessel formation when cultured with MAB. • H-MVEC SPNS2 is critical for morphogenesis and migration induced by H-MVEC CM of MAB. • CM from SK1- and SK2-siRNA H-MVEC impaired morphogenesis and migration of MAB. • S1P1/3 were involved on CM-induced morphogenesis and migration of MAB. • Matrigel plug assay showed the role of S1P axis in MAB-endothelial cell interaction.
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Affiliation(s)
- Anna Laurenzana
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Francesca Cencetti
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Simona Serratì
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy.,Department of Experimental Oncology, Hematology Unit, Advanced Cellular Therapy Centre, Bari, Italy
| | - Gennaro Bruno
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Lukasz Japtok
- Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558, Potsdam, Nuthetal, Germany
| | - Francesca Bianchini
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Eugenio Torre
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Gabriella Fibbi
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Mario Del Rosso
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Paola Bruni
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy
| | - Chiara Donati
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy.
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Bosteen MH, Dahlbäck B, Nielsen LB, Christoffersen C. Protein unfolding allows use of commercial antibodies in an apolipoprotein M sandwich ELISA. J Lipid Res 2015; 56:754-759. [PMID: 25561460 DOI: 10.1194/jlr.d055947] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
apoM is a member of the lipocalin superfamily and circulates in plasma attached to HDL particles. apoM plays a role in cholesterol metabolism and has recently been identified as transporter for the signaling lipid, sphingosine-1-phosphate (S1P), in plasma. S1P is implicated in several inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. The ability to accurately measure apoM is crucial for investigating its biological functions and possible clinical implications. However, reliable commercial methods have been lacking so far. Therefore, we have developed an assay that specifically recognizes human apoM in plasma using commercially available reagents. Commercial apoM antibodies were screened for compatibility in a sandwich ELISA-based assay. One optimal pair of antibodies was chosen, and sample preparation, buffers, and incubation times were optimized to generate a simple and reproducible method. Validation and comparison to a previously described ELISA for apoM confirmed that the assay displays a high degree of sensitivity, specificity, and precision. Our results show that commercially available antibodies can be used to accurately measure human plasma apoM. This method can be implemented in every laboratory and will help promote high quality research.
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Affiliation(s)
- Markus Høybye Bosteen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Biomedical SciencesUniversity of Copenhagen, Copenhagen, Denmark
| | - Björn Dahlbäck
- Department of Clinical Chemistry, University of Lund, Malmö, Sweden
| | - Lars Bo Nielsen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Biomedical SciencesUniversity of Copenhagen, Copenhagen, Denmark.
| | - Christina Christoffersen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Biomedical SciencesUniversity of Copenhagen, Copenhagen, Denmark.
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Riwanto M, Rohrer L, von Eckardstein A, Landmesser U. Dysfunctional HDL: from structure-function-relationships to biomarkers. Handb Exp Pharmacol 2015; 224:337-366. [PMID: 25522994 DOI: 10.1007/978-3-319-09665-0_10] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipid-modifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.
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Affiliation(s)
- Meliana Riwanto
- Cardiology, University Heart Center, University Hospital Zurich and Center of Molecular Cardiology, University of Zurich, Rämistrasse 100, CH 8091, Zurich, Switzerland
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Abstract
High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.
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Affiliation(s)
- Wijtske Annema
- Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland,
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Kontush A, Lindahl M, Lhomme M, Calabresi L, Chapman MJ, Davidson WS. Structure of HDL: particle subclasses and molecular components. Handb Exp Pharmacol 2015; 224:3-51. [PMID: 25522985 DOI: 10.1007/978-3-319-09665-0_1] [Citation(s) in RCA: 171] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
A molecular understanding of high-density lipoprotein (HDL) will allow a more complete grasp of its interactions with key plasma remodelling factors and with cell-surface proteins that mediate HDL assembly and clearance. However, these particles are notoriously heterogeneous in terms of almost every physical, chemical and biological property. Furthermore, HDL particles have not lent themselves to high-resolution structural study through mainstream techniques like nuclear magnetic resonance and X-ray crystallography; investigators have therefore had to use a series of lower resolution methods to derive a general structural understanding of these enigmatic particles. This chapter reviews current knowledge of the composition, structure and heterogeneity of human plasma HDL. The multifaceted composition of the HDL proteome, the multiple major protein isoforms involving translational and posttranslational modifications, the rapidly expanding knowledge of the HDL lipidome, the highly complex world of HDL subclasses and putative models of HDL particle structure are extensively discussed. A brief history of structural studies of both plasma-derived and recombinant forms of HDL is presented with a focus on detailed structural models that have been derived from a range of techniques spanning mass spectrometry to molecular dynamics.
