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Targeting defective sphingosine kinase 1 in Niemann-Pick type C disease with an activator mitigates cholesterol accumulation.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingoli…

Loss of sphingosine 1-phosphate receptor 3 gene function impairs injury-induced stromal angiogenesis in mouse cornea.

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid generated through sphingosine kinase1 (SPK1)-mediated phosphorylation of sphingosine. We show here that injury-induced S1P upregulation increases corneal neovascularization through stimulating S1PR3, a cognate receptor. since this response was suppressed in S1PR3-knockout mice. Furthermore, Cayman10444, a selective S1PR3 inhibitor, reduced this response in WT mice. Such reductions in neovascularization were associated with reduced vascular endothelial growth factor A (VEGF-A) mRNA expression levels in WT TKE2 corneal epithelial cells an…

Serum sphingosine-1-phosphate levels in bladder pain syndrome/interstitial cystitis patients: could it help in diagnosis?

PURPOSE: To find if there is any potential benefit of serum Sphingosine-1-Phosphate (S1P) level in the diagnosis of Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC). METHODS AND MATERIALS: Patients newly or previously diagnosed with BPS/IC between September 2017 and December 2018 were included. Healthy individuals who volunteered to enter the study were included as control group. The measurements of serum S1P in both groups were compared. Multiple regression analysis was conducted to find out the significant factors affecting S1P results. RESULTS: A total of 47 BPS/IC patients and 47 hea…

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

The sphingosine-1-phosphate 1 receptor (S1P1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) an…

Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1.

Apolipoprotein M (ApoM) transports sphingosine-1-phosphate (S1P) in plasma, and ApoM-deficient mice (Apom(-/-)) have ∼50% reduced plasma S1P levels. There are 5 known S1P receptors, and S1P induces adherens junction formation between endothelial cells through the S1P1 receptor, which in turn suppresses vascular leak. Increased vascular permeability is a hallmark of inflammation. The purpose of this study was to explore the relationships between vascular leakage in ApoM deficiency and S1P1 function in normal physiology and in inflammation. Vascular permeability in the lungs was assessed by accu…

Inhibition of sphingosine kinase prevents lipopolysaccharide-induced preterm birth and suppresses proinflammatory responses in a murine model.

Premature delivery occurs in 12% of all births, and accounts for nearly half of long-term neurological morbidity, and 60% to 80% of perinata … in-1 activates the phospholipase C pathway, leading to activation of protein kinase C and, in turn, sphingosine kinase (SphK). The inhibition of SphK has been recently shown to control the proinflammatory response associated with sepsis. We show herein, for the first time, that SphK inhibition prevents inflammation-associated preterm birth in a murine model. …

Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice.

UNLABELLED: The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up-regulated by tunicamycin and lipopoly…

The sphingosine 1-phosphate receptor modulator FTY720 prevents iodide-induced autoimmune thyroiditis in non-obese diabetic mice.

FTY720 is an immunomodulator that alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. This compound has been shown to be effective in suppressing autoimmune diseases in experimental and clinical settings. In the present study, we tested whether FTY720 prevented autoimmune thyroiditis in iodide-treated non-obese diabetic (NOD) mice, a model of Hashimoto's thyroiditis (HT) in humans. Mice were given 0.05% iodide water for 8 weeks, and this treatment effectively induced thyroiditis. Iodide-treated mice were injected intraperitoneally with either saline or FTY720 duri…

Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm.

Initial and early tissue injury associated with severe influenza virus infection is the result of both virus-mediated lysis of infected pulm … ted the host's ability to control virus replication. Here, we discuss a novel therapy that utilizes sphingosine-1-phosphate (S1P) receptor signaling that has the ability to significantly limit immunopathologic injury caused by the host's innate and adaptive immune response, thereby significantly aborting morbidity and mortality associated with influenza virus …

Cross-linking of FcepsilonRI causes Ca2+ mobilization via a sphingosine kinase pathway in a clathrin-dependent manner.

Clathrin-coated pits are now recognized to be involved in cell signaling in addition to receptor down-regulation. Here we tried to identify … ediated Ca(2+) response was almost completely abolished, which was accompanied by the inhibition of sphingosine 1-phosphate (S1P) production with no changes in inositol 1,4,5-trisphosphate (IP(3)) production. This suggests that the Ca(2+) signaling pathway via a sphingosine kinase (SK) is dependent on clathrin. Furthermore, antigen-induced tyrosine phosphoryl …

Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ.

Fumonisins, mycotoxins produced by Fusarium moniliforme and a number of other fungi, cause neuronal degeneration, liver and renal toxicity, cancer, and other injury to animals. Recent work with rat hepatocytes (Wang, E., Norred, W. P., Bacon, C. W., Riley, R. T., and Merrill, A. H., Jr. (1991) J. Biol. Chem. 266, 14486-14490) found that fumonisins block sphingosine biosynthesis by inhibiting the conversion of sphinganine to dihydroceramides, which precedes introduction of the 4,5-trans-double bond of sphingosine. The current study utilized mouse cerebellar neurons in culture to evaluate how th…

Corrigendum to "Therapeutic potential of the sphingosine kinase 2 inhibitor opaganib" [Pharmaceut. Sci. Adv. 4, (2026), 100125].

