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Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization.

Deficiency of elastin (ELN), the major component of elastic fibers, leads to excess smooth muscle cells (SMCs), which characterizes arterial diseases (for example, supravalvular aortic stenosis (SVAS)) as well as physiological ductus arteriosus (DA) closure. Here we demonstrate that sphingosine kinase 1 (SPHK1) is a key node in these contexts. Sphk1 is the most upregulated transcript in Eln(-/-) aortic SMCs at embryonic day 15.5 when these cells are initially hyperproliferative. The aorta of humans with SVAS also upregulates SPHK1. Reduced ELN increases levels of transcription factor early gro…

Sphingosine Kinase 2 Inhibition Ameliorates Neuroinflammation in Diet-Induced Obese Mice.

Obesity is associated with low-grade inflammation and microgliosis, contributing to brain dysfunction and cognitive decline. Sphingosine-1-phosphate (S1P) and its generating enzymes sphingosine kinase 1/2 (SphK1/2) have been implicated in metabolic and inflammatory regulation. Plasma S1P levels are elevated in obese mice and humans, and genetic ablation of SphK2 in mice protects from age- and diet-induced weight gain. As SphK2 is the predominant isoform in the brain, the present study examined whether pharmacological SphK2 inhibition mitigates obesity-associated microgliosis. Male C57BL/6J mic…

Sphingosine-1-phosphate signaling in respiratory diseases: mechanisms and therapeutic perspectives.

Sphingosine-1-phosphate (S1P) is a pivotal bioactive sphingolipid functioning as both a structural membrane component and a signaling mediator. It orchestrates diverse physiological and pathological processes including cellular proliferation, migration, differentiation, and immune regulation. The biological efficacy of S1P is controlled by metabolic networks that coordinate its biosynthesis, transport, and degradation to maintain intra/extracellular homeostasis and to activate cell surface S1P receptors (S1PRs) to initiate downstream signaling. Contemporary research increasingly has increasing…

Discovery of Potent, Orally Bioavailable Sphingosine-1-Phosphate Transporter (Spns2) Inhibitors.

Targeting the S1P pathway has resulted in the development of S1P1 receptor modulators for the treatment of multiple sclerosis and ulcerative colitis. We hypothesize that targeting an upstream node of the S1P pathway may provide an improved adverse event profile. In this report, we performed a structure-activity relationship study focusing on the benzoxazole scaffold in SLB1122168, which lead to the discovery of 11i (SLF80821178) as a potent inhibitor of S1P release from HeLa cells (IC50: 51 ± 3 nM). Administration of SLF80821178 to mice induced ∼50% reduction in circulating lymphocyte counts,

Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2…

Reduced Sphingosine in Cystic Fibrosis Increases Susceptibility to Mycobacterium abscessus Infections.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by the deficiency of the cystic fibrosis transmembrane conductance regulator … tic interventions targeting affected CF patients. Here, we show that the deficiency of CFTR reduces sphingosine levels in bronchial and alveolar epithelial cells and macrophages from CF mice and humans. Decreased sphingosine contributes to the susceptibility of CF tissues to M. abscessus infection, resulting in a higher incidence of infections in CF mice. Not …

Sphingosine 1-phosphate and its regulatory role in vascular endothelial cells.

Sphingosine 1-phosphate (S1P) is a bioactive metabolite of sphingomyelin. S1P activates a series of signaling cascades by acting on its receptors S1PR1-3 on endothelial cells (ECs), which plays an important role in endothelial barrier maintenance, anti-inflammation, antioxidant and angiogenesis, and thus is considered as a potential therapeutic biomarker for ischemic stroke, sepsis, idiopathic pulmonary fibrosis, cancers, type 2 diabetes and cardiovascular diseases. We presently review the levels of S1P in those vascular and vascular-related diseases. Plasma S1P levels were reduced in various …

Нейропсихиатрический системный Lupus Erythematosus зависит от Sphingosine-1-Фосфатного сигнала.

Около 40% пациентов с системной волшебной эритематозой испытывают диффузные нейропсихиатрические проявления, включая слабое сознание и депрессию. Хотя патогенез диффузной нейропсихиатрии (NPSLE) не в полной мере понятен, потеря целостности мозгового барьера, самореактивные антитела и провоспалительные цитокины являются основными факторами, способствующими развитию заболеваний. Fingolimod, фингозин-1-фосфатный модулятор рецептора (S1P), предотвращает выпадение лимфоцитов из лимфоидных органов посредством функционального антагонизма рецепторов S1P. Помимо сокращения циркуляции самореактивных лим

Совпадение в аннотации оригинала
About 40% of patients with systemic lupus erythematosus experience diffuse neuropsychiatric manifestations, including impaired cognition and … bodies, and pro-inflammatory cytokines are major contributors to disease development. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, prevents lymphocyte egress from lymphoid organs through functional antagonism of S1P receptors. In addition to reducing the circulation of autoreactive lymphocytes, fingolimod has direct neuroprotective effects …

Sphingosine-1-phosphate restores endothelial barrier integrity in ovarian hyperstimulation syndrome.

STUDY QUESTION: Are follicular fluid (FF) sphingosine-1-phosphate (S1P) levels in patients at risk of developing ovarian hyperstimulation syndrome (OHSS) altered and in part responsible for the high vascular permeability observed in these patients. STUDY ANSWER: FF S1P levels are lower in FF from patients at risk of OHSS and treatment with S1P may reduce vascular permeability in these patients. WHAT IS KNOWN ALREADY: Although advances have been made in the diagnosis, and management of OHSS and in basic knowledge of its development, complete prevention has proven difficult. STUDY DESIGN, SIZ…

Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity.

