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Inhibition of sphingosine-1-phosphate receptor-2 attenuates chronic gastritis via blocking nuclear translocation of S1P2 receptors in epithelial cells.

BACKGROUND AND PURPOSE: Although there is a decline in the overall incidence of chronic gastritis through antibiotic treatment, the public health burden remains significant because of low eradication rates. Herein, we explore the role of sphingosine-1-phosphate receptor-2 (S1P2 receptor) in mediating the development of chronic gastritis, as well as the effect of S1P2 receptor antagonists in attenuating its development. EXPERIMENTAL APPROACH: Chronic gastritis model was established through long-term exposure to lipopolysaccharide (LPS) in mice. S1P2 receptor antagonists were administrated via …

Ozanimod, a functional sphingosine-1-phosphate receptor 1 antagonist, restores brainstem descending pain pathways in murine models of neuropathic pain.

Activation of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) in the spinal cord contributes to neuropathic pain; however, its role at supraspinal sites remains unexplored. Ozanimod is a new FDA-approved S1PR1 antagonist for multiple sclerosis. Here, we show that systemic ozanimod administration reverses behavioral hypersensitivities in male rodents induced by chronic sciatic nerve constriction and chemotherapy (oxaliplatin and paclitaxel). Moreover, bilateral ozanimod injection in the rostral ventral medulla (RVM) reversed behavioral hypersensitivities in a time-dependent manner, evincing a …

Severe infections in pediatric MS and related disorders patients on B-cell depleting therapies compared to sphingosine-1-receptor modulators.

BACKGROUND: There is limited data on infection risk in pediatric onset multiple sclerosis and related disorders (MSARD). OBJECTIVES: Analyze rate of severe infections in pediatric MSARD patients on B-cell depleting therapies (BCT) compared to fingolimod. METHODS: This was a retrospective chart review of pediatric MSARD patients from the Harvard Multiple Sclerosis Patient Database and the MGH Pediatric Multiple Sclerosis Center database treated with BCT or fingolimod. Infections were defined as severe if requiring hospitalization, or if there were two outpatient infections within six months r

Обнаружение сфингосин-1-Фосфатных модуляторов-рецепторов в качестве потенциальных CHI3L1 Inhibitors с помощью лигандского виртуального скрининга и моделирования молекулярной динамики.

Множественный склероз характеризуется воспалением центральной нервной системы, обезвоживанием и нейронным дегенерацией. Нынешние методы диагностики и прогнозирования не являются точными, что требует использования биомаркеров для индивидуализированных методов лечения. Читинас 3-подобный 1 (CHI3L1) стал потенциальным прогнозным маркером с повышенными уровнями, связанными с серьезностью заболеваний и риском рецидива. Несмотря на его терапевтический потенциал, было выявлено несколько ингибиторов CHI3L1. На основе виртуального скрининга на основе лиганда и моделирования молекулярной динамики разреш

Совпадение в аннотации оригинала
Multiple sclerosis is characterized by central nervous system inflammation, demyelination, and neuronal degeneration. Current diagnostic and … inflammatory diseases, offering promising therapeutic approaches. This investigation suggests that sphingosine-1-phosphate receptor modulators such as fingolimod could be potential inhibitors for CHI3L1.

Sphingosine kinase inhibitor, SKI-II confers protection against the ionizing radiation by maintaining redox homeostasis most likely through Nrf2 signaling.

Exposure to ionizing radiation (IR) set a series of deleterious events causing acute radiation syndrome and mortality, posing the need for a potent and safe radio-protective drug. IR induces cell death predominantly by causing oxidative stress and macromolecular damage. The pre-existing antioxidant defence machinery of the cellular system plays a crucial role in protecting the cells against oxidative stress by activation of Nrf2. The current study was undertaken to investigate the radio-protective potential of sphingosine kinase inhibitor (SKI-II), which was demonstrated to activate Nrf2 signa…

Osteoclastogenesis and sphingosine-1-phosphate secretion from human osteoclast precursor monocytes are modulated by the cystic fibrosis transmembrane conductance regulator.

