共查询到20条相似文献，搜索用时 15 毫秒
1.
Kwang Hong Tay Xiaoying Liu Mengna Chi Lei Jin Chen Chen Jiang Su Tang Guo Nicole M. Verrills Hsin‐Yi Tseng Xu Dong Zhang 《Pigment cell & melanoma research》2015,28(2):171-183
Targeting the sphingosine 1‐phosphate (S1P)/S1P receptor (S1PR) signalling axis is emerging as a promising strategy in the treatment of cancer. However, the effect of such an approach on survival of human melanoma cells remains less understood. Here, we show that the sphingosine analogue FTY720 that functionally antagonises S1PRs kills human melanoma cells through a mechanism involving the vacuolar H+‐ATPase activity. Moreover, we demonstrate that FTY720‐triggered cell death is characterized by features of necrosis and is not dependent on receptor‐interacting protein kinase 1 or lysosome cathepsins, nor was it associated with the activation of protein phosphatase 2A. Instead, it is mediated by increased production of reactive oxygen species and is antagonized by activation of autophagy. Collectively, these results suggest that FTY720 and its analogues are promising candidates for further development as new therapeutic agents in the treatment of melanoma. 相似文献
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Jie Ouyang Zhihao Shu Shuhua Chen Hong Xiang Hongwei Lu 《Journal of cellular and molecular medicine》2020,24(18):10290-10301
There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1‐phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P‐based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT‐1303) and the non‐selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases. 相似文献
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Sathya Narayanan Patmanathan Lee Fah Yap Paul G. Murray Ian C. Paterson 《Journal of cellular and molecular medicine》2015,19(10):2329-2340
Almost all drugs approved for use in humans possess potentially beneficial ‘off‐target’ effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re‐purposing FTY720 (also known as fingolimod, Gilenya?), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1‐phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer‐associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti‐cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer‐related cellular processes, and discuss its potential use as an anti‐cancer drug. 相似文献
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Vessey DA Kelley M Zhang J Li L Tao R Karliner JS 《Journal of biochemical and molecular toxicology》2007,21(5):273-279
Fractionation of cytosolic sphingosine kinase (SKase) activity by gel filtration chromatography gave rise to a 96-kDa peak that contained only the SK2 form of SKase (by Western analysis) and a broad ca. 46 kDa peak that contained only SK1 forms. SK2 appeared to have a bound accessory protein. When tested with the classic SKase inhibitor dimethylsphingosine (DMS), SK1 was extensively inhibited; however, SK2 was not inhibited but unexpectedly was activated. Activation of SK2 was the result of DMS enhancing the affinity of the enzyme for sphingosine, and, at low concentrations of ATP and sphingosine, activated by more than 100%. Activation of SK2 could be demonstrated in the cytosolic fraction indicating it was unrelated to the purification step. The immunomodulator FTY720 also activated SK2 (although to a lesser extent), but was a potent inhibitor of SK1. SK2 from rat liver and spleen was also not inhibited by DMS. L-Sphingosine and to a lesser extent dihydrosphingosine and phytosphingosine were effective inhibitors of both forms. 相似文献
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Miao Xiong Li Li Yang Liu Fangfang Zhou Nana Shi Hongling Huang Jun Wang Jieping Zhu 《Journal of cellular biochemistry》2019,120(2):1869-1877
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Saba JD 《Journal of cellular biochemistry》2004,92(5):967-992
Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are endogenous bioactive lipids that participate in the regulation of mammalian cell proliferation, apoptosis, migration, and angiogenesis. These processes are each critical for successful embryogenesis, raising the possibility that lysophospholipid signaling may contribute to normal animal development. In fact, recent studies in developmental model systems have established that S1P and LPA are necessary for diverse developmental programs including those required for morphogenesis of vertebrate reproductive, cardiovascular and central and peripheral nervous systems (PNS), as well as the establishment of maternal-fetal circulation and the immune system. Genetic, morphological, and biochemical characterization of developmental model systems offer powerful approaches to elucidating the molecular mechanisms of lysophospholipid signaling and its contributions to animal development and postnatal physiology. In this review, the routes of S1P and LPA metabolism and our current understanding of lysophospholipid-mediated signal transduction in mammalian cells will be summarized. The evidence implicating lysophospholipid signaling in the development of specific vertebrate systems will then be reviewed, with an emphasis on signals mediated through G protein-coupled receptors of the Edg family. Lastly, recent insights derived from the study of simple metazoan models and implications regarding lysophospholipid signaling in organisms in which Edg receptors are not conserved will be explored. 相似文献