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Affiliation(s)
- Anatol Kontush
- National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France,
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Li Q, Chen B, Zeng C, Fan A, Yuan Y, Guo X, Huang X, Huang Q. Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells. Exp Physiol 2014; 100:95-107. [PMID: 25557733 DOI: 10.1113/expphysiol.2014.082149] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 10/21/2014] [Indexed: 01/08/2023]
Abstract
NEW FINDINGS What is the central question of this study? Why do different doses of sphingosine-1-phosphate (S1P) induce distinct biological effects in endothelial cells? What is the main finding and its importance? S1P at physiological concentrations preserved endothelial barrier function by binding to S1P receptor 1, then triggering Ca(2+) release from endoplasmic reticulum through phosphoinositide phospholipase C and inositol triphosphate, and consequently strengthening tight junction and F-actin assembly through Rac1 activation. Excessive S1P induced endothelial malfunction by activating S1P receptor 2 and RhoA/ROCK pathway, causing F-actin and tight junction disorganisation. Extracellular Ca(2+) influx was involved in this process. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid in plasma, and its plasma concentration can be adjusted through a complex metabolic process. The alterations in S1P levels and the activation of receptors collaboratively regulate distinct biological effects. This study was performed to investigate comparatively the effect of different concentrations of S1P on endothelial barrier function and to explore the roles of S1P receptors (S1PRs), Rho GTPases and calcium in S1P-induced endothelial responses. Endothelial barrier function was studied using transendothelial electric resistance and a resistance meter in human umbilical vein endothelial cells. Specific agonists or antagonists were applied to control the activation of S1P receptors and the release of calcium from different cellular compartments. The results indicated that at physiological concentrations, S1P preserved endothelial barrier function by binding with S1PR1. The activation of S1PR1 triggered the release of intracellular Ca(2+) from the endoplasmic reticulum through the PI-phospholipase C and inositol trisphosphate pathways. Consequently, the Rho GTPase Rac1 was activated, strengthening the assembly of tight junction proteins and F-actin. However, excessive S1P induced endothelial barrier dysfunction by activating S1PR2 followed by the RhoA/RhoA kinase pathway, causing the disorganization of F-actin and the disassembly of the tight junction protein ZO-1. An influx of extracellular Ca(2+) was involved in this process. These data suggest that physiological and excessive amounts of S1P induce different responses in human umbilical vein endothelial cells; the activation of the 1PR1-PLC-IP3 R-Ca(2+) -Rac1 pathway governs the low-dose S1P-enhanced endothelial barrier integrity, and the activation of S1PR2-calcium influx-RhoA/ROCK dominates the high-dose S1P-induced endothelial monolayer hyperpermeability response.
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Affiliation(s)
- Qiang Li
- Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, 510515, PR China
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Ocwieja M, Meiser K, David OJ, Valencia J, Wagner F, Schreiber SJ, Pleyer U, Ziemer S, Schmouder R. Effect of fingolimod (FTY720) on cerebral blood flow, platelet function and macular thickness in healthy volunteers. Br J Clin Pharmacol 2014; 78:1354-65. [PMID: 24976291 PMCID: PMC4256624 DOI: 10.1111/bcp.12454] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 06/23/2014] [Indexed: 12/16/2022] Open
Abstract
AIM Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral disease modifying therapy approved for the treatment of relapsing multiple sclerosis. The aim of this double-blind, placebo-controlled study was to evaluate the effect of fingolimod on cerebral blood flow, platelet function and macular thickness in healthy volunteers. METHODS The study included 88 healthy volunteers who received fingolimod 0.5 mg or 1.25 mg or matched placebo over a period of 4 weeks. Transcranial colour coded sonography was performed to measure mean blood flow velocities, the platelet function was measured by the PFA-100® assay using a collagen/epinephrine cartridge and macular thickness was measured using optical coherence tomography. An assessment of non-inferiority of fingolimod vs. placebo was performed against a reference value (20% of the overall baseline value). RESULTS All 88 randomized participants completed the study. At day 28 compared with baseline value, for 0.5 mg, 1.25 mg and placebo treatments, the mean middle cerebral artery blood flow velocity decreased by 4, 1 and 3.7 cm s(-1), respectively. The platelet function analyzer closure time increase was not significant (7.8, 7.5 and 10.4 s, respectively). The mean percentage change in the central foveal thickness from baseline for both eyes was below 3% for all groups. The safety profile of fingolimod in this study was found consistent with the previous reports. CONCLUSIONS In healthy volunteers, the changes seen with both fingolimod doses were found to be within normal variability, non-inferior and comparable with those observed with placebo for all the pharmacodynamic parameters assessed.