Osteopenia and increased fracture rates are well-recognized in patients with cystic fibrosis (CF) disease. In CF pathology, F508del is the m … nts bearing the F508del-CFTR mutation, to modulate their bone-resorptive abilities and the level of sphingosine-1-phosphate (S1P) produced by OCs, a key factor in the bone mineral density and formation. In the present study, a severe, defective differentiation of CF-F508del PBMCs to CF-F508del OCs without any significant difference in nuclei number per OC was …

CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy.

PURPOSE: Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. METHODS: OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluor…

Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk.

BACKGROUND AND PURPOSE: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators. EXPERIMENTAL APPROACH: The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of G-protein-coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determi…

Reinforced Epithelial Barrier Integrity via Matriptase Induction with Sphingosine-1-Phosphate Did Not Result in Disturbances in Physiological Redox Status.

Objectives. The relationship among matriptase function, cellular redox status, and maintenance of intestinal barrier integrity has not been established yet. The aim of this study is to reveal if the crosstalk between matriptase activators and intestinal epithelial monolayers can lead to perturbations in physiological redox regulation in vitro. Methods. The effects of suramin and sphingosine-1-phosphate (S1P) were tested on viability of intestinal porcine epithelial IPEC-J2 cells using MTS assay. Measurements of transepithelial electrical resistance (TER) were performed to determine changes in …

Reconceptualizing adult neurogenesis: role for sphingosine-1-phosphate and fibroblast growth factor-1 in co-ordinating astrocyte-neuronal precursor interactions.

Despite the powerful induction of neurogenesis by sphingosine-1-phosphate (S1P), its study in the role of adult neurogenesis has been relatively neglected. S1P, via its differential effects at different S1P receptor subtypes, is a significant determinant of neuronal precursor/stem cell and astrocyte cellular organization. The variations in neurogenesis, classically modelled via the interactions of phosphatase and tensin homolog and Notch, are intimately associated with the co-ordinated regulation of S1P and fibroblast growth factor-1. Incorporating S1P better explains the plasticity and cellul…

Sphingosine-1-Phosphate Receptor 3 Mediated Neuroinflammation is Critically Involved in the Development of Brain Injury Following Cardiac Arrest in Mice.

Brain injury after cardiac arrest (CA) is a major cause of death and disability, with neuroinflammation increasingly recognized as a key driver. Although the sphingosine-1-phosphate receptor 3 (S1PR3)-a G protein-coupled receptor-has been linked to neurological disorders, its role in CA-induced brain injury remains unclear. We induced CA in mice via intravenous potassium chloride injection. S1PR3 expression and subcellular localization were assessed in cortex and hippocampus. Mice received intraperitoneal CAY10444 (a selective S1PR3 antagonist) alone or with Colivelin TFA (a Janus Kinase 2 (JA…

Chronic exposure to aerosolized PM2.5 in rats alters plasma protein levels and ex vivo coronary artery response to sphingosine-1-phosphate.

Growing evidence shows that air pollution exposure plays a critical role in the development and progression of cardiovascular disease. Pollu … mploying a wire myograph. Also, systemic effects were assessed through plasma biomarkers of soluble Sphingosine-1-phosphate (S1P) and Endothelin-1 (ET-1) together with immunohistochemical assessment of coronary arteries. In our translational experimental set-up, we observed that only the accumulative dose from the chronic exposure played a significant role on …

Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.

The tumor immune microenvironment (TIME) is significance to the occurrence and development of tumors. Macrophages, making great contributes to TIME, develop into tumor-associated macrophages (TAM) under the influence of the tumor microenvironment (TME), resulting in altered metabolic pathways. Sphingosine 1-phosphate (S1P) is involved in immune regulation as a lipid metabolite. The role of S1P in the differentiation and metabolic regulation of tumor-associated macrophages is unknown. Meanwhile, the source of S1P in TME is not very clear. Our research found that hepatic stellate cells co-cultur…

Inhibition of sphingosine-1-phosphate receptor-2 attenuates idiopathic pulmonary fibrosis by preventing its binding to dapper1 in bronchial epithelial cells.

