1,868 results on '"Receptors, Lysosphingolipid"'
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2. Sphingosine-1-phosphate Attenuates Endoplasmic Reticulum Stress-induced Cardiomyocyte Apoptosis Through Sphingosine-1-phosphate Receptor 1
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Kengquan, Chen, Zhongqin, Wang, Chao, Liu, Xing, Yang, and Jiangang, Jiang
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Mitogen-Activated Protein Kinase Kinases ,Heart Diseases ,Tunicamycin ,Imidazoles ,General Medicine ,Endoplasmic Reticulum Stress ,Mice ,Phosphatidylinositol 3-Kinases ,Receptors, Lysosphingolipid ,Sphingosine ,Animals ,Thapsigargin ,Myocytes, Cardiac ,Lysophospholipids ,Proto-Oncogene Proteins c-akt ,Sphingosine-1-Phosphate Receptors ,Signal Transduction - Abstract
Endoplasmic reticulum stress (ER stress) is involved in the development and progression of various forms of heart disease and may lead to myocardial apoptosis. Sphingosine-1-phosphate (S1P) possesses cardioprotective properties, including anti-apoptosis. However, little is known about the link between S1P and ER stress-induced myocardial apoptosis. This study investigated the regulatory role of S1P in ER stress-induced apoptosis in cardiomyocytes.ER stress and myocardial apoptosis were induced by transverse aortic constriction (TAC) or tunicamycin in mice, which were then treated with 2-acetyl-5-tetrahydroxybutyl imidazole (THI) or S1P. AC16 cells were treated with tunicamycin or thapsigargin, or pretreated with S1P, sphingosine-1-phosphate receptor (S1PR) subtype antagonists, S1PR1 agonist, and PI3K and MEK inhibitors. Cardiac function, the level of S1P in plasma and heart, ER stress markers, cell viability, and apoptosis were detected.S1P reduced the expression of ER stress-related molecules and ER stress-induced myocardial apoptosis in mice subjected to TAC or an injection of tunicamycin. Furthermore, in AC16 cells exposed to thapsigargin or tunicamycin, S1P decreased the expression of ER stress-related molecules, promoting cell viability and survival. Nevertheless, the S1PR1 antagonist abrogated the protection of S1P. Subsequently, in TAC S1PR1 heterozygous (S1PR1sup+/-/sup) mice, S1P had no effect on ER stress and apoptosis in cardiomyocytes. Notably, in vitro, the impact of anti-ER stress-induced myocardial apoptosis by the S1PR1 agonist was reversed by PI3K and MEK inhibitors.This study is the first to demonstrate that S1P relieves ER stress-induced myocardial apoptosis via S1PR1/AKT and S1PR1/ERK1/2, which are potential therapeutic targets for heart disease.
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- 2022
3. Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases
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Nathalie Burg, Jane E. Salmon, and Timothy Hla
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Receptors, Lysosphingolipid ,Multiple Sclerosis ,Rheumatology ,Rheumatic Diseases ,Humans ,Lupus Erythematosus, Systemic ,Sphingosine-1-Phosphate Receptors ,Article ,Signal Transduction - Abstract
Sphingosine 1-phosphate (S1P), which acts via G protein-coupled S1P receptors (S1PRs), is a bioactive lipid essential for vascular integrity and lymphocyte trafficking. The S1P–S1PR signalling axis is a key component of the inflammatory response in autoimmune rheumatic diseases. Several drugs that target S1PRs have been approved for the treatment of multiple sclerosis and inflammatory bowel disease and are under clinical testing for patients with systemic lupus erythematosus (SLE). Preclinical studies support the hypothesis that targeting the S1P–S1PR axis would be beneficial to patients with SLE, rheumatoid arthritis (RA) and systemic sclerosis (SSc) by reducing pathological inflammation. Whereas most preclinical research and development efforts are focused on reducing lymphocyte trafficking, protective effects of circulating S1P on endothelial S1PRs, which maintain the vascular barrier and enable blood circulation while dampening leukocyte extravasation, have been largely overlooked. In this Review, we take a holistic view of S1P–S1PR signalling in lymphocyte and vascular pathobiology. We focus on the potential of S1PR modulators for the treatment of SLE, RA and SSc and summarize the rationale, pathobiology and evidence from preclinical models and clinical studies. Improved understanding of S1P pathobiology in autoimmune rheumatic diseases and S1PR therapeutic modulation is anticipated to lead to efficacious and safer management of these diseases.
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- 2022
4. Downregulation of miR-33a/b and miR-181a contributes to recurrent pregnancy loss by upregulating S1PR1 and repressing regulatory T cell differentiation
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Xujing Geng, Genhong Mao, Dongmei Zhao, Yungai Xiang, Meng Wang, Guo Yu, and Li Tan
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Abortion, Habitual ,Placenta ,Down-Regulation ,Obstetrics and Gynecology ,Hematopoiesis ,MicroRNAs ,Receptors, Lysosphingolipid ,Reproductive Medicine ,Pregnancy ,Sphingosine ,Humans ,Female ,Lysophospholipids ,Sphingosine-1-Phosphate Receptors ,Developmental Biology - Abstract
Successful pregnancy in humans requires adequate maternal-fetal immune tolerance. During regulatory T (Treg) cells play a key role. Sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) signaling represses Treg cell differentiation, but whether this relates to the process of recurrent pregnancy loss is still unclear.Treg cells in the placenta were examined using flow cytometry. The expression of sphingosine kinase-1 and -2(SPHK1 and SPHK2), two key kinases controlling S1P production, was detected in placenta samples from 36 patients with recurrent pregnancy loss (RPL) and 40 control participants using immunoblotting. The level of sphingosine-1-phosphate receptor-1 (S1PR1) in placental T cells was examined using RT-qPCR and immunoblotting. Cell surface S1PR1 levels were detected using flow cytometry. The interactions between miRNAs and S1PR1 mRNA were predicted using bioinformatics tools and were confirmed by dual luciferase assay and immunoblotting.RPL patients had fewer Treg cells (p = 0.034) in the placenta, especially TIM3+ Treg cells (p = 0.0076). S1PR1 protein levels were significantly increased in placental T cells of patients with RPL (p = 0.0065). MiR-33a, miR-33b, and miR-181a were reduced in the placenta from patients with RPL, which were identified to repress S1PR1 expression by targeting the 3'UTR. Knockdown of miR-33a, miR-33b and miR-181a in human naïve T cells inhibits Treg cell differentiation by upregulating S1PR1 in vitro.This study, for the first time, successfully constructed the correlation between dysregulated miRNAs in placenta and RPL, which partially unveiled the etiology of RPL and provided a therapeutic potential for RPL treatment.
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- 2022
5. Targeting neuroinflammation in neuropathic pain and opioid use
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Daniela Salvemini and Timothy M. Doyle
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Analgesics, Opioid ,Receptors, Lysosphingolipid ,Sphingosine ,Neuroinflammatory Diseases ,Immunology ,Animals ,Neuralgia ,Immunology and Allergy ,Lysophospholipids - Abstract
Neuropathic pain arises from injuries to the nervous system. It affects 20% of the adult US population and poses a major socioeconomic burden yet remains exceedingly difficult to treat. Current therapeutic approaches have limited efficacy and a large side effect profile that impedes their ability to treat neuropathic pain effectively. Preclinical research over the last 30 yr has established the critical role that pro-inflammatory neuro–immune cell interactions have in the development and maintenance of neuropathic pain arising from various etiologies. Pro-inflammatory neuro–immune cell interactions also underlie the development of adverse side effects of opioids and the loss of their efficacy to treat pain. Evidence from work in our lab and others in preclinical animal models have shown that signaling from the bioactive sphingolipid, sphingosine-1-phosphate (S1P), through the S1P receptor subtype 1 (S1PR1) modulates neuro–immune cell interactions. Here, we discuss how targeting S1P/S1PR1 signaling with S1PR1 antagonists already Food and Drug Administration–approved or in clinical trials for multiple sclerosis can provide a viable pharmacotherapeutic approach to reduce neuro-immune cell inflammatory signaling and potentially treat patients suffering neuropathic pain and the adverse effects of opioids.
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- 2022
6. Differential Upregulation and Functional Activity of S1PR1 in Human Peripheral Blood Basophils of Atopic Patients
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Natalie Gray, Maren M. Limberg, Daniela Wiebe, Tobias Weihrauch, Anna Langner, Nicola Brandt, Anja U. Bräuer, and Ulrike Raap
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basophils ,S1P ,S1PR ,atopy ,apoptosis ,chemotaxis ,Organic Chemistry ,General Medicine ,Catalysis ,Computer Science Applications ,Up-Regulation ,Basophils ,Inorganic Chemistry ,Receptors, Lysosphingolipid ,Sphingosine ,Humans ,Physical and Theoretical Chemistry ,Lysophospholipids ,Molecular Biology ,Sphingosine-1-Phosphate Receptors ,Spectroscopy - Abstract
Basophils are key effector cells in atopic diseases, and the signaling sphingolipid Sphigosine-1-phosphate (S1P) is emerging as an important mediator in these conditions. The possible interaction of S1P and basophils and the resulting biological effects have not yet been studied. We hypothesize that S1P influences the function of basophils in atopy and aim to elucidate the modes of interaction. S1P receptor (S1PR) expression in human peripheral blood basophils from atopic and non-atopic patients was assessed through qRT-PCR and flow cytometry analysis. Functional effects of S1P were assessed through a basophil activation test (BAT), calcium flux, apoptosis, and chemotaxis assays. Immunofluorescence staining was performed to visualize intracellular S1P. Human basophils express S1PR1, S1PR2, S1PR3, and S1PR4 on the mRNA level. 0.1 µM S1P have anti-apoptotic, while 10 µM exhibits apoptotic effects on basophils. Basophils from atopic patients show less chemotactic activity in response to S1P than those from healthy donors. Protein expression of S1PR1 is downregulated in atopic patients, and basophils in lesional AD skin possess intracellular S1P. These findings suggest that the interaction of S1P and basophils might be an important factor in the pathophysiology of atopy.
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- 2022
7. Sphingosine-1-phosphate receptor 3 signaling
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Yi Li, Guang-Hui Yi, Cai Lei, Qian Li, and Ying Tan
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0301 basic medicine ,Clinical Biochemistry ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Sphingosine ,Fibrosis ,medicine ,Receptor ,Sphingosine-1-Phosphate Receptors ,Cells, Cultured ,S1PR1 ,Cell Proliferation ,Sphingosine 1-Phosphate Receptor 3 ,S1PR2 ,S1PR3 ,Biochemistry (medical) ,General Medicine ,medicine.disease ,Cell biology ,Receptors, Lysosphingolipid ,030104 developmental biology ,030220 oncology & carcinogenesis ,Lysophospholipids ,Function (biology) ,Signal Transduction - Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid which regulates a series of physiological and pathological processes via binding to five S1P receptors (S1PR1-5). Although S1PR1-3 are widely expressed, the study of S1PRs, however, mainly addressed S1PR1 and S1PR2, and few studies focus on S1PR3-5. In recent years, a growing number of studies have shown that S1PR3 plays an important role in cell proliferation, differentiation, apoptosis, and migration, but its function is still controversial. This is the first comprehensive review paper about the role of S1PR3 signaling in cardiovascular function, tissue fibrosis, cancer, immune response, and neurological function. In addition, existing S1PR3 agonists and antagonists are listed at the end of the article, and we also put forward our opinion on the dispute of S1PR3 function.