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Affiliation(s)
| | | | | | | | - Frank Wagner
- Charité Research Organisation GmbHCharitéplatz 1, Berlin, Germany
| | - Stephan J Schreiber
- Department of Neurology, Universitätsmedizin BerlinCharitéplatz 1, Berlin, Germany
- Department of Neurology, Charité UniversitätsmedizinCharitéplatz 1, Berlin, Germany
| | - Uwe Pleyer
- Department of Ophthalmology, Universitätsmedizin BerlinAugustenburger Platz 1, Berlin, Germany
- Department of Ophthalmology, Charité UniversitätsmedizinCharitéplatz 1, Berlin, Germany
| | - Sabine Ziemer
- Institute for Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Universitätsmedizin BerlinCharitéplatz 1, Berlin, Germany
- Coagulation Laboratory, Charité UniversitätsmedizinCharitéplatz 1, Berlin, Germany
| | - Robert Schmouder
- Novartis Institutes for Biomedical Research, Inc.Massachusetts Avenue, Cambridge, MA, USA
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Tran-Dinh A, Diallo D, Delbosc S, Varela-Perez LM, Dang QB, Lapergue B, Burillo E, Michel JB, Levoye A, Martin-Ventura JL, Meilhac O. HDL and endothelial protection. Br J Pharmacol 2014; 169:493-511. [PMID: 23488589 DOI: 10.1111/bph.12174] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 02/07/2013] [Accepted: 02/24/2013] [Indexed: 12/23/2022] Open
Abstract
High-density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apoA-I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity.
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Samarska IV, Bouma HR, Buikema H, Mungroop HE, Houwertjes MC, Absalom AR, Epema AH, Henning RH. S1P1 receptor modulation preserves vascular function in mesenteric and coronary arteries after CPB in the rat independent of depletion of lymphocytes. PLoS One 2014; 9:e97196. [PMID: 24819611 PMCID: PMC4018292 DOI: 10.1371/journal.pone.0097196] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 04/16/2014] [Indexed: 11/25/2022] Open
Abstract
Background Cardiopulmonary bypass (CPB) may induce systemic inflammation and vascular dysfunction. Sphingosine 1-phosphate (S1P) modulates various vascular and immune responses. Here we explored whether agonists of the S1P receptors, FTY720 and SEW2871 improve vascular reactivity after CPB in the rat. Methods Experiments were done in male Wistar rats (total n = 127). Anesthesia was induced by isoflurane (2.5–3%) and maintained by fentanyl and midazolam during CPB. After catheterization of the left femoral artery, carotid artery and the right atrium, normothermic extracorporeal circulation was instituted for 60 minutes. In the first part of the study animals were euthanized after either 1 hour, 1 day, 2 or 5 days of the recovery period. In second part of the study animals were euthanized after 1 day of postoperative period. We evaluated the contractile response to phenylephrine (mesenteric arteries) or to serotonin (coronary artery) and vasodilatory response to acethylcholine (both arteries). Results Contractile responses to phenylephrine were reduced at 1 day recovery after CPB and Sham as compared to healthy control animals (Emax, mN: 7.9±1.9, 6.5±1.5, and 11.3±1.3, respectively). Mainly FTY720, but not SEW2871, caused lymphopenia in both Sham and CPB groups. In coronary and mesenteric arteries, both FTY720 and SEW2871 normalized serotonin and phenylephrine-mediated vascular reactivity after CPB (p<0.05) and FTY720 increased relaxation to acetylcholine as compared with untreated rats that underwent CPB. Conclusion Pretreatment with FTY720 or SEW2871 preserves vascular function in mesenteric and coronary artery after CPB. Therefore, pharmacological activation of S1P1 receptors may provide a promising therapeutic intervention to prevent CPB-related vascular dysfunction in patients.