[This corrects the article DOI: 10.1016/j.pscia.2026.100125.].

Targeting Sphingosine-1-Phosphate Receptor 1 Protects Pulmonary Vascular Endothelial Integrity During Human Ex Vivo Lung Perfusion.

BACKGROUND: Pulmonary edema due to vascular endothelial injury in donor lungs reduces organ utilization and exacerbates ischemia/reperfusion injury, resulting in poor posttransplant outcomes. Sphingosine-1-phosphate (S1P) improves vascular integrity through S1P receptor 1 (S1PR1) signaling. This study assessed whether S1PR1 agonism during ex vivo lung perfusion (EVLP) reduces vascular permeability and edema formation in human donor lungs. METHODS: S1PR1 agonist CYM5442 was administered to human donor lungs declined for transplant, during 6 h of EVLP, using a paired split-lung model with one l…

Decreased Sphingosine 1-Phosphate Levels in the Prefrontal Cortex of Mice Susceptible to Repeated Social Defeat Stress.

Repeated psychological stress is a major risk factor for psychiatric disorders. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is known to contribute to regulating central nervous system functions. However, the relationship between the onset of psychological stress-induced behavioral disorders and S1P metabolism in the brain remains poorly understood. Because prefrontal cortex (PFC) and hippocampus are key brain regions involved in psychological stress responses, we investigated whether repeated social defeat stress (SDS) alters S1P metabolism in these regions. The S1P levels in the …

Exercise improves depressive-like behavior in adolescent mice by regulating sphingosine and ceramide metabolism through microglial CerS1.

Given the unique onset period of adolescent depression, it is crucial to prioritize treatment modalities that are not only effective but als … he expression of microglial ceramide synthase 1 (CerS1), promote the synthesis of C18 ceramide from sphingosine, and improve depressive-like behaviors in adolescent mice. Overexpression of CerS1 in the CA1 region using microglia specific adeno-associated virus (AAV) inhibits chronic unpredictable mild stress (CUMS) induced neuroinflammation. Meanwhile, overex …

Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism.

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improv…

Small EVs From Adipose-Derived MSCs Modulate Epidermal Barrier and Inflammation Via Sphingosine-1-Phosphate Signaling Pathway.

Epidermal permeability barrier defects are associated with several skin diseases, including atopic dermatitis (AD). Using an AD mouse model, … -sEVs versus donor ASCs, while the synthetic enzymes of ceramide (and acidic sphingomyelinase), and sphingosine-1-phosphate (sphingosine kinase) are significantly higher in ASC-sEVs versus donor ASCs. Conversely, ceramide (ceramidase), and sphingosine-1-phosphate hydrolytic enzymes (sphingosine-1-phosphate lyase and sphingosine-1-phosphate phosphatase) are lo …

Oncogenic small extracellular vesicles enriched in sphingosine-1-phosphate play a crucial role in pancreatic cancer progression.

Small extracellular vesicles (sEVs) from tumour cells mediate intercellular communication and signalling to regulate the progression of panc … to non-malignant cells, PDAC-derived sEVs were enriched in specific lysophospholipids, particularly sphingosine-1-phosphate (S1P), a lipid known for its pivotal role in cancer pathogenesis. S1P enrichment was validated in plasma-derived sEVs from KPC mice compared to WT. To explore the functional implications of S1P enrichment, we conducted assays demonstrati …

Лимфопенсия, связанная с фингозином 1-phosphate Рецепторные модуляторы (S1PRM) в множестве склерозов: анализ европейских данных о фармакологической бдительности.

В течение последних нескольких десятилетий значительно возрос уровень лечения множественных склерозов (MS) благодаря внедрению методов коррекции заболеваний (ДМР). Финголимод, сипонимод, озанимод и понсимод относятся к новому поколению пероральных ДМТ, отнесенных к категории фингозина 1-phosphate Рецепторные модуляторы (S1PRM). Благодаря своему механизму действий они могут повысить риск лимфакопсии, которая может повлиять на терапевтическое управление людьми с НР. Цель этого исследования заключалась в том, чтобы описать и сопоставить частоту представления данных о лимфопопиях, связанных four S

Совпадение в аннотации оригинала
BACKGROUND: The treatment landscape for Multiple Sclerosis (MS) has increased significantly over the past few decades, thanks to the introduction of disease-modifying therapies (DMTs). Fingolimod, siponimod, ozanimod, and ponesimod belong to the newer generation of oral DMTs categorized as sphingosine 1-phosphate receptor modulators (S1PRMs). Because of thei…

Knockdown of nicotinamide N-methyltransferase ameliorates renal fibrosis caused by ischemia-reperfusion injury and remodels sphingosine metabolism.

BACKGROUND: CKD currently affects 8.2% to 9.1% of the global population and the CKD mortality rate has increased during recent decades, making it necessary to identify new therapeutic targets. This study investigated the role of nicotinamide N-methyltransferase (NNMT) in renal fibrosis following ischemia-reperfusion injury (IRI), a key factor in chronic kidney disease (CKD) progression. METHODS: We established a mouse model with a knockdown of NNMT to investigate the impact of this enzyme on renal fibrosis after unilateral IRI. We then utilized histology, immunohistochemistry, and metabolomic