BACKGROUND AND PURPOSE: Activation of the sphingosine-1-phosphate receptor-2 (S1P2 receptor) promotes idiopathic pulmonary fibrosis (IPF). However, the mechanisms associated with IPF development via S1P2 receptor signalling are poorly understood and no S1P2 receptor antagonists have been approved for clinical use. EXPERIMENTAL APPROACH: Western blotting and immunohistochemical assays analysed inflammatory factors and epithelial-mesenchymal transition (EMT) markers. Co-immunoprecipitation and immunofluorescence analysed the binding of S1P2 receptor to dapper1 (Dpr1) and cyclic AMP response-bin…

Differences in lipid metabolism in acquired versus preexisting glucose intolerance during gestation: role of free fatty acids and sphingosine-1-phosphate.

BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. There is increasing evidence that GDM is a hetero … n (SM) concentrations in the liver decreased during gestation concomitantly with an increase in the sphingosine-1-phosphate (S1P) concentration in plasma. Further, preIGT mice showed impaired hepatic weight adjustment and alterations in hepatic FFA metabolism during gestation. This was accompanied by decreased expression of peroxisome proliferator-activated r …

Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1.

Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere

Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin II and interleukin-6.

Cardiac fibroblasts, together with cardiomyocytes, occupy the majority of cells in the myocardium and are involved in myocardial remodeling. The lysophospholipid mediator sphigosine-1-phosphate (S1P) regulates functions of cardiovascular cells through multiple receptors including S1PR1-S1PR3. S1PR1 but not other S1P receptors was upregulated in angiotensin II-induced hypertrophic hearts. Therefore, we investigated a role of S1PR1 in fibroblasts for cardiac remodeling by employing transgenic mice that overexpressed S1PR1 under the control of α-smooth muscle actin promoter. In S1PR1-transgenic m

In vivo intrabursal administration of bioactive lipid sphingosine-1-phosphate enhances vascular integrity in a rat model of ovarian hyperstimulation syndrome.

STUDY QUESTION: Can the bioactive lipid sphingosine-1 phosphate (S1P) act as an endothelial barrier-enhancing molecule and, in turn, restore the vascular integrity and homoeostasis in a rat model of ovarian hyperstimulation syndrome (OHSS). STUDY ANSWER: In vivo administration of S1P may prevent the early onset of OHSS and decrease its severity. WHAT IS KNOWN ALREADY: Although advances in the prediction and treatment of OHSS have been made, complete prevention has not been possible yet. S1P in follicular fluid from women at risk of developing OHSS are lower in comparison from women who are n…

Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human.

The role of sphingosine 1-phosphate (S1P) in liver fibrosis or inflammation was not fully examined in human. Controversy exists which S1P receptors, S1P1 and S1P3 vs S1P2, would be importantly involved in its mechanism. To clarify these matters, 80 patients who received liver resection for hepatocellular carcinoma and 9 patients for metastatic liver tumor were enrolled. S1P metabolism was analyzed in background, non-tumorous liver tissue. mRNA levels of sphingosine kinase 1 (SK1) but not SK2 were increased in livers with fibrosis stages 3-4 compared to those with 0-2 and to normal liver. Howev…

Review: The Prolonged QT Interval: Role of Pro-inflammatory Cytokines, Reactive Oxygen Species and the Ceramide and Sphingosine-1 Phosphate Pathways.

Patients with QT prolongation have delayed cardiac repolarization and may suffer fatal ventricular arrhythmias. To determine the role of cyt … hospholipidosis and on QT-shortening agents suggests a key role in QT prolongation for the ceramide/sphingosine-1-phosphate rheostat. We conclude that the cause of prolonged QT in inflammatory conditions is cytokine induction of reactive oxygen species and then ceramides, and believe that QT-prolonging agents bypass initial steps of this pathway and directly …