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Affiliation(s)
- Iryna V. Samarska
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands
- * E-mail:
| | - Hjalmar R. Bouma
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Hendrik Buikema
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Hubert E. Mungroop
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Martin C. Houwertjes
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Anthony R. Absalom
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Anne H. Epema
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Robert H. Henning
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
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Poitevin S, Cussac D, Leroyer AS, Albinet V, Sarlon-Bartoli G, Guillet B, Hubert L, Andrieu-Abadie N, Couderc B, Parini A, Dignat-George F, Sabatier F. Sphingosine kinase 1 expressed by endothelial colony-forming cells has a critical role in their revascularization activity. Cardiovasc Res 2014; 103:121-30. [PMID: 24743591 DOI: 10.1093/cvr/cvu104] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIMS Cell therapy based on endothelial colony-forming cells (ECFCs) is a promising option for ischaemic cardiovascular diseases. A better understanding of the mechanisms by which these cells promote revascularization remains a critical challenge to improving their therapeutic potential. We aimed to identify the critical mechanisms involved in the revascularization activity of ECFCs by using the paracrine properties of mesenchymal stem cells (MSC). METHODS AND RESULTS Conditioned medium from human bone marrow-derived MSCs (MSC-CM) increased the angiogenic activity of cord blood ECFCs in vitro (proliferation, migration, and pseudo-tube formation), the survival of ECFCs in mice (Matrigel Plug assay), and the capacity of ECFCs to promote the recovery of blood perfusion in mice with hindlimb ischaemia. Furthermore, the capillary density in ischaemic gastrocnemius muscle was significantly increased in mice transplanted with the ECFCs pre-treated with the MSC-CM. The enhancement of ECFCs activity involved the up-regulation of sphingosine kinase 1 (SphK1) expression and activity. The inhibition of SphK1 in ECFCs by using an inhibitor or a siRNA knockdown of SphK1 prevented the stimulation of the ECFCs induced by the MSC-CM. The improvement of ECFC activity by MSC-CM also involved the up-regulation of sphingosine-1-phosphate receptor 1 (S1P1) and a S1P/S1P1/3-dependent mechanism. Finally, we showed that the stimulation of ECFCs with exogenous S1P increased angiogenesis and promoted blood perfusion in hindlimb ischaemia. CONCLUSION The up-regulation of SphK1 and S1P-dependent pathways is critical for the angiogenic/vasculogenic activity of ECFCs. The identification of this pathway provides attractive targets to optimize cell-based therapy for revascularization in ischaemic diseases.
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Affiliation(s)
- Stéphane Poitevin
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Daniel Cussac
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse III, 1 Av Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France
| | - Aurélie S Leroyer
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Virginie Albinet
- Centre de Recherche en Cancérologie, INSERM UMR-1037, Université de Toulouse III, BP 84225, CHU Rangueil, 31432 Toulouse Cedex 4, France
| | - Gabrielle Sarlon-Bartoli
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Benjamin Guillet
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Lucas Hubert
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Nathalie Andrieu-Abadie
- Centre de Recherche en Cancérologie, INSERM UMR-1037, Université de Toulouse III, BP 84225, CHU Rangueil, 31432 Toulouse Cedex 4, France
| | - Bettina Couderc
- EA 4553: Individualisation des Traitements des Cancers Ovariens et ORL, Institut Claudius Regaud, 20-24 rue du Pont St Pierre, 31052 Toulouse Cedex 4, France
| | - Angelo Parini
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse III, 1 Av Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France
| | - Françoise Dignat-George
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Florence Sabatier
- Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
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Kondo S, Bottos A, Allegood JC, Masson R, Maurer FG, Genoud C, Kaeser P, Huwiler A, Murakami M, Spiegel S, Hynes NE. Memo has a novel role in S1P signaling and is [corrected] crucial for vascular development. PLoS One 2014; 9:e94114. [PMID: 24714781 PMCID: PMC3979765 DOI: 10.1371/journal.pone.0094114] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 03/13/2014] [Indexed: 11/24/2022] Open
Abstract
Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation.