Adipocyte lipolysis can increase the production of inflammatory cytokines such as interleukin-6 (IL-6) that promote insulin resistance. However, the mechanisms that link lipolysis with inflammation remain elusive. Acute activation of β3-adrenergic receptors (ADRB3) triggers lipolysis and up-regulates production of IL-6 in adipocytes, and both of these effects are blocked by pharmacological inhibition of hormone-sensitive lipase. We report that stimulation of ADRB3 induces expression of sphingosine kinase 1 (SphK1) and increases sphingosine 1-phosphate production in adipocytes in a manner that …

Sphingosine 1-phosphate receptor modulator FTY720 suppresses rat experimental autoimmune prostatitis.

Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of male sex accessory glands and is characterized by a cellu … esponses and infiltration into the prostate gland, and therapeutic effect of FTY720, a modulator of sphingosine-1-phosphate receptors which has shown promising protective effects in animal models and clinical trials of several autoimmune diseases. Significant accumulations of total MNCs, pan-T cells and CD8(+) cells were observed in prostatic stroma as early …

Colo-Protective Effects of Pentoxifylline Alone or in Combination With Mesalamine in Colitis Through Sphingosine Kinase 1/Sphingosine 1 Phosphate, and Zonula Occuldin 1 Pathways: New Molecular Approach.

Multiple signaling pathways have been implicated in the pathogenesis of ulcerative colitis (UC), including Sphingosine Kinase 1 (SPHK)/Sphingosine-1-Phosphate (S1P), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/NLR family pyrin domain-containing 3 (NLRP3), zonula occludens-1 (ZO-1), and signal transducer and activator of transcription 3 (STAT3). We aimed to investigate the Colo protective and anti-ulcerative effects of pentoxifylline (PTX) in a rat model of UC. Colitis was induced by intracolonic administration of 2 mL of 3% (v/v) acetic acid (AA). Thirty-five rats …

The sphingosine-1-phosphate pathway is differentially activated in human gestational tissues.

BACKGROUND: Dysregulated myometrial contractility contributes to obstetric complications. Sphingosine-1-phosphate (S1P), a bioactive lipid, modulates inflammation and smooth muscle contractility, including uterine contractility. However, its metabolic dynamics during pregnancy are poorly characterized. This study profiled S1P metabolic enzymes and receptors, and quantified sphingolipid metabolites in human gestational tissues across pregnancy. METHODS: Myometrium, decidua parietalis, and chorioamnion were collected from women undergoing cesarean sections at term (≥37 weeks' gestation) without…

Effect of Sphingosine-1-Phosphate Receptor Modulators on Insulin Resistance: A Review.

OBJECTIVE: The objective is to review the potential impact of sphingosine-1-phosphate (S1P) receptor modulators on insulin resistance in patients with multiple sclerosis, including underlying mechanisms and clinical evidence. DATA SOURCES: A literature search was conducted in PubMed for publications from inception through November 2025. Additional sources, including therapeutic positioning reports and official product information (Summary of Product Characteristics), were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English and Spanish language articles were extracted and eva…

The Sphingosine-1-phosphate pathway is differentially activated in human gestational tissues.

BACKGROUND: Dysregulated myometrial contractility contributes to obstetric complications. Sphingosine-1-phosphate (S1P) is an important inflammatory regulator in the myometrium and decidua, yet its metabolic dynamics during pregnancy are poorly characterized. This study aimed to profile the expression of S1P metabolic enzymes and receptors, and quantify sphingolipid metabolism in human gestational tissues across pregnancy. METHODS: Myometrium, decidua parietalis, and chorioamnion were collected from women undergoing cesarean sections at term (≥37 weeks' gestation) without labor (TNL), at term…

Expression of sphingosine-1-phosphate receptor 1 in neuroinflammation of canine brains.

Sphingosine-1-phosphate (S1P) is a signaling lipid mediator that is involved in multiple biological processes. The S1P/S1P receptor (S1PR) signaling pathway has an important role in the central nervous system. It contributes to physiologic cellular homeostasis and is also associated with neuroinflammation. Therefore, this study was performed to evaluate the expression of S1PR in dogs with meningoencephalitis of unknown etiology (MUE) and experimental autoimmune encephalomyelitis (EAE). The analysis used 12 brain samples from three neurologically normal dogs, seven dogs with MUE, and two canine…

Sphingosine 1-phosphate and osteoporosis: pathophysiology and therapeutic aspects-a narrative review.

Sphingosine 1-phosphate (S1P) regulates many cellular functions, such as differentiation, proliferation, migration, morphogenesis, cytoskeletal organization, adhesion, tight junction assembly, apoptosis and the localization of different cell types. S1P also controls the migration of osteoclast precursors between the blood and bone, and it keeps osteoclast precursors away from bone surfaces to reduce bone degradation, thus preventing bone decay. Osteoporosis is a systemic bone disease that predisposes patients to bone fracture due to decreased bone density and quality, disrupted bone microarchi…

Sphingosine 1-Phosphate in Malaria Pathogenesis and Its Implication in Therapeutic Opportunities.

Sphingosine 1-Phosphate (S1P) is a bioactive lipid intermediate in the sphingolipid metabolism, which exist in two pools, intracellular and extracellular, and each pool has a different function. The circulating extracellular pool, specifically the plasma S1P is shown to be important in regulating various physiological processes related to malaria pathogenesis in recent years. Although blood cells (red blood cells and platelets), vascular endothelial cells and hepatocytes are considered as the important sources of plasma S1P, their extent of contribution is still debated. The red blood cells (R…

Reduction of Sphingosine