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- 2021
8. Modulation of Specific Sphingosine-1-Phosphate Receptors Augments a Repair Mediating Schwann Cell Phenotype
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Jessica Schira-Heinen, Luzhou Wang, Seda Akgün, Sofia Blum, Brigida Ziegler, André Heinen, Hans-Peter Hartung, and Patrick Küry
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Fingolimod Hydrochloride ,dedifferentiation ,glia ,peripheral nerve regeneration ,PNS ,S1P ,transdifferentiation ,Organic Chemistry ,Becaplermin ,General Medicine ,Catalysis ,Nerve Regeneration ,Computer Science Applications ,Inorganic Chemistry ,Receptors, Lysosphingolipid ,Phenotype ,Schwann Cells ,Physical and Theoretical Chemistry ,Sphingosine-1-Phosphate Receptors ,Molecular Biology ,Spectroscopy - Abstract
Transdifferentiation of Schwann cells is essential for functional peripheral nerve regeneration after injury. By activating a repair program, Schwann cells promote functional axonal regeneration and remyelination. However, chronic denervation, aging, metabolic diseases, or chronic inflammatory processes reduce the transdifferentiation capacity and thus diminish peripheral nerve repair. It was recently described that the sphingosine-1-phosphate receptor (S1PR) agonist Fingolimod enhances the Schwann cell repair phenotype by activation of dedifferentiation markers and concomitant release of trophic factors resulting in enhanced neurite growth. Since Fingolimod targets four out of five S1PRs (S1P1, S1P3-5) possibly leading to non-specific adverse effects, identification of the main receptor(s) responsible for the observed phenotypic changes is mandatory for future specific treatment approaches. Our experiments revealed that S1P3 dominates and that along with S1P1 acts as the responsible receptor for Schwann cell transdifferentiation as revealed by the combinatory application of specific agonists and antagonists. Targeting both receptors reduced the expression of myelin-associated genes, increased PDGF-BB representing enhanced trophic factor expression likely to result from c-Jun induction. Furthermore, we demonstrated that S1P4 and S1P5 play only a minor role in the adaptation of the repair phenotype. In conclusion, modulation of S1P1 and S1P3 could be effective to enhance the Schwann cell repair phenotype and thus stimulate proper nerve repair.
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- 2022
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9. Controlled mechanical loading improves bone regeneration by regulating type H vessels in a <scp>S1Pr1</scp> ‐dependent manner
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Chengyu Yang, Yang Liu, Ziyan Wang, Minmin Lin, and Chao Liu
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Receptors, Lysosphingolipid ,Bone Regeneration ,Fingolimod Hydrochloride ,Genetics ,Endothelial Cells ,Sphingosine-1-Phosphate Receptors ,Molecular Biology ,Biochemistry ,Biotechnology - Abstract
Despite the best treatment, approximately 10% of fractures still face undesirable repair and result in delayed unions or non-unions. Dynamic mechanical stimulation promotes bone formation, when applied at the correct time frame, with optimal loading magnitude, frequency, and repetition. Controlled mechanical loading significantly increases osteogenic cells during the matrix deposition phase of bone repair. In the bone defect, the blood vessel network guides the initial bone formation activities. A unique blood vessel subtype (Type H) exists in bone, which expresses high levels of CD31 and endomucin, and functions to couple angiogenesis and osteogenesis. However, how this form of controlled mechanical loading regulates the Type H vessels and promotes bone formation is still not clear. Sphingosine 1-phosphate (S1P) participates in the bone anabolic process and is a key regulator of the blood vessel. Its receptor, sphingosine 1-phosphate receptor 1 (S1Pr1), is a mechanosensitive protein that regulates vascular integrity. Therefore, we hypothesis that controlled anabolic mechanical loading promotes bone repair by acting on Type H vessels. To study the effect of S1Pr1 on loading induced-bone repair, we utilized a stabilized tibial defect model, which allows for the application of anabolic mechanical loading. Mechanical loading upregulated S1Pr1 within the entire defect, with up to 80% expressed in blood vessels, as observed by deep tissue imaging. Additionally, S1Pr1 antagonism by W146 inhibited the anabolic effects of mechanical loading. We showed that mechanical loading or activating S1Pr1 could induce YAP nuclear translocation, a key regulator in the cell's mechanical response, in endothelial cells (ECs) in vitro. Inhibition of S1Pr1 in endothelial cells by siRNA reduced loading-induced YAP nuclear translocation and expressions of angiogenic genes. In vivo, YAP nuclear translocation in Type H vessels was up-regulated after mechanical loading but was inhibited by antagonizing S1Pr1. S1Pr1 agonist, FTY720, increased bone volume and Type H vessel volume, similar to that of mechanical stimulation. In conclusion, controlled anabolic mechanical loading enhanced bone formation mainly through Type H vessels in a S1Pr1-dependent manner.
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- 2022
10. Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment
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Silvia Squillace, Michael L. Niehoff, Timothy M. Doyle, Michael Green, Emanuela Esposito, Salvatore Cuzzocrea, Christopher K. Arnatt, Sarah Spiegel, Susan A. Farr, and Daniela Salvemini
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Central Nervous System ,Mice ,Receptors, Lysosphingolipid ,Fingolimod Hydrochloride ,Mice, Inbred NOD ,Sphingosine ,Animals ,Cognitive Dysfunction ,General Medicine ,Cisplatin ,Lysophospholipids ,Sphingosine-1-Phosphate Receptors - Abstract
Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain-containing protein 3 inflammasomes, and increased IL-1β formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.
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- 2022
11. Sphingosine-1-phosphate receptor modulators in stroke treatment
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Wanzhou Zhang, Yudi Li, Fangming Li, and Li Ling
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Sphingosine 1 Phosphate Receptor Modulators ,Stroke ,Cellular and Molecular Neuroscience ,Receptors, Lysosphingolipid ,Multiple Sclerosis ,Fingolimod Hydrochloride ,Animals ,Lysophospholipids ,Biochemistry ,Sphingosine-1-Phosphate Receptors ,Immunosuppressive Agents - Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that can influence a broad range of biological processes through its binding to five distinct G-protein-coupled receptors. S1P receptor modulators are a new group of immunosuppressive agents currently used in the immunotherapy of multiple sclerosis. Inflammation following stroke can exacerbate neuronal injury. Given that S1P signaling is linked to multiple immune processes, therapies targeting the S1P axis may be suitable for treating stroke. In this review, we outline S1P metabolism and S1P receptors, discuss the mechanisms of action of S1P receptor modulators in lymphocyte migration and their direct action on cells of the central nervous system, and provide a concise summary of the efficacy of S1P receptor modulators in animal studies and clinical trials on treatments for stroke.
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- 2022
12. A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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Zhenhua Shao, Wei Yan, Chang Zhao, Fan Xia, Xiaowen Tian, Lantian Su, and Lin Cheng
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Receptors, Lysosphingolipid ,General Immunology and Microbiology ,Sphingosine ,General Chemical Engineering ,General Neuroscience ,Cryoelectron Microscopy ,COVID-19 ,Humans ,Lysophospholipids ,Sphingosine-1-Phosphate Receptors ,General Biochemistry, Genetics and Molecular Biology ,Signal Transduction - Abstract
Lysophospholipids (LPLs) are bioactive lipids that include sphingosine 1-phosphate (S1P), lysophosphatidic acid, etc. S1P, a metabolic product of sphingolipids in the cell membrane, is one of the best-characterized LPLs that regulates a variety of cellular physiological responses via signaling pathways mediated by sphingosine 1-phosphate receptors (S1PRs). This implicated that the S1P-S1PRs signaling system is a remarkable potential therapeutic target for disorders, including multiple sclerosis (MS), autoimmune disorders, cancer, inflammation, and even COVID-19. S1PRs, a small subset of the class A G-protein coupled receptor (GPCR) family, are composed of five subtypes: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. The lack of detailed structural information, however, impedes the drug discovery targeting S1PRs. Here, we applied the cryo-electron microscopy method to solve the structure of the S1P-S1PRs complex, and elucidated the mechanism of activation, selective drug recognition, and G-protein coupling by using cell-based functional assays. Other lysophospholipid receptors (LPLRs) and GPCRs can also be studied using this strategy.
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- 2022
13. Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases
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Hongyu Chen, Junmin Wang, Caiyun Zhang, Peilun Ding, Shuxia Tian, Junming Chen, Guang Ji, and Tao Wu
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Pharmacology ,Receptors, Lysosphingolipid ,Neoplasms ,Humans ,General Medicine ,Sphingosine-1-Phosphate Receptors - Abstract
Sphingosine 1-phosphate receptor (S1PR), as a kind of G protein-coupled receptor, has five subtypes, including S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. Sphingosine 1-phosphate receptor (S1P) and S1PR regulate the trafficking of neutrophils and some cells, which has great effects on immune systems, lung tissue, and liver tissue. Presently, many related reports have proved that S1PR has a strong effect on the migration of lymphocytes, tumor cells, neutrophils, and many other cells via the regulation of signals, pathways, and enzymes. In this way, S1PR can regulate the relative response of the organism. Thus, S1PR has become a possible target for the treatment of autoimmune diseases, pulmonary disease, liver disease, and cancer. In this review, we mainly focus on the research of the S1PR for the new therapeutic directions of different diseases and is expected to assist support in the clinic and drug use.
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- 2022
14. Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway Modulators, from Current Insights to Future Perspectives
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Gary Álvarez Bravo, René Robles Cedeño, Marc Puig Casadevall, and Lluís Ramió-Torrentà
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Receptors, Lysosphingolipid ,Multiple Sclerosis ,Fingolimod Hydrochloride ,Sphingosine ,Humans ,General Medicine ,Lysophospholipids ,Autoimmune Diseases ,Signal Transduction - Abstract
Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the immune system. S1P-S1PR signaling has been well characterized in immune trafficking and activation in both innate and adaptive immune systems. Despite this knowledge, the full scope in the pathogenesis of autoimmune disorders is not well characterized yet. From the discovery of fingolimod, the first S1P modulator, until siponimod, the new molecule recently approved for the treatment of secondary progressive multiple sclerosis (SPMS), there has been a great advance in understanding the S1P functions and their involvement in immune diseases, including multiple sclerosis (MS). Modulation on S1P is an interesting target for the treatment of various autoimmune disorders. Improved understanding of the mechanism of action of fingolimod has allowed the development of the more selective second-generation S1PR modulators. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are known to play a major role in MS pathogenesis. The understanding of S1PR1’s role facilitated the development of pharmacological strategies directed to this target, and theoretically reduced the safety concerns derived from the use of fingolimod. A great advance in the MS treatment was achieved in March 2019 when the Food and Drug Association (FDA) approved Siponimod, for both active secondary progressive MS and relapsing–remitting MS. Siponimod became the first oral disease modifying therapy (DMT) specifically approved for active forms of secondary progressive MS. Additionally, for the treatment of relapsing forms of MS, ozanimod was approved by FDA in March 2020. Currently, there are ongoing trials focused on other new-generation S1PR1 modulators. This review approaches the fundamental aspects of the sphingosine phosphate modulators and their main similarities and differences.