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Ye Zeng 《Journal of cellular and molecular medicine》2017,21(8):1457-1462
The glycocalyx covers the human mammalian cells and plays important roles in stroke, inflammation and atherosclerosis. It has also been shown to be involved in endothelial mechanotransduction of shear stress. Shear stress induces the remodelling of the major component of the glycocalyx including glypican‐1, a cell membrane heparan sulphate proteoglycan. Other factors, such as sphingosine‐1‐phosphate (S1P), protect the glycocalyx against syndecan‐1 ectodomain shedding and induce the synthesis of heparan sulphate. In this study, we reviewed the role of shear stress and S1P in glycocalyx remodelling and revealed that the glycocalyx is a critical signalling platform, integrating the extracellular haemodynamic forces and chemical signalling, such as S1P, for determining the fate of endothelial cells and vascular diseases. This review integrated our current understanding of the structure and function of the glycocalyx and provided new insight into the role of the glycocalyx that might be helpful for investigating the underlying biological mechanisms in certain human diseases, such as atherosclerosis. 相似文献
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The sphingosine‐1‐phosphate (S1P) receptor modulator, fingolimod (FTY720), has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular (AV) conduction block have been reported in some patients after the first dose. The underlying mechanism of this AV node conduction blockade is still not well‐understood. In this study, we hypothesize that expression of this particular arrhythmia might be related to a direct effect of FTY720 on AV node rather than a parasympathetic mimetic action. We, therefore, investigated the effect of FTY720 on AV nodal, using in vitro rat model preparation, under both basal as well as ischaemia/reperfusion conditions. We first look at the expression pattern of S1P receptors on the AV node using real‐time PCR. Although all three S1P receptor isoforms were expressed in AVN tissues, S1P1 receptor isoform expression level was higher than S1P2 and S1P3. The effect of 25 nM FTY720 on cycle length (CL) was subsequently studied via extracellular potentials recordings. FTY720 caused a mild to moderate prolongation in CL by an average 9% in AVN (n = 10, P < 0.05) preparations. We also show that FTY720 attenuated both ischaemia and reperfusion induced AVN rhythmic disturbance. To our knowledge, these remarkable findings have not been previously reported in the literature, and stress the importance for extensive monitoring period in certain cases, especially in patients taking concurrently AV node blocker agents. 相似文献
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Birker-Robaczewska M Studer R Haenig B Menyhart K Hofmann S Nayler O 《Journal of cellular biochemistry》2008,105(4):1139-1145
Sphingosine-1-phosphate (S1P), acting through five closely related G-protein coupled receptors termed S1P1-5, has recently emerged as a possible regulator of smooth muscle cell (SMC) physiology with the potential to induce contraction, proliferation and stress fiber formation. In the present study, real-time quantitative PCR was used to determine the expression patterns of S1P receptor subtypes in human primary pulmonary artery smooth muscle cells (PASMC). We report here that subconfluent PASMC express predominantly S1P2 and S1P3 receptors and we show that S1P1 receptor mRNA levels are significantly up-regulated following basic fibroblast growth factor (bFGF) treatment. As a consequence, increased responsiveness, as measured by impedance and ERK1/2 phosphorylation, was observed upon stimulation with a specific S1P1 receptor agonist SEW2871. We therefore demonstrate, for the first time, that a growth factor that was previously shown to be involved in physiological and pathological changes of SMC function induced S1P1 receptor expression and we propose that S1P1 receptor up-regulation could contribute to vascular remodeling. 相似文献
