Sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions in both intracellular and extracellular compartments. It interacts with five G protein-coupled receptors subtypes (S1PR(1-5)) to generate multiple downstream signaling. Activation of S1PR1 has been validated to be involved in the process of immune modulation. Fingolimod (FTY720), the novel S1PR1 agonist, has been approved for the treatment of multiple sclerosis in clinical trials. The study towards discovery of selective S1PR1 agonists has become hot spot for immunological diseases. This article summarized the research progress of S1PR1 agonists, emphasizing their structure types, structure-activity relationship and direction of development.
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Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington's disease.
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Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, Norway; Institute of Nutritional Medicine (INUM) and Lübeck Institute of Dermatology (LIED), University of Lübeck (UzL) and University Medical Center Schleswig-Holstein (UKSH), Ratzeburger Allee 160, Lübeck D-23538, Germany; Department of Neuromedicine and Neuroscience, Faculty of Medicine and Life Sciences, University of Latvia (LU), Jelgavas iela 3, Rīga LV-1004, Latvia; Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The Georg S. Wise Faculty of Life Sciences, Tel Aviv University (TAU), Ramat Aviv IL-6997801, Israel. Electronic address:
Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions.
View Article and Find Full Text PDFDysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment.
Elife
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Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
Memory impairment in chronic pain patients is substantial and common, and few therapeutic strategies are available. Chronic pain-related memory impairment has susceptible and unsusceptible features. Therefore, exploring the underlying mechanisms of its vulnerability is essential for developing effective treatments.
View Article and Find Full Text PDFBroad and diverse roles of sphingosine-1-phosphate/sphingosine-1-phosphate receptors in the prostate.
iScience
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Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Article Synopsis
- Benign prostatic hyperplasia (BPH) is a common issue in older males, but how it develops is still not fully understood, prompting research into the role of sphingosine-1-phosphate (S1P) and its receptors (S1PRs) in the prostate.
- The study found that S1P and its receptors are highly expressed in the prostate, and S1PR1, S1PR2, and S1PR3 are involved in promoting cell growth, muscle contraction, and reducing inflammation via various cellular pathways.
- Treatment with S1P and specific receptor agonists led to prostate enlargement in rats, while antagonists of S1PR1 and S1PR3 reduced BPH symptoms
Sphingosine 1-phosphate receptor 1signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice.
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Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy.
Sphingosine 1-phosphate (S1P) is a lysosphingolipid with antiatherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet-fed LDL receptor-deficient mice with high or low overexpression levels of S1P receptor 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.
View Article and Find Full Text PDFCD83 mediates the inhibitory effect of the S1PR1 agonist CYM5442 on LPS-induced M1 polarization of macrophages through the ERK-STAT-1 signaling pathway.
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December 2024
Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000 Sichuan, China. Electronic address:
Macrophages possess M1/M2 polarization, which perform an essential role in immunology and inflammation studies. However, few studies have investigated the specific molecules involved in the polarization process beyond its induction and characterization. Here, we determined that the molecule S1PR1 regulates M1 polarization in macrophages and that the surface marker CD83 is involved in this process.
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