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- 2022
15. Autoimmunity to Sphingosine-1-Phosphate-Receptors in Systemic Sclerosis and Pulmonary Arterial Hypertension
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Gluschke, Hans, Siegert, Elise, Minich, Waldemar B., Hackler, Julian, Riemekasten, Gabriela, Kuebler, Wolfgang M., Simmons, Szandor, and Schomburg, Lutz
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Pulmonary Arterial Hypertension ,Scleroderma, Systemic ,autoantibodies ,rheumatology ,autoimmune disease ,Autoimmunity ,Autoantigens ,immunology ,Receptors, Lysosphingolipid ,Sphingosine ,G-protein coupled receptor ,sphingosine-1-phosphate ,Immunology and Allergy ,Humans ,sphingolipid ,Lysophospholipids ,immunoglobulin ,Sphingosine-1-Phosphate Receptors ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit - Abstract
Context: Pulmonary arterial hypertension (PAH) is a frequent extracutaneous manifestation of systemic sclerosis (SSc). PAH is characterized by increased vasomotor tone, progressive remodeling of pulmonary arteries and arterioles, consequentially increased pulmonary vascular resistance, right heart hypertrophy, and eventually right ventricular failure. Autoimmunity against G-protein coupled receptors (GPCRs) has been implicated in the development of SSc-associated PAH. Sphingosine-1-phosphate (S1P) receptors (S1PR) present a potential, yet so far untested antigen for PAH autoimmunity, given the documented role of S1P/S1PR signaling in PAH pathogenesis. Objective: We hypothesized that S1P receptors (S1PR) may constitute autoantigens in human patients, and that the prevalence of autoantibodies (aAb) to S1PR1, S1PR2 and S1PR3 is elevated in SSc patients and associated with PAH. Methods: For this exploratory study, serum samples from 158 SSc patients, 58 of whom with PAH, along with 333 healthy control subjects were screened for S1PR-aAb. S1PR1-3 were expressed as fusion proteins with luciferase in human embryonic kidney cells and used to establish novel in-vitro assays for detecting and quantifying S1PR-aAb. The fusion proteins were incubated with serum samples, the aAb-S1PR complexes formed were precipitated by protein-A, washed and tested for luciferase activity. Commercial anti-S1PR-antibodies were used to verify specificity of the assays. Results: All three assays showed dose-dependent signal intensities when tested with S1PR-subtype specific commercial antibodies. Natural aAb to each S1PR were detected in healthy controls with a prevalence of
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- 2022
16. An overview of ozanimod as a therapeutic option for adults with moderate-to-severe active ulcerative colitis
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Catherine Rowan, Ryan Ungaro, Saurabh Mehandru, and Jean-Frederic Colombel
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Pharmacology ,Adult ,Oxadiazoles ,Receptors, Lysosphingolipid ,Indans ,Humans ,Immunologic Factors ,Pharmacology (medical) ,Colitis, Ulcerative ,General Medicine ,Sphingosine-1-Phosphate Receptors - Abstract
Ulcerative colitis (UC) is a chronic inflammatory condition of the gastrointestinal tract involving a dysregulated immune response. Sphingosine-1-phosphate (S1P) is involved in immune cell regulation. S1P-receptor modulators, such as ozanimod, inhibit lymphocyte migration and have therapeutic potential in UC.Ozanimod is the first S1P-receptor modulator approved for the treatment of UC. It acts as a functional antagonist, causing internalization of S1P receptors on T-cells. Lymphocyte egress from lymph nodes is inhibited, and migration to sites of active inflammation is curtailed. There are several S1P-receptor subtypes, present in various organs, which inform understanding of ozanimod's side-effect profile including bradycardia and macular edema. In this review, the authors discuss the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of ozanimod in the treatment of patients with moderate-to-severe UC.The S1P-receptor modulator ozanimod is an oral small molecule with a rapid onset of action and a novel therapeutic mechanism in the treatment of UC. It is an effective treatment both in bio-naïve and bio-exposed patients. Although the safety profile of ozanimod looks favorable, more long-term data are needed. Further studies are required to compare ozanimod to currently available therapies to best define its positioning in UC treatment algorithms.
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- 2022
17. Synthesis and Evaluation of Serinolamide Derivatives as Sphingosine-1-Phosphate-1 (S1P
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Sun Jun, Park, Jushin, Kim, Jaehwan, Kim, Yoowon, Kim, Elijah Hwejin, Lee, Hyeon Jeong, Kim, Siwon, Kim, Byungeun, Kim, Rium, Kim, Ji Won, Choi, Jong-Hyun, Park, and Ki Duk, Park
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Receptors, Lysosphingolipid ,Fingolimod Hydrochloride ,Sphingosine ,Lymphocytes ,Lysophospholipids - Abstract
Sphingosine-1-phosphate-1 (S1P
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- 2022
18. TLR4 activation induces inflammatory vascular permeability via Dock1 targeting and NOX4 upregulation
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Jin H. Song, Joseph B. Mascarenhas, Saad Sammani, Carrie L. Kempf, Hua Cai, Sara M. Camp, Tadeo Bermudez, Donna D. Zhang, Viswanathan Natarajan, and Joe G.N. Garcia
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Lipopolysaccharides ,Swine ,Acute Lung Injury ,Ligands ,GTP Phosphohydrolases ,Rats ,Up-Regulation ,Capillary Permeability ,Toll-Like Receptor 4 ,Mice ,Receptors, Lysosphingolipid ,NADPH Oxidase 4 ,Molecular Medicine ,Animals ,Reactive Oxygen Species ,Molecular Biology ,Sphingosine-1-Phosphate Receptors ,Adaptor Proteins, Signal Transducing - Abstract
The loss of vascular integrity is a cardinal feature of acute inflammatory responses evoked by activation of the TLR4 inflammatory cascade. Utilizing in vitro and in vivo models of inflammatory lung injury, we explored TLR4-mediated dysregulated signaling that results in the loss of endothelial cell (EC) barrier integrity and vascular permeability, focusing on Dock1 and Elmo1 complexes that are intimately involved in regulation of Rac1 GTPase activity, a well recognized modulator of vascular integrity. Marked reductions in Dock1 and Elmo1 expression was observed in lung tissues (porcine, rat, mouse) exposed to TLR4 ligand-mediated acute inflammatory lung injury (LPS, eNAMPT) in combination with injurious mechanical ventilation. Lung tissue levels of Dock1 and Elmo1 were preserved in animals receiving an eNAMPT-neutralizing mAb in conjunction with highly significant decreases in alveolar edema and lung injury severity, consistent with Dock1/Elmo1 as pathologic TLR4 targets directly involved in inflammation-mediated loss of vascular barrier integrity. In vitro studies determined that pharmacologic inhibition of Dock1-mediated activation of Rac1 (TBOPP) significantly exacerbated TLR4 agonist-induced EC barrier dysfunction (LPS, eNAMPT) and attenuated increases in EC barrier integrity elicited by barrier-enhancing ligands of the S1P1 receptor (sphingosine-1-phosphate, Tysiponate). The EC barrier-disrupting influence of Dock1 inhibition on S1PR1 barrier regulation occurred in concert with: 1) suppressed formation of EC barrier-enhancing lamellipodia, 2) altered nmMLCK-mediated MLC2 phosphorylation, and 3) upregulation of NOX4 expression and increased ROS. These studies indicate that Dock1 is essential for maintaining EC junctional integrity and is a critical target in TLR4-mediated inflammatory lung injury.
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- 2022
19. Sphingosine 1-Phoshpate Receptors are Located in Synapses and Control Spontaneous Activity of Mouse Neurons in Culture
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Cecilia Skoug, Isak Martinsson, Gunnar K. Gouras, Anja Meissner, and João M. N. Duarte
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Neurons ,Cellular and Molecular Neuroscience ,Mice ,Receptors, Lysosphingolipid ,Sphingosine ,Synapses ,Animals ,ddc:610 ,General Medicine ,Lysophospholipids ,Biochemistry - Abstract
Sphingosine-1-phosphate (S1P) is best known for its roles as vascular and immune regulator. Besides, it is also present in the central nervous system (CNS) where it can act as neuromodulator via five S1P receptors (S1PRs), and thus control neurotransmitter release. The distribution of S1PRs in the active zone and postsynaptic density of CNS synapses remains unknown. In the current study, we investigated the localization of S1PR1-5 in synapses of the mouse cortex. Cortical nerve terminals purified in a sucrose gradient were endowed with all five S1PRs. Further subcellular fractionation of cortical nerve terminals revealed S1PR2 and S1PR4 immunoreactivity in the active zone of presynaptic nerve terminals. Interestingly, only S1PR2 and S1PR3 immunoreactivity was found in the postsynaptic density. All receptors were present outside the active zone of nerve terminals. Neurons in the mouse cortex and primary neurons in culture showed immunoreactivity against all five S1PRs, and Ca2+ imaging revealed that S1P inhibits spontaneous neuronal activity in a dose-dependent fashion. When testing selective agonists for each of the receptors, we found that only S1PR1, S1PR2 and S1PR4 control spontaneous neuronal activity. We conclude that S1PR2 and S1PR4 are located in the active zone of nerve terminals and inhibit neuronal activity. Future studies need to test whether these receptors modulate stimulation-induced neurotransmitter release.