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Sphingosine-1-phosphate (S1P) is a bioactive lysosphingophospholipid that has been implicated in the regulation of vital biological processes. Abundant evidence indicates that S1P acts as both an intracellular messenger and an extracellular ligand for a family of five specific G protein-coupled S1P receptors (S1PRs). Cellular levels of S1P are tightly regulated in a spatio-temporal manner through its synthesis catalyzed by sphingosine kinases (SphKs) and degradation by S1P lyase (SPL) and specific S1P phosphohydrolases. Over the past decade, the identification and cloning of genes encoding S1P metabolizing enzymes has increased rapidly. Overexpression and deletion of these enzymes has provided important insights into the intracellular and the \"inside-out\" functions of S1P. The purpose of this review is to summarize the current knowledge of S1P metabolizing enzymes, their enzymatic properties, and their roles in the control of cellular functions by S1P. 相似文献
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Buzard D Han S Thoresen L Moody J Lopez L Kawasaki A Schrader T Sage C Gao Y Edwards J Barden J Thatte J Fu L Solomon M Liu L Al-Shamma H Gatlin J Le M Xing C Espinola S Jones RM 《Bioorganic & medicinal chemistry letters》2011,21(19):6013-6018
S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists. 相似文献
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Xiao‐Jing Sun Min Chen Ming‐Hui Zhao 《Journal of cellular and molecular medicine》2018,22(9):4550-4554
Sphingosine‐1‐phosphate (S1P) is a crucial regulator in vascular inflammation. Our recent study found that under pathophysiological concentration in active anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV), S1P participated in MPO‐ANCA‐positive IgG‐induced glomerular endothelial cell (GEnC) activation via a S1P receptor (S1PR)‐dependent way. However, the downstream signalling pathways are not fully clear yet. In this study, we demonstrated that Rho guanosine triphosphatases (GTPases) signalling pathways, RhoA and Rac1 in particular, were implicated in MPO‐ANCA‐positive IgG‐mediated GEnCs activation enhanced by pathophysiological concentration of S1P in AAV. These results provide mechanistic insights into vascular barrier dysfunction in AAV, which may facilitate the development of effective therapies. 相似文献
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Roelofsen T Akkers R Beumer W Apotheker M Steeghs I van de Ven J Gelderblom C Garritsen A Dechering K 《Journal of cellular biochemistry》2008,105(4):1128-1138
The development and maintenance of a healthy skeleton depends on the migration of cells to areas of new bone formation. Osteoblasts, the bone forming cells of the body, mature from mesenchymal stem cells under the influence of bone morphogenetic protein. It is unclear at what developmental stage the osteoblasts start to migrate to their functional location. We have studied migration of immature pre-osteoblasts and of mature osteoblasts in response to Platelet-derived growth factor (PDGF) and sphingosine-1-phosphate (S1P). PDGF is a growth factor involved in bone remodeling and fracture healing whereas S1P is a circulating sphingolipid known to control cell trafficking. Our data indicate that PDGF acts as a chemotactic cue for pre-osteoblasts. In contrast, S1P is a chemorepellent to these cells. Upon Bone Morphogenetic Protein 2-induced conversion to the osteoblast phenotype, the chemotaxis response to PDGF is retained whereas the sensitivity to S1P is lost. By RNA interference and overexpression experiments we showed that the expression level of the S1P2 receptor is the sole determinant controlling responsiveness to S1P. The combined data indicate that migration of osteoblasts is controlled by the balance between PDGF, S1P and the differentiation state of the cells. We propose that this mechanism preserves the osteoprogenitor pool in the bone marrow, only allowing the more differentiated cell to travel to sites of bone formation. 相似文献
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Shao H Xu Q Wu Q Ma Q Salgueiro L Wang J Eton D Webster KA Yu H 《Journal of cellular and molecular medicine》2011,15(10):2046-2056
The chemokine stromal cell-derived factor-1 (SDF-1) plays a critical role in mobilizing precursor cells in the bone marrow and is essential for efficient vascular regeneration and repair. We recently reported that calcium augments the expression of chemokine receptor CXCR4 and enhances the angiogenic potential of bone marrow derived cells (BMCs). Neovascularization is impaired by aging therefore we suggested that aging may cause defects of CXCR4 expression and cellular responses to calcium. Indeed we found that both the basal and calcium-induced surface expression of CXCR4 on BMCs was significantly reduced in 25-month-old mice compared with 2-month-old mice. Reduced Ca-induced CXCR4 expression in BMC from aged mice was associated with defective calcium influx. Diminished CXCR4 surface expression