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Affiliation(s)
- Shunya Kondo
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Alessia Bottos
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Jeremy C. Allegood
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Regis Masson
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | | | - Christel Genoud
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Patrick Kaeser
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Andrea Huwiler
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Masato Murakami
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Nancy E. Hynes
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- University of Basel, Basel, Switzerland
- * E-mail:
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Hamidi S, Schäfer-Korting M, Weindl G. TLR2/1 and sphingosine 1-phosphate modulate inflammation, myofibroblast differentiation and cell migration in fibroblasts. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1841:484-94. [DOI: 10.1016/j.bbalip.2014.01.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 12/30/2013] [Accepted: 01/06/2014] [Indexed: 02/04/2023]
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Abstract
Lymphangiogenesis, the growth of lymphatic vessels, is essential in embryonic development. In adults, it is involved in many pathological processes such as lymphedema, inflammatory diseases, and tumor metastasis. Advances during the past decade have dramatically increased the knowledge of the mechanisms of lymphangiogenesis, including the roles of transcription factors, lymphangiogenic growth factors and their receptors, and intercellular and intracellular signaling cascades. Strategies based on these mechanisms are being tested in the treatment of various human diseases such as cancer, lymphedema, and tissue allograft rejection. This Review summarizes the recent progress on lymphangiogenic mechanisms and their applications in disease treatment.
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Adamson RH, Clark JF, Radeva M, Kheirolomoom A, Ferrara KW, Curry FE. Albumin modulates S1P delivery from red blood cells in perfused microvessels: mechanism of the protein effect. Am J Physiol Heart Circ Physiol 2014; 306:H1011-7. [PMID: 24531813 DOI: 10.1152/ajpheart.00829.2013] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Removal of plasma proteins from perfusates increases vascular permeability. The common interpretation of the action of albumin is that it forms part of the permeability barrier by electrostatic binding to the endothelial glycocalyx. We tested the alternate hypothesis that removal of perfusate albumin in rat venular microvessels decreased the availability of sphingosine-1-phosphate (S1P), which is normally carried in plasma bound to albumin and lipoproteins and is required to maintain stable baseline endothelial barriers (Am J Physiol Heart Circ Physiol 303: H825-H834, 2012). Red blood cells (RBCs) are a primary source of S1P in the normal circulation. We compared apparent albumin permeability coefficients [solute permeability (Ps)] measured using perfusates containing albumin (10 mg/ml, control) and conditioned by 20-min exposure to rat RBCs with Ps when test perfusates were in RBC-conditioned protein-free Ringer solution. The control perfusate S1P concentration (439 ± 46 nM) was near the normal plasma value at 37 °C and established a stable baseline Ps (0.9 ± 0.4 × 10(-6) cm/s). Ringer solution perfusate contained 52 ± 8 nM S1P and increased Ps more than 10-fold (16.1 ± 3.9 × 10(-6) cm/s). Consistent with albumin-dependent transport of S1P from RBCs, S1P concentrations in RBC-conditioned solutions decreased as albumin concentration, hematocrit, and temperature decreased. Protein-free Ringer solution perfusates that used liposomes instead of RBCs as flow markers failed to maintain normal permeability, reproducing the "albumin effect" in these mammalian microvessels. We conclude that the albumin effect depends on the action of albumin to facilitate the release and transport of S1P from RBCs that normally provide a significant amount of S1P to the endothelium.
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Affiliation(s)
- R H Adamson
- Department of Physiology and Membrane Biology, University of California, Davis, California; and
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Review: Novel insights into the regulation of vascular tone by sphingosine 1-phosphate. Placenta 2014; 35 Suppl:S86-92. [DOI: 10.1016/j.placenta.2013.12.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 12/10/2013] [Accepted: 12/11/2013] [Indexed: 11/17/2022]
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50
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Combined delivery of HMGB-1 box A peptide and S1PLyase siRNA in animal models of acute lung injury. J Control Release 2014; 175:25-35. [DOI: 10.1016/j.jconrel.2013.12.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 11/23/2013] [Accepted: 12/09/2013] [Indexed: 12/24/2022]
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