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- 2022
20. Structural basis for receptor selectivity and inverse agonism in S1P
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Elizaveta, Lyapina, Egor, Marin, Anastasiia, Gusach, Philipp, Orekhov, Andrey, Gerasimov, Aleksandra, Luginina, Daniil, Vakhrameev, Margarita, Ergasheva, Margarita, Kovaleva, Georgii, Khusainov, Polina, Khorn, Mikhail, Shevtsov, Kirill, Kovalev, Sergey, Bukhdruker, Ivan, Okhrimenko, Petr, Popov, Hao, Hu, Uwe, Weierstall, Wei, Liu, Yunje, Cho, Ivan, Gushchin, Andrey, Rogachev, Gleb, Bourenkov, Sehan, Park, Gisu, Park, Hyo Jung, Hyun, Jaehyun, Park, Valentin, Gordeliy, Valentin, Borshchevskiy, Alexey, Mishin, and Vadim, Cherezov
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Receptors, Lysosphingolipid ,Sphingosine ,Immune System ,Humans ,Lysophospholipids - Abstract
The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P
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- 2022
21. Current status and new developments in sphingosine-1-phosphate receptor antagonism: fingolimod and more
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Victor Constantinescu, Katja Akgün, and Tjalf Ziemssen
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Pharmacology ,Receptors, Lysosphingolipid ,Multiple Sclerosis, Relapsing-Remitting ,Multiple Sclerosis ,Fingolimod Hydrochloride ,Sphingosine ,Humans ,Immunologic Factors ,General Medicine ,Toxicology ,Sphingosine-1-Phosphate Receptors - Abstract
Fingolimod was the first oral disease-modifying treatment approved for relapsing-remitting multiple sclerosis (MS) that serves as a sphingosine-1-phosphate receptor (S1PR) agonist. The efficacy is primarily mediated by S1PR subtype 1 activation, leading to agonist-induced down-modulation of receptor expression and further functional antagonism, blocking the egression of auto-aggressive lymphocytes from the lymph nodes in the peripheral compartment. The role of S1P signaling in the regulation of other pathways in human organisms through different S1PR subtypes has received much attention due to its immune-modulatory function and its significance for the regeneration of the central nervous system. The more selective second-generation S1PR modulators have improved safety and tolerability profiles. This review has been carried out based on current data on S1PR modulators, emphasizing the benefits of recent advances in this emergent class of immunomodulatory treatment for MS. Ongoing clinical research suggests that S1PR modulators represent an alternative to first-line therapies in selected cases of MS. A better understanding of the relevance of selective S1PR pathways and the ambition to optimize selective modulation has improved the safety and tolerability of S1PR modulators in MS therapy and opened new perspectives for the treatment of other diseases.
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- 2022
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22. The atypical sphingosine 1-phosphate variant, d16:1 S1P, mediates CTGF induction via S1P2 activation in renal cell carcinoma
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Melanie Glueck, Alexander Koch, Robert Brunkhorst, Nerea Ferreiros Bouzas, Sandra Trautmann, Liliana Schaefer, Waltraud Pfeilschifter, Josef Pfeilschifter, and Rajkumar Vutukuri
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Sphingolipids ,Connective Tissue Growth Factor ,Serine C-Palmitoyltransferase ,Cell Biology ,Biochemistry ,Carbon ,Kidney Neoplasms ,Mice ,Receptors, Lysosphingolipid ,Sphingosine ,Animals ,Humans ,Lysophospholipids ,Molecular Biology ,Carcinoma, Renal Cell ,Sphingosine-1-Phosphate Receptors - Abstract
The FEBS journal 289(18), 5670-5681 (2022). doi:10.1111/febs.16446, Published by Wiley-Blackwell, Oxford [u.a.]
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- 2022
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23. FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment
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Kiyohiro Houkin, Zifeng Wang, and Masahito Kawabori
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Agonist ,FTY720 ,medicine.drug_class ,Inflammation ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neural Stem Cells ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Animals ,Humans ,fingolimod ,Receptor ,sphingosinc-l-phosphatc ,Stroke ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Microglia ,business.industry ,Fingolimod Hydrochloride ,Multiple sclerosis ,Organic Chemistry ,Endothelial Cells ,medicine.disease ,Fingolimod ,stroke ,Receptors, Lysosphingolipid ,medicine.anatomical_structure ,inflammation ,sphingosine kinase ,Propylene Glycols ,Brain Injuries ,sphingosine-1-phosphate ,sphingosinc kinase ,Molecular Medicine ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery ,Immunosuppressive Agents ,medicine.drug - Abstract
FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional “antagonist” and “agonist” mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.
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- 2020
24. S1PR5 regulates NK cell responses in preventing graft‐versus‐host disease while preserving graft‐versus‐tumour activity in a murine allogeneic haematopoietic stem cell transplantation model
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Nan Yang, Xiao-Li Zhao, Tong Liu, Shu Fang, Zhenyang Gu, Lan Luo, Chengying Zhu, Feiyan Wang, Shasha Zhao, Meng Li, Li Wang, Lili Wang, Li-Xun Guan, and Chun-Ji Gao
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Cancer Research ,CD3 ,Cell ,Graft vs Host Disease ,CD8-Positive T-Lymphocytes ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Transplantation, Homologous ,Medicine ,Mice, Inbred BALB C ,biology ,business.industry ,Graft vs Tumor Effect ,Hematopoietic Stem Cell Transplantation ,Hematology ,General Medicine ,medicine.disease ,Killer Cells, Natural ,Mice, Inbred C57BL ,Transplantation ,Disease Models, Animal ,Receptors, Lysosphingolipid ,Haematopoiesis ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Bone marrow ,Stem cell ,business ,CD8 ,030215 immunology - Abstract
Graft-versus-host disease (GVHD) remains a major complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT) leading to high transplant-related mortality. Natural killer (NK) cells have been found to mitigate GVHD without attenuating the graft-versus-tumour (GVT) activity in the murine model of haematopoietic stem cell transplantation. Sphingosine-1-phosphate receptor 5 (S1PR5) is a very important chemokine receptor on NK cells that governs NK cell distribution in vivo and trafficking at lesion sites. Our preliminary studies showed that the incidence of GVHD was negatively correlated with S1PR5 expression in the NK cells of patients after allo-HSCT. In the present study, we found that S1PR5 deficiency in murine NK cells blocked the migration of NK cells from the bone marrow to the GVHD target organs and attenuated the inhibitory effects on the alloreactive T cells, especially CD3+ CD8+ T cells, which may be the reason why the loss of S1PR5 in NK cells could aggravate GVHD in recipient mice. Furthermore, we also demonstrated that the absence of S1PR5 expression in NK cells did not interfere with the antitumour effects of NK cells and T cells in vivo. Taken together, our data indicate that S1PR5 plays an essential role in balancing GVHD and GVT activity.
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- 2019
25. FTY720 induces non-canonical phosphatidylserine externalization and cell death in acute myeloid leukemia
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Van Bui, Hong Gang Wang, Megan M. Young, and Chong Chen
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Sphingosine 1 Phosphate Receptor Modulators ,Cell death ,Cancer Research ,Programmed cell death ,Cancer therapy ,Necroptosis ,Immunology ,Apoptosis ,Phosphatidylserines ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Annexin ,hemic and lymphatic diseases ,Humans ,lcsh:QH573-671 ,030304 developmental biology ,0303 health sciences ,Sphingosine ,Fingolimod Hydrochloride ,lcsh:Cytology ,Cell Membrane ,030302 biochemistry & molecular biology ,Pyroptosis ,Myeloid leukemia ,Cell Biology ,Phosphatidylserine ,3. Good health ,Leukemia, Myeloid, Acute ,Receptors, Lysosphingolipid ,chemistry ,Preclinical research ,Caspases ,Cancer research ,Signal Transduction - Abstract
FTY720 (fingolimod) is a FDA-approved sphingosine analog that is phosphorylated in vivo to modulate sphingosine-1-phosphate receptor (S1PR) signaling for immunosuppression in patients with refractory multiple sclerosis. FTY720 also exhibits promising anticancer efficacy in several preclinical models. While FTY720-induced cytotoxicity is not due to S1PR signaling, the mechanism remains unclear and is reported to occur through various cell death pathways. Here, we performed a systematic, mechanistic study of FTY720-induced cell death in acute myeloid leukemia (AML). We found that FTY720 induced cell death in a panel of genetically diverse AML cell lines that was accompanied by rapid phosphatidylserine (PS) externalization. Importantly, FTY720-induced PS exposure was not due to any direct effects on plasma membrane integrity and was independent of canonical signaling by regulated cell death pathways known to activate lipid flip-flop, including caspase-dependent apoptosis/pyroptosis, necroptosis, ferroptosis, and reactive oxygen species-mediated cell death. Notably, PS exposure required cellular vacuolization induced by defects in endocytic trafficking and was suppressed by the inhibition of PP2A and shedding of Annexin V-positive subcellular particles. Collectively, our studies reveal a non-canonical pathway underlying PS externalization and cell death in AML to provide mechanistic insight into the antitumor properties of FTY720.
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- 2019
26. Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer
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Mayuko Ikarashi, Junko Tsuchida, Masayuki Nagahashi, Shiho Takeuchi, Kazuki Moro, Chie Toshikawa, Shun Abe, Hiroshi Ichikawa, Yoshifumi Shimada, Jun Sakata, Yu Koyama, Nobuaki Sato, Nitai C. Hait, Yiwei Ling, Shujiro Okuda, Kazuaki Takabe, and Toshifumi Wakai
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Adult ,QH301-705.5 ,Gene Expression ,Breast Neoplasms ,Catalysis ,Article ,progesterone receptor ,Inorganic Chemistry ,Plasma ,breast cancer ,Sphingosine ,Cell Line, Tumor ,Biomarkers, Tumor ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Sphingosine-1-Phosphate Receptors ,Spectroscopy ,mass spectrometry ,Aged ,lymph node metastasis ,hormone therapy ,Fingolimod Hydrochloride ,Organic Chemistry ,General Medicine ,Middle Aged ,Computer Science Applications ,Chemistry ,sphingosine-1-phosphate ,plasma ,estrogen receptor ,Receptors, Lysosphingolipid ,Receptors, Estrogen ,Lymphatic Metastasis ,Disease Progression ,MCF-7 Cells ,lipids (amino acids, peptides, and proteins) ,Female ,Lysophospholipids ,Signal Transduction - Abstract
Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.
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- 2021
27. Sphingosine-1-Phosphate and Its Signal Modulators Alleviate Psoriasis-Like Dermatitis: Preclinical and Clinical Evidence and Possible Mechanisms
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Liu Liu, Jiao Wang, Hong-jin Li, Shuo Zhang, Meng-zhu Jin, Si-ting Chen, Xiao-ying Sun, Ya-qiong Zhou, Yi Lu, Dan Yang, Ying Luo, Yi Ru, Bin Li, and Xin Li
- Subjects
Immunology ,psoriasis ,RC581-607 ,sphingosine kinase 2 inhibitors ,systematic review and meta-analysis ,Mice ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Sphingosine ,sphingosine-1-phosphate ,sphingosine-1-phosphate signaling modulators ,Animals ,Humans ,Immunology and Allergy ,preclinical evidence ,Systematic Review ,Enzyme Inhibitors ,Lysophospholipids ,Immunologic diseases. Allergy ,S1P receptor (S1PR) agonists ,Immunosuppressive Agents ,Software ,Randomized Controlled Trials as Topic - Abstract
BackgroundPsoriasis is an autoimmune skin disease associated with lipid metabolism. Sphingosine-1-phosphate (S1P) is a bioactive lipid that plays a key role in the development of autoimmune diseases. However, there is currently a lack of comprehensive evidence of the effectiveness of S1P on psoriasis.ObjectiveTo assess the efficacy and possible mechanism of S1P and its signal modulators in the treatment of psoriasis-like dermatitis.MethodsSix databases were searched through May 8, 2021, for studies reporting S1P and its signal modulators. Two reviewers independently extracted information from the enrolled studies. Methodological quality was assessed using SYRCLE’s risk of bias tool. RevMan 5.3 software was used to analyze the data. For clinical studies, the Psoriasis Area and Severity Index score were the main outcomes. For preclinical studies, we clarified the role of S1P and its regulators in psoriasis in terms of phenotype and mechanism.ResultsOne randomized double-blind placebo-controlled trial and nine animal studies were included in this study. The pooled results showed that compared with control treatment, S1P receptor agonists [mean difference (MD): −6.80; 95% confidence interval (CI): −8.23 to −5.38; p+ T cells (pConclusionsS1P receptor agonists and sphingosine kinase 2 inhibitors could be potential methods for treating psoriasis by decreasing immune responses and inflammatory factors.