in BMC from aged mice correlated with diminished neovascularization in an ischemic hindlimb model with less accumulation of CD34(+) progenitor cells in the ischemic muscle with or without local overexpression of SDF-1. Intravenous injection of BMCs from old mice homed less efficiently to ischemic muscle and stimulated significantly less neovascularization compared with the BMCs from young mice. Transplantation of old BMCs into young mice did not reconstitute CXCR4 functions suggesting that the defects were not reversible by changing the environment. We conclude that defects of basal and calcium-regulated functions of the CXCR4/SDF-1 axis in BMCs contribute significantly to the age-related loss of vasculogenic responses. 相似文献
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Brindley DN 《Journal of cellular biochemistry》2004,92(5):900-912
Lipid phosphates initiate key signaling cascades in cell activation. Lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are produced by activated platelets. LPA is also formed from circulating lysophosphatidylcholine by autotaxin, a protein involved tumor progression and metastasis. Extracellular LPA and S1P stimulate families of G-protein coupled receptors that elicit diverse responses. LPA is involved in wound repair and tumor growth. Exogenous S1P is a potent stimulator of angiogenesis, a process vital in development, tissue repair and the growth of aggressive tumors. Inside the cell, phosphatidate (PA), ceramide 1-phosphate (C1P), LPA, and S1P act as signaling molecules with distinct functions including the stimulation of cell division, cytoskeletal rearrangement, Ca(2+) transients, and membrane movement. These observations imply that phosphatases that degrade lipid phosphates on the cell surface, or inside the cell, regulate cell signaling under physiological and pathological conditions. This occurs through attenuation of signaling by the lipid phosphates and by the production of bioactive products (diacylglycerol, ceramide, and sphingosine). Three lipid phosphate phosphatases (LPPs) and a splice variant dephosphorylate LPA, PA, CIP, and S1P. Two S1P phosphatases (SPPs) act specifically on S1P. In addition, there is family of four LPP-related proteins (LPRs, or plasticity-related genes, PRGs). PRG-1 expression in neurons has been reported to increase extracellular LPA breakdown and attenuate LPA-induced axonal retraction. It is unclear whether the LRPs dephosphorylate LPA directly, stimulate LPP activity, or bind LPA and S1P. Also, the importance of extra- versus intra-cellular actions of the LPPs and SPPs, and the individual roles of different isoforms is not firmly established. Understanding the functions and regulation of the LPPs, SPPs and related proteins will hopefully contribute to interventions to correct dysfunctions in conditions such as wound repair, inflammation, angiogenesis, tumor growth, and metastasis. 相似文献
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David J. Swan John A. Kirby Simi Ali 《Journal of cellular and molecular medicine》2010,14(9):2211-2222
The vascular and immune systems of mammals are closely intertwined: the individual components of the immune system must move between various body compartments to perform their function effectively. Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, exerts effects on the two organ systems and influences the interaction between them. In the resting state, the vascular S1P gradient contributes to control of lymphocyte recirculation through the blood, lymphoid tissue and lymphatic vasculature. The high level of S1P in blood helps maintain endothelial barrier integrity. During the inflammatory process, both the level of S1P in different immune compartments and S1P receptor expression on lymphocytes and endothelial cells are modified, resulting in functionally important changes in endothelial cell and lymphocyte behaviour. These include transient arrest of lymphocytes in secondary lymphoid tissue, crucial for generation of adaptive immunity, and subsequent promotion of lymphocyte recruitment to sites of inflammation. This review begins with an outline of the basic biochemistry of S1P. S1P receptor signalling is then discussed, followed by an exploration of the roles of S1P in the vascular and immune systems, with particular focus on the interface between them. The latter part concerns crosstalk between S1P and other signalling pathways, and concludes with a look at therapies targeting the S1P-S1P receptor axis. 相似文献
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1- 磷酸鞘氨醇是一种有生物活性的脂质代谢产物,具有调节细胞增殖、再生、迁移,细胞内钙离子移动,黏附分子表达以及激活单核细胞黏附内皮细胞等功效,在血管生理性再生及动脉粥样硬化斑块发生发展中发挥重要作用。1- 磷酸鞘氨醇在高密度脂蛋白中含量在所有脂蛋白中最高,其参与调节高密度脂蛋白的抗氧化、抗血栓、抗炎等效应,而这些反应与1- 磷酸鞘氨醇的生物学功能如血管发生、内皮保护、抑制平滑肌细胞迁移、心肌缺血再灌注损伤的保护等密切相关。对1- 磷酸鞘氨醇信号通路在心血管系统中的作用及以该通路为靶点的相关药物研究进展进行综述,为今后研究提供参考。 相似文献