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- 2021
28. [IGF-1 activates the PI3K pathway through S1P/S1PR1 signaling to promote the migration of mouse alveolar epithelial cells]
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Jian, Geng, Mimi, Mu, Caili, Ji, Mengting, Li, Li, Ma, Zixuan, Wang, Mengqing, Hua, and Chuanwang, Song
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Mice ,Phosphatidylinositol 3-Kinases ,Receptors, Lysosphingolipid ,Sphingosine ,Alveolar Epithelial Cells ,Animals ,Insulin-Like Growth Factor I ,Proto-Oncogene Proteins c-akt - Abstract
Objective To investigate the effect of insulin-like growth factor 1 (IGF-1) on the migration of alveolar epithelial cells (AECs) and its related mechanisms. Methods The MLE-12 cells (mouse AEC line) were stimulated by IGF-1 and sphingosine 1 phosphate (S1P) in the presence or absence of the PI3K inhibitor Wortmannin. Then, the cell migration was detected by the scratch test and the expression of p-Akt was detected by Western blot. With AECs stimulated by IGF-1, the secretion and expression of S1P were tested by ELISA and Western blot respectively. In the blocking experiment, the effect of IGF-1 on cell migration or p-Akt expression was detected by scratch test or Western blot after the interference of AEC S1P receptor 1 (S1PR1) or the action of S1PR1 blocking antibody. Results After 12 hours of IGF-1 stimulation, the expression of p-Akt in AECs increased and the migration of AECs accelerated. When blocking PI3K signal, the effect of IGF-1 on promoting AEC migration was partially eliminated. IGF-1 induced AECs to produce S1P, which accelerated AEC migration through S1PR1. The expression of p-Akt in AECs increased after S1P stimulation. When blocking the PI3K pathway, the ability of S1P to accelerate the migration of AECs was reduced. When S1PR1 in AECs was blocked or interfered, the effect of IGF-1 on accelerating AEC migration and promoting AEC p-Akt expression was partially reduced. Conclusion IGF-1 activates the PI3K pathway through S1P-S1PR1 signal to promote the migration of AECs.
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- 2021
29. Sphingosine-1-phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy
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Miku Okawara, Katsuhiko Yanaga, Hiroyoshi Doi, Shiori Yoshikawa, Keisuke Yanagida, Hironori Kusano, Masaya Sugiyama, Yuriko Tsutsui, Yosuke Osawa, Tomoyuki Tsunoda, Tomonari Shimagaki, Taizo Mori, Yuichi Yoshida, Kana Hashi, Ayano Inui, Daisuke Okuzaki, Daisuke Hishikawa, Hideo Shindou, Sachiyo Yoshio, Taiji Yamazoe, Toru Ikegami, Masayoshi Kage, Yuzuru Sakamoto, Hironari Kawai, Tatsuya Kanto, Chinatsu Oyama, Michitaka Matsuda, Haruki Komatsu, and Miwa Tamura-Nakano
- Subjects
Lipopolysaccharides ,Liver Cirrhosis ,Liver tumor ,Carcinoma, Hepatocellular ,Inferior vena cava ,Liver disease ,Mice ,Fibrosis ,Sphingosine ,medicine ,Animals ,Humans ,Vascular Diseases ,Heart Failure ,Hepatology ,biology ,business.industry ,Liver Neoplasms ,medicine.disease ,Disease Models, Animal ,Receptors, Lysosphingolipid ,Congestive hepatopathy ,medicine.vein ,Sphingosine kinase 1 ,Hepatocellular carcinoma ,Cancer research ,biology.protein ,Lysophospholipids ,Liver cancer ,business - Abstract
Background & aims Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and hepatocellular carcinoma (HCC). However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood. Approach & results Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce liver sinusoidal endothelial cells (LSECs) capillarization in mice and in vitro. LSECs capillarization was also confirmed in FALD patients. Mitogenic factor, sphingosine-1-phosphate (S1P) was increased in congestive liver and expression of sphingosine kinase 1 (SphK1), a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR)1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobials treatment lowered portal blood LPS concentration, LSECs capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver. Conclusions In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for RHF patients with primary or metastatic liver cancer.
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- 2021
30. S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P1 and S1P3 Receptor Activation and HIF-2α Stabilization
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Andrea Huwiler, Redona Hafizi, Faik Imeri, Roland H. Wenger, University of Zurich, and Huwiler, Andrea
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MAPK/ERK pathway ,1607 Spectroscopy ,Pharmacology ,Kidney ,10052 Institute of Physiology ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Sphingosine ,hemic and lymphatic diseases ,Basic Helix-Loop-Helix Transcription Factors ,Erythropoiesis ,Biology (General) ,610 Medicine & health ,Cells, Cultured ,Spectroscopy ,0303 health sciences ,Gene knockdown ,General Medicine ,Computer Science Applications ,Receptors, Lysosphingolipid ,Chemistry ,medicine.anatomical_structure ,S1P receptors ,renal interstitial fibroblasts ,030220 oncology & carcinogenesis ,lipids (amino acids, peptides, and proteins) ,erythropoietin ,1606 Physical and Theoretical Chemistry ,Protein Binding ,Signal Transduction ,medicine.drug ,1503 Catalysis ,QH301-705.5 ,Article ,Catalysis ,Cell Line ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,1312 Molecular Biology ,1706 Computer Science Applications ,Animals ,Humans ,Sphingosine-1-phosphate ,Renal Insufficiency, Chronic ,Physical and Theoretical Chemistry ,fingolimod ,Protein kinase A ,Sphingosine-1-Phosphate Receptors ,Molecular Biology ,QD1-999 ,Protein kinase C ,sphingosine 1-phosphate ,030304 developmental biology ,Fingolimod Hydrochloride ,1604 Inorganic Chemistry ,hypoxia ,Organic Chemistry ,Fibroblasts ,chemistry ,Erythropoietin ,570 Life sciences ,biology ,Lysophospholipids ,protein kinase C ,1605 Organic Chemistry - Abstract
Erythropoietin (Epo) is the critical hormone for erythropoiesis. In adults, Epo is mainly produced by a subset of interstitial fibroblasts in the kidney, with minor amounts being produced in the liver and the brain. In this study, we used the immortalized renal interstitial fibroblast cell line FAIK F3-5 to investigate the ability of the bioactive sphingolipid sphingosine 1-phosphate (S1P) to stimulate Epo production and to reveal the mechanism involved. Stimulation of cells with exogenous S1P under normoxic conditions (21% O2) led to a dose-dependent increase in Epo mRNA and protein levels and subsequent release of Epo into the medium. S1P also enhanced the stabilization of HIF-2α, a key transcription factor for Epo expression. S1P-stimulated Epo mRNA and protein expression was abolished by HIF-2α mRNA knockdown or by the HIF-2 inhibitor compound 2. Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P1 and S1P3 antagonists NIBR-0213 and TY-52156, but not by the S1P2 antagonist JTE-013. Moreover, inhibitors of the classical MAPK/ERK, the p38-MAPK, and inhibitors of protein kinase (PK) C and D all blocked the effect of S1P on Epo expression. Finally, the S1P and FTY720 effects were recapitulated in the Epo-producing human neuroblastoma cell line Kelly, suggesting that S1P receptor-dependent Epo synthesis is of general relevance and not species-specific. In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P1 and 3 receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs.
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- 2021
31. ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P
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Bisera, Stepanovska Tanturovska, Aleksandra, Zivkovic, Faik, Imeri, Thomas, Homann, Burkhard, Kleuser, Holger, Stark, and Andrea, Huwiler
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Multiple Sclerosis ,Fingolimod Hydrochloride ,T-Lymphocytes ,ST-2191 ,functional antagonism ,S1P1 receptor ,anellated bismorpholino ,CHO Cells ,lymphopenia ,Article ,Mice, Inbred C57BL ,Mice ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Cricetulus ,Sphingosine ,Animals ,Humans ,Lymphocyte Count ,Lysophospholipids ,sphingosine 1-phosphate ,Signal Transduction - Abstract
Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.
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- 2021
32. Antagonizing S1P
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Angela, Corvino, Ida, Cerqua, Alessandra, Lo Bianco, Giuseppe, Caliendo, Ferdinando, Fiorino, Francesco, Frecentese, Elisa, Magli, Elena, Morelli, Elisa, Perissutti, Vincenzo, Santagada, Giuseppe, Cirino, Elisabetta, Granato, Fiorentina, Roviezzo, Elisa, Puliti, Caterina, Bernacchioni, Antonio, Lavecchia, Chiara, Donati, and Beatrice, Severino
- Subjects
Male ,Cell-Penetrating Peptides ,molecular dynamics simulations ,Fibrosis ,Peptide Fragments ,Article ,Myoblasts ,Mice ,Receptors, Lysosphingolipid ,Muscular Diseases ,S1P3 receptor antagonist ,sphingosine-1-phosphate ,Animals ,Muscle, Skeletal ,Sphingosine-1-Phosphate Receptors ,skeletal muscle fibrosis - Abstract
S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.
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- 2021
33. S1PR1 modulators in multiple sclerosis: Efficacy, safety, comparison, and chemical structure insights.
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Kandjani OJ, Yaqoubi S, Vahdati SS, Borhannejad B, Dastmalchi S, and Alizadeh AA
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- Humans, Fingolimod Hydrochloride pharmacology, Fingolimod Hydrochloride therapeutic use, Fingolimod Hydrochloride chemistry, Structure-Activity Relationship, Antibodies, Receptors, Lysosphingolipid, Sphingosine-1-Phosphate Receptors, Multiple Sclerosis drug therapy
- Abstract
Multiple sclerosis (MS) is a neurological disease that leads to severe physical and cognitive disabilities. Drugs used in the treatment of MS vary from small synthetic molecules to large macromolecules such as antibodies. Sphingosine 1-phosphate receptor modulators are frequently used for the treatment of MS. These medicines prevent the egress of lymphocytes from secondary lymphoid organs leading to immune system suppression. Currently, four S1PR modulators are on the market and several potential drug candidates are in clinical trials for the treatment of MS. These compounds differ in chemical structure, adverse effects, and efficacy points of view. The current article reviews the latest studies on S1PR1 modulators and compares them with other MS drugs in terms of efficacy, tolerability, and safety. A special focus was dedicated to discussing the structure-activity relationships of these compounds and performing a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to gain better insight into the ligand-receptor interaction mode., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2023
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34. Pharmacokinetic-Pharmacodynamic Modeling of the Ponesimod Effect on Heart Rate in Patients With Multiple Sclerosis.
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Valenzuela B, Poggesi I, Luyckx N, Vaclavkova A, and Pérez-Ruixo JJ
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- Humans, Heart Rate, Thiazoles, Receptors, Lysosphingolipid, Multiple Sclerosis drug therapy
- Abstract
The purpose of this study was to characterize the ponesimod effect on the heart rate (HR) in patients with multiple sclerosis (MS). A previous pharmacokinetic (PK) and pharmacodynamic model developed in healthy participants was updated using data from phase II and III trials conducted in patients with MS. Clinically relevant covariates were assessed. Simulations were conducted to evaluate the impact of the lack of adherence to ponesimod treatment and provide guidance in cases of treatment re-initiation. The maximal effect parameter of the PK/HR model was lower in patients with MS (23.5% decrease) compared with healthy volunteers (43.2%). The effect of patient covariates on PK/HR was similar to those identified in healthy participants and not clinically relevant in patients with MS. The population PK/HR model well characterized the effect of ponesimod on the time course of HR in patients with MS. After 2 weeks of treatment with 10 mg or higher doses, the model indicated full tolerance development. After repeated dosing at 20 mg, tolerance was maintained > 60% of the steady-state tolerance for up to 4 days after the last dose. Re-initiating with gradual uptitration is recommended if drug discontinuation lasts ≥ 4 days. This managed the negative chronotropic effects of ponesimod. No bradycardia events were observed within the first 2 weeks of treatment in patients with relapsing MS with a baseline HR > 55 bpm. This justifies the recommendation included in the human prescription drug labeling to monitor HR after the first ponesimod dose in these patients., (© 2022 Janssen Pharmaceuticals. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2023
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35. Targeting neuroinflammation in neuropathic pain and opioid use.
- Author
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Salvemini D and Doyle TM
- Subjects
- Animals, Neuroinflammatory Diseases, Sphingosine pharmacology, Lysophospholipids, Receptors, Lysosphingolipid, Analgesics, Opioid adverse effects, Neuralgia drug therapy, Neuralgia chemically induced
- Abstract
Neuropathic pain arises from injuries to the nervous system. It affects 20% of the adult US population and poses a major socioeconomic burden yet remains exceedingly difficult to treat. Current therapeutic approaches have limited efficacy and a large side effect profile that impedes their ability to treat neuropathic pain effectively. Preclinical research over the last 30 yr has established the critical role that pro-inflammatory neuro-immune cell interactions have in the development and maintenance of neuropathic pain arising from various etiologies. Pro-inflammatory neuro-immune cell interactions also underlie the development of adverse side effects of opioids and the loss of their efficacy to treat pain. Evidence from work in our lab and others in preclinical animal models have shown that signaling from the bioactive sphingolipid, sphingosine-1-phosphate (S1P), through the S1P receptor subtype 1 (S1PR1) modulates neuro-immune cell interactions. Here, we discuss how targeting S1P/S1PR1 signaling with S1PR1 antagonists already Food and Drug Administration-approved or in clinical trials for multiple sclerosis can provide a viable pharmacotherapeutic approach to reduce neuro-immune cell inflammatory signaling and potentially treat patients suffering neuropathic pain and the adverse effects of opioids., (© 2022 Salvemini and Doyle.)
- Published
- 2023
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- View/download PDF
36. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases.
- Author
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Tourkochristou E, Mouzaki A, and Triantos C
- Subjects
- Humans, Sphingosine-1-Phosphate Receptors therapeutic use, Lysophospholipids metabolism, Sphingosine therapeutic use, Sphingosine metabolism, Cytokines, Receptors, Lysosphingolipid, Sphingosine 1 Phosphate Receptor Modulators therapeutic use, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases metabolism
- Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function., Competing Interests: Conflict-of-interest statement: There is no conflict of interest associated with the senior author or any of the other coauthors who contributed their efforts in this manuscript., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)
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- 2023
- Full Text
- View/download PDF
37. Bioorthogonal azido-S1P works as substrate for S1PR1.
- Author
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Sternstein C, Schlegel J, Sauer M, and Seibel J
- Subjects
- Sphingosine-1-Phosphate Receptors, Lysophospholipids, Receptors, Lysosphingolipid, Sphingosine
- Abstract
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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- 2023
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- View/download PDF
38. Angiogenesis Model of Cornea to Understand the Role of Sphingosine 1-Phosphate.
- Author
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Wilkerson JL, Basu SK, and Mandal NA
- Subjects
- Humans, Sphingosine, Lysophospholipids, Cornea, Receptors, Lysosphingolipid, Endothelial Cells
- Abstract
The bioactive sphingolipid sphingosine 1-phosphate (S1P) and its five cognate receptors (S1PR1-5) have been implicated to play important role in multiple aspects of human physiology and diseases. The S1P-S1PR1 signaling axis in endothelial cells is crucial for establishing flow competent blood vessels. The role of S1P in neovascular pathology is of great interest and is evolving as a promising target for treatment. Here we describe an easy and affordable in vivo model of corneal neovascularization using an alkali chemical burn to the cornea. This method gives a consistent and easy-to-quantitate procedure for neovascularization and angiogenesis studies., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
- Full Text
- View/download PDF
39. The emerging role of FTY720 as a sphingosine 1‐phosphate analog for the treatment of ischemic stroke: The cellular and molecular mechanisms
- Author
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Maryam Naseh, Ali Rafati, Mahnaz Bayat, Masoud Haghani, and Jafar Vatanparast
- Subjects
Agonist ,FTY720 ,medicine.drug_class ,Sphingosine-1-phosphate receptor ,Reviews ,Inflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Review ,Pharmacology ,Neuroprotection ,050105 experimental psychology ,Brain Ischemia ,03 medical and health sciences ,Behavioral Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Sphingosine ,medicine ,ischemic stroke ,Animals ,Humans ,0501 psychology and cognitive sciences ,Sphingosine-1-phosphate ,Receptor ,Fingolimod Hydrochloride ,business.industry ,sphingosine 1‐phosphate (S1P) receptor ,05 social sciences ,Endothelial Cells ,Fingolimod ,Stroke ,Receptors, Lysosphingolipid ,chemistry ,Propylene Glycols ,neuroprotection ,Lysophospholipids ,medicine.symptom ,business ,Immunosuppressive Agents ,030217 neurology & neurosurgery ,medicine.drug ,RC321-571 - Abstract
Finding novel and effective drugs for the treatment of ischemic stroke is warranted because there is not a definitive treatment for this prevalent disease. Due to the relevance between the sphingosine 1‐phosphate (S1P) receptor and several neurological diseases including ischemic stroke, it seems that fingolimod (FTY720), as an agonist of S1P receptor, can be a useful therapeutic strategy in these patients. FTY720 is the first oral drug approved by the US food and drug administration for the treatment of multiple sclerosis. Three important mechanisms for neuroprotective effects of FTY720 have been described. First, the functional antagonistic mechanism that is associated with lymphopenia and reduced lymphocytic inflammation. This effect results from the down‐regulation and degradation of lymphocytes' S1P receptors, which inhibits lymph node lymphocytes from entering the bloodstream. Second, a functional agonistic activity that is mediated through direct effects via targeting S1P receptors on the membrane of various cells including neurons, microglia, oligodendrocytes, astrocytes, and endothelial cells of blood vessels in the central nervous system (CNS), and the third, receptor‐independent mechanisms that are displayed by binding to specific cellular proteins that modulate intracellular signaling pathways or affect epigenetic transcriptions. Therefore, we review these mechanisms in more detail and describe the animal model and in clinical trial studies that support these three mechanisms for the neuroprotective action of FTY720 in ischemic stroke., Three important mechanisms for neuroprotective effects of FTY720 have been described. Functional antagonistic, functional agonistic and receptor‐independent mechanisms. Here, we review these mechanisms in more details and describe animal model and in clinical trial studies
- Published
- 2021
40. CLIC1 and CLIC4 mediate endothelial S1P receptor signaling to facilitate Rac1 and RhoA activity and function
- Author
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Timothy Hla, Jan Kitajewski, Hideru Obinata, Matthew L. Kleinjan, Yulia Komarova, Bhairavi Swaminathan, Jilishitz Irina, Kayla J. Bayless, and De Yu Mao
- Subjects
rac1 GTP-Binding Protein ,RHOA ,GTPase ,Biochemistry ,Article ,Cell Line ,Mitochondrial Proteins ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Chloride Channels ,Sphingosine ,Animals ,Small GTPase ,Molecular Biology ,Sphingosine-1-Phosphate Receptors ,S1PR1 ,Cells, Cultured ,030304 developmental biology ,S1PR2 ,G protein-coupled receptor ,S1PR3 ,0303 health sciences ,biology ,Chemistry ,Neuropeptides ,Endothelial Cells ,Cell Biology ,Cell biology ,Endothelial stem cell ,Receptors, Lysosphingolipid ,biology.protein ,Lysophospholipids ,rhoA GTP-Binding Protein ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Chloride intracellular channels 1 (CLIC1) and 4 (CLIC4) are expressed in endothelial cells and regulate angiogenic behaviors in vitro, and the expression of Clic4 is important for vascular development and function in mice. Here, we found that CLIC1 and CLIC4 in endothelial cells regulate critical G-protein-coupled receptor (GPCR) pathways associated with vascular development and disease. In cultured endothelial cells, we found that CLIC1 and CLIC4 transiently translocated to the plasma membrane in response to sphingosine-1-phosphate (S1P). Both CLIC1 and CLIC4 were essential for mediating S1P-induced activation of the small guanosine triphosphatase (GTPase) Rac1 downstream of the S1P receptor 1 (S1PR1). In contrast, only CLIC1 was essential for S1P-induced activation of the small GTPase RhoA downstream of S1PR2 and S1PR3. Neither were required for other S1P-S1PR signaling outputs. Rescue experiments revealed that CLIC1 and CLIC4 were not functionally interchangeable, suggesting distinct and specific functions for CLICs in transducing GPCR signaling. These CLIC-mediated mechanisms were critical for S1P-induced stimulation of the barrier function in endothelial cell monolayers. Our results define CLICs as previously unknown players in the pathways linking GPCRs to small GTPases and vascular endothelial function.
- Published
- 2021
41. Sphingosine-1-phosphate receptor-1 (S1PR1) signalling: the homeostatic pathway of the heart
- Author
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Annarita Di Lorenzo
- Subjects
Ventricular Remodeling ,Physiology ,Chemistry ,Macrophages ,Sphingosine-1-phosphate receptor ,Myocardial Infarction ,Cell biology ,Receptors, Lysosphingolipid ,Signalling ,Physiology (medical) ,Humans ,Cardiology and Cardiovascular Medicine ,Sphingosine-1-Phosphate Receptors ,S1PR1 ,Homeostasis ,Cell Proliferation - Published
- 2020
42. Cytokine‐Induced and Stretch‐Induced Sphingosine 1‐Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis
- Author
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David Magne, Anne Briolay, Carole Bougault, Benoit Le Goff, Leyre Brizuela, Frédéric Blanchard, Alaeddine El Jamal, and Saida Mebarek
- Subjects
Male ,0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Osteogenesis ,Sphingosine ,Synovial Fluid ,Orthopedics and Sports Medicine ,Cells, Cultured ,biology ,Middle Aged ,Up-Regulation ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Cytokine ,Sphingosine kinase 1 ,Cytokines ,Female ,medicine.symptom ,Metabolic Networks and Pathways ,Signal Transduction ,Adult ,medicine.medical_specialty ,Adolescent ,030209 endocrinology & metabolism ,Inflammation ,Young Adult ,03 medical and health sciences ,Calcification, Physiologic ,Chondrocytes ,Internal medicine ,Spondylarthritis ,medicine ,Animals ,Humans ,Synovial fluid ,Sphingosine-1-phosphate ,Aged ,Osteoblasts ,Fingolimod Hydrochloride ,Ossification ,Enthesis ,Tenocytes ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,Stress, Mechanical ,Lysophospholipids - Abstract
Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1-phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF-α and IL-17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro-inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR-induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P1/3 , but their contribution to S1P-impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.
- Published
- 2019
43. Combined Signature of the Fecal Microbiome and Plasma Metabolome in Patients with Ulcerative Colitis
- Author
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Meiling Sun, Yang Shi, Yangyang Zhou, Bing Du, Yue Lu, and Bingrong Liu
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,030204 cardiovascular system & hematology ,Gastroenterology ,Pathogenesis ,Feces ,Methylamines ,Plasma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Crohn Disease ,Clinical Research ,RNA, Ribosomal, 16S ,Internal medicine ,Metabolome ,Humans ,Medicine ,Microbiome ,Colitis ,Aged ,biology ,Sphingosine ,business.industry ,Microbiota ,Case-control study ,General Medicine ,Middle Aged ,medicine.disease ,biology.organism_classification ,Ulcerative colitis ,digestive system diseases ,Gastrointestinal Microbiome ,Receptors, Lysosphingolipid ,chemistry ,Case-Control Studies ,030220 oncology & carcinogenesis ,Colitis, Ulcerative ,Female ,Roseburia ,business - Abstract
BACKGROUND Ulcerative colitis is a chronic, idiopathic inflammatory disease that destroys the colon structure. Nevertheless, the exact pathogenesis is not clear and needs to be fully elucidated. MATERIAL AND METHODS Stool and plasma samples were used for 16S ribosomal RNA sequencing and liquid chromatography mass spectrometry, respectively. In addition, we detected the level of trimethylamine N-oxide. Finally, we performed Pearson correlation analysis between the microbiome and the metabolome. RESULTS Twenty-three active ulcerative colitis, 25 inactive ulcerative colitis, and 30 control cases were included. Thirty-four significantly different metabolites were found between the active ulcerative colitis and control groups, 38 were found between the inactive ulcerative colitis and control groups, and only 1 was found between the active ulcerative colitis and inactive ulcerative colitis groups. The plasma trimethylamine N-oxide level of the inactive ulcerative colitis and active ulcerative colitis groups was significantly higher than that of the control group. Moreover, we identified significant changes in 24, 18, and 12 bacterial genera for active ulcerative colitis-control, inactive ulcerative colitis-control, and active ulcerative colitis-inactive ulcerative colitis, respectively. Cross-correlation indicated an association between sphingosine 1-phosphate and Roseburia, Klebsiella, and Escherichia-Shigella. Through the pathway analysis, we found sphingolipid metabolism was one of the most significantly increased pathways. CONCLUSIONS Although levels of trimethylamine N-oxide were higher in ulcerative colitis patients, they did not achieve statistical significance in active ulcerative colitis and inactive ulcerative colitis groups. Sphingosine 1-phosphate was increased in ulcerative colitis patients and there were several microbiota associated with it. Although further study is still needed, sphingosine 1-phosphate will probably become a new target for treatment of ulcerative colitis.
- Published
- 2019
44. FTY720 controls disease severity and attenuates sciatic nerve damage in chronic experimental autoimmune neuritis
- Author
-
Laurent Kremer, Susana Brun, Jérôme De Seze, Omar Taleb, Ayikoe Guy Mensah-Nyagan, Nelly Boehm, Elisabeth Trifilieff, Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Institut d'Histologie, Institut de Chimie de Strasbourg, Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut de Chimie du CNRS (INC), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Immunologie et chimie thérapeutiques (ICT), and Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,0301 basic medicine ,Agonist ,Chronic inflammatory demyelinating polyradiculoneuropathy ,FTY720 ,medicine.medical_specialty ,Pathology ,Neurology ,medicine.drug_class ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Immunology ,Neuritis ,Severity of Illness Index ,lcsh:RC346-429 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Myelin ,0302 clinical medicine ,hemic and lymphatic diseases ,Neurites ,Animals ,Medicine ,Macrophage ,ComputingMilieux_MISCELLANEOUS ,lcsh:Neurology. Diseases of the nervous system ,Inflammatory neuropathies ,Fingolimod Hydrochloride ,business.industry ,Research ,General Neuroscience ,Polyradiculoneuropathy ,c-EAN ,medicine.disease ,Neuritis, Autoimmune, Experimental ,Sciatic Nerve ,Rats ,3. Good health ,Receptors, Lysosphingolipid ,030104 developmental biology ,medicine.anatomical_structure ,Polyradiculoneuropathy, Chronic Inflammatory Demyelinating ,Rats, Inbred Lew ,Peripheral nervous system ,Sciatic nerve ,business ,Immunosuppressive Agents ,030217 neurology & neurosurgery - Abstract
Background Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune-mediated inflammatory disease of the peripheral nervous system characterized by a response directed against certain myelin proteins and for which therapies are limited. Previous studies have suggested a beneficial role of FTY720, a sphingosine 1-phosphate (S1P) receptor agonist, known to deplete lymphocytes from the peripheral blood by sequestering them into lymph nodes, in the treatment of experimental autoimmune neuritis (EAN). Therefore, we investigated whether FTY720 is also beneficial in chronic experimental autoimmune neuritis (c-EAN), a recently developed rat model mimicking human CIDP. Methods c-EAN was induced in Lewis rats by immunization with S-palm P0(180–199) peptide. Rats were treated with FTY720 (1 mg/kg) or vehicle intraperitoneally once daily from the onset of clinical signs for 18 days; clinical signs were assessed daily until 60 days post-immunization (dpi). Electrophysiological and histological features were examined at different time points. We also evaluated the serum levels of different pro- and anti-inflammatory cytokines by ELISA or flow cytometry at 18, 40, and 60 dpi. Results Our data demonstrate that FTY720 decreased the severity and abolished the chronicity of the disease in c-EAN rats. Therapeutic FTY720 treatment reversed electrophysiological and histological anomalies, suggesting that myelinated fibers were subsequently preserved, it inhibited macrophage and IL-17+ cell infiltration in PNS, and it significantly reduced circulating pro-inflammatory cytokines. Conclusions FTY720 treatment has beneficial effects on c-EAN, a new animal model mimicking human CIDP. We have shown that FTY720 is an effective immunomodulatory agent, improving the disease course of c-EAN, preserving the myelinated fibers, attenuating the axonal degeneration, and decreasing the number of infiltrated inflammatory cells in peripheral nerves. These data confirm the interest of testing FTY720 or molecules targeting S1P in human peripheral neuropathies. Electronic supplementary material The online version of this article (10.1186/s12974-019-1441-4) contains supplementary material, which is available to authorized users.
- Published
- 2019
45. Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas
- Author
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Silvia Arcucci, Sophie Tartare-Deckert, Corine Bertolotto, Justine Noujarède, Florian Rambow, Thierry Levade, Nathalie Andrieu-Abadie, Julia Gilhodes, Caroline Imbert, Stéphanie Brayer, Thomas Filleron, Nicolas Meyer, Jean-Christophe Marine, Bruno Ségui, Marie-Lise Bats, Virginie Garcia, Justine Leclerc, David Garandeau, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Cancer Research ,Piperazines ,Nitrophenols ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Sphingosine ,Medicine ,Enzyme Inhibitors ,Vemurafenib ,Melanoma ,S1PR1 ,Sulfonamides ,Drug Synergism ,3. Good health ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Oncology ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,Proto-Oncogene Proteins B-raf ,Ceramide ,Cell Survival ,Down-Regulation ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,Sphingosine-1-phosphate ,Sphingosine-1-Phosphate Receptors ,Sphingolipids ,business.industry ,Biphenyl Compounds ,medicine.disease ,Xenograft Model Antitumor Assays ,Sphingolipid ,030104 developmental biology ,chemistry ,Article RECHERCHE ,Drug Resistance, Neoplasm ,Cancer research ,Lysophospholipids ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,V600E - Abstract
BRAF inhibitors (BRAFi) are used to treat patients with melanoma harboring the V600E mutation. However, resistance to BRAFi is inevitable. Here, we identified sphingosine 1-phosphate (S1P) receptors as regulators of BRAFV600E-mutant melanoma cell-autonomous resistance to BRAFi. Moreover, our results reveal a distinct sphingolipid profile, that is, a tendency for increased very long-chain ceramide species, in the plasma of patients with melanoma who achieve a response to BRAFi therapy as compared with patients with progressive disease. Treatment with BRAFi resulted in a strong decrease in S1PR1/3 expression in sensitive but not in resistant cells. Genetic and pharmacologic interventions, that increase ceramide/S1P ratio, downregulated S1PR expression and blocked BRAFi-resistant melanoma cell growth. This effect was associated with a decreased expression of MITF and Bcl-2. Moreover, the BH3 mimetic ABT-737 improved the antitumor activity of approaches targeting S1P-metabolizing enzymes in BRAFi-resistant melanoma cells. Collectively, our findings indicate that targeting the S1P/S1PR axis could provide effective therapeutic options for patients with melanoma who relapse after BRAFi therapy.
- Published
- 2019
46. S1PR2 deficiency enhances neuropathic pain induced by partial sciatic nerve ligation
- Author
-
Jin-Chao Hou, Qiang Gu, and Xiang-Ming Fang
- Subjects
medicine.medical_specialty ,matrix metalloproteinase ,Neuropathic pain,S1PR2,partial sciatic nerve ligation,matrix metalloproteinase ,Vascular permeability ,030204 cardiovascular system & hematology ,Neuropathic pain ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,Medicine ,Animals ,Receptor ,partial sciatic nerve ligation ,Sphingosine-1-Phosphate Receptors ,S1PR2 ,Mice, Knockout ,0303 health sciences ,biology ,Sphingosine ,030306 microbiology ,business.industry ,General Medicine ,Sciatic Nerve ,Matrix Metalloproteinases ,Myelin basic protein ,Mice, Inbred C57BL ,Disease Models, Animal ,Receptors, Lysosphingolipid ,Endocrinology ,chemistry ,Neutrophil Infiltration ,Spinal Cord ,biology.protein ,Cytokines ,Neuralgia ,Sciatic nerve ,business ,Cell activation - Abstract
Background/aim: Sphingosine 1-phosphate receptor 2 (S1PR2), a member of the seven-transmembrane receptor family, can be activated by its natural ligand sphingosine 1-phosphate (S1P) to initiate signal transduction and is involved in a wide range of biological effects such as immune cell migration and vascular permeability. Its relationship with neuropathic pain (NP) has not been reported. In this study, the effects of S1PR2 on the development of NP were studied.Materials and methods: We generated a model of NP by partial sciatic nerve ligation (pSNL). The 50% paw withdrawal threshold of the wild-type (WT) group and the S1PR2 deficiency group were measured at several time points after surgery. The inflammatory factor levels of the two groups were measured by real-time quantitative polymerase chain reaction (RT-PCR). Neutrophil infiltration and glial cell activation were detected by immunofluorescence. Matrix metalloproteinase 9 (MMP9) and its substrate myelin basic protein (MBP) were measured by RT-PCR, western blotting, and immunofluorescence.Result: The S1PR2 deficiency group showed a reduction in 50% paw withdrawal threshold compared with WT mice (P < 0.05) at 3 days after the operation. In the ligated sciatic nerve of the S1PR2 deficiency group, the mRNA expression of IL-1ß was increased; the numbers of infiltrating neutrophils and activated astrocytes were also increased. The expression of MMP9 was elevated while MBP was decreased. Conclusion: S1PR2 deficiency could increase the pain sensitivity of a NP mouse model and promote the development of NP.
- Published
- 2019
47. Involvement of sphingosine-1-phosphate receptors 2/3 in IR-induced sudden cardiac death
- Author
-
Jiaqi Wang, Jinding Liu, Hualin Guo, Deqing Chen, Xiaojia Zhang, and Gengqian Zhang
- Subjects
Male ,Agonist ,medicine.drug_class ,Sphingosine-1-phosphate receptor ,Myocardial Ischemia ,Connexin ,Infarction ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Pharmacology ,Sudden cardiac death ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,030212 general & internal medicine ,Receptor ,Sphingosine-1-Phosphate Receptors ,Heptanol ,business.industry ,Antagonist ,medicine.disease ,Rats ,Receptors, Lysosphingolipid ,Death, Sudden, Cardiac ,Connexin 43 ,cardiovascular system ,Peptides ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Abstract
It has been demonstrated that S1P receptors affect heart ischaemia-reperfusion (IR) induced injury. However, whether S1P receptors affect IR-induced cardiac death has not been investigated. The aim of this paper is to demonstrate the role of S1P receptors in IR-induced cardiac death. Healthy adult male Sprague-Dawley rats were assigned to the following groups: non-operation control group, sham operation group, IR group, IR group pretreated with DMSO, IR group pretreated with S1P3 agonist, IR group pretreated with an antagonist of S1P3, IR group pretreated with S1P2 and S1P3 antagonists, IR group pretreated with heptanol and antagonists of S1P2/3, and IR group pretreated with Gap26 and antagonists of S1P2/3 (heptanol acts as a Cx43 uncoupler and the mimic peptide Gap26 as Cx43 blocker). The groups with S1P2 or S1P3 agonist application before reperfusion were used to assess whether these can be used for therapy of IR. The haemodynamics, electrocardiograms (ECG), infarction area, and mortality rates were recorded. Immunohistological connexin 43 (Cx43) expression in the heart was detected in each group. Blocking S1P2/3 receptors with specific antagonists resulted in an increment of IR-induced mortality, increased infarction size, redistribution of Cx43 expression, as well as affecting the heart function. The infarction size, heart function, and mortality were totally or partially restored in the S1P2, S1P3 agonist-pretreated IR group, and the heptanol/Gap26-treated S1P2/3-blocked IR group. The S1P receptor S1P2/3 and Cx43 are involved in the IR-induced cardiac death.
- Published
- 2019
48. CD62L Is a Functional and Phenotypic Marker for Circulating Innate Lymphoid Cell Precursors
- Author
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Jasper J. Koning, Reina E. Mebius, Vera P. Mourits, Tanja Konijn, Louis Boon, Joke M. M. den Haan, Estefany Burniol Ruiz, Kim Lakeman, Marijn Bögels, J. Peter van Maanen, Gerd Bouma, Marjolein van Egmond, Rogier M. Reijmers, Yotam E. Bar-Ephraim, Molecular cell biology and Immunology, CCA - Cancer biology and immunology, Surgery, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, AII - Inflammatory diseases, and Gastroenterology and hepatology
- Subjects
Male ,Immunology ,Inflammation ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Immunity ,medicine ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,Lymphocytes ,L-Selectin ,Receptor ,Cells, Cultured ,Blood Cells ,Natural Cytotoxicity Triggering Receptor 2 ,Innate lymphoid cell ,hemic and immune systems ,Lymphoid Progenitor Cells ,Phenotype ,Immunity, Innate ,Mice, Inbred C57BL ,Receptors, Lysosphingolipid ,Female ,Lymph Nodes ,Lymph ,medicine.symptom ,030215 immunology ,Homing (hematopoietic) - Abstract
Innate lymphoid cells (ILCs) guard epithelial tissue integrity during homeostasis, but can be potent immune effector cells during inflammation. Precursors to all ILC subsets (ILC precursors [ILCP]) have been identified in human peripheral blood (PB). We found that during homeostasis, ILCP in PB of mouse and human expressed homing receptors for secondary lymphoid organs, mainly CD62L. These ILCP entered mouse lymph nodes in a CD62L-dependent way and relied on S1P receptors for their exit. Importantly, CD62L expression was absent on human ILCs expressing NKp44 in tonsils and PB of Crohn disease patients, and relatively fewer CD62L+ ILCP were present in PB of Crohn disease patients. These data are in agreement with selective expression of CD62L on nonactivated ILCP. As such, we conclude that CD62L not only serves as a functional marker of ILCP, but has potential to be used in the clinic as a diagnostic marker in inflammatory disorders.
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- 2019
49. Requirement for sphingosine kinase 1 in mediating phase 1 of the hypotensive response to anandamide in the anaesthetised mouse
- Author
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Greig, Fiona H., Nather, Katrin, Ballantyne, Margaret D., Kazi, Zeshan H., Alganga, Husam, Ewart, Marie-Ann, Zaborska, Karolina E., Fertig, Bracy, Pyne, Nigel J., Pyne, Susan, and Kennedy, Simon
- Subjects
Male ,RM ,Sphingosine-1-phosphate ,Mouse ,Polyunsaturated Alkamides ,Blood Pressure ,Anandamide ,Arachidonic Acids ,Article ,Sphingosine kinase ,Isoenzymes ,Mice, Inbred C57BL ,Vasodilation ,Mice ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Animals ,lipids (amino acids, peptides, and proteins) ,Hypotension ,Enzyme Inhibitors ,Antihypertensive Agents ,Aorta ,Endocannabinoids - Abstract
In the isolated rat carotid artery, the endocannabinoid anandamide induces endothelium-dependent relaxation via activation of the enzyme sphingosine kinase (SK). This generates sphingosine-1-phosphate (S1P) which can be released from the cell and activates S1P receptors on the endothelium. In anaesthetised mice, anandamide has a well-characterised triphasic effect on blood pressure but the contribution of SK and S1P receptors in mediating changes in blood pressure has never been studied. Therefore, we assessed this in the current study.\ud \ud The peak hypotensive response to 1 and 10 mg/kg anandamide was measured in control C57BL/6 mice and in mice pretreated with selective inhibitors of SK1 (BML-258, also known as SK1-I) or SK2 ((R)-FTY720 methylether (ROMe), a dual SK1/2 inhibitor (SKi) or an S1P1 receptor antagonist (W146). Vasodilator responses to S1P were also studied in isolated mouse aortic rings.\ud \ud The hypotensive response to anandamide was significantly attenuated by BML-258 but not by ROMe. Antagonising S1P1 receptors with W146 completely blocked the fall in systolic but not diastolic blood pressure in response to anandamide. S1P induced vasodilation in denuded aortic rings was blocked by W146 but caused no vasodilation in endothelium-intact rings.\ud \ud This study provides evidence that the SK1/S1P regulatory-axis is necessary for the rapid hypotension induced by anandamide. Generation of S1P in response to anandamide likely activates S1P1 to reduce total peripheral resistance and lower mean arterial pressure. These findings have important implications in our understanding of the hypotensive and cardiovascular actions of cannabinoids.
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- 2019
50. Are there any clinical and electrocardiographic predictors of heart rate reduction in relapsing- remitting multiple sclerosis patients treated with fingolimod?
- Author
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Muhammed Ulvi Yalcin, Kadri Murat Gurses, Rana Karabudak, Duygu Kocyigit, and Lale Tokgozoglu
- Subjects
Adult ,Male ,Agonist ,Bradycardia ,medicine.medical_specialty ,medicine.drug_class ,Electrocardiography ,03 medical and health sciences ,Multiple Sclerosis, Relapsing-Remitting ,0302 clinical medicine ,Heart Rate ,Internal medicine ,Heart rate ,medicine ,Humans ,030212 general & internal medicine ,Retrospective Studies ,medicine.diagnostic_test ,Fingolimod Hydrochloride ,business.industry ,Multiple sclerosis ,General Medicine ,medicine.disease ,Fingolimod ,Receptors, Lysosphingolipid ,Blood pressure ,Neurology ,Relapsing remitting ,Cardiology ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for treatment of relapsing-remitting multiple sclerosis (RRMS). S1P receptors that fingolimod acts upon have also been shown to be expressed on atrial myocytes. This expression pattern has been linked with the drug's cardiovascular effects, such as bradycardia. We aimed to evaluate the clinical and electrocardiographic predictors of heart rate (HR) reduction in patients receiving first-dose fingolimod.We retrospectively analyzed subjects diagnosed with RRMS who were allocated to fingolimod treatment. HR, systolic and diastolic blood pressure values and electrocardiography during the first dose of fingolimod were accessed.A total of 114 RRMS patients (65.8% female, 33.58 ± 8.63 years) were included. After the initial dose of fingolimod, the heart rate decreased significantly at each hour (each p 0.001). Nadir heart rate was reached at 4 h. The multivariate binary logistic regression analysis revealed that BMI (OR: 0.878, p = 0.045), optic nerve involvement (OR: 3.205, p = 0.018), baseline HR (OR: 1.079, p = 0.002) and T-peak-T-end interval (OR: 1.046, p = 0.030) were independent predictors of greater HR reduction. During 6-h monitorization, none of the patients had relevant adverse reactions.Our findings provide an insight on clinical and electrocardiographic predictors of HR reduction that occurs in RRMS patients receiving first dose of fingolimod.
- Published
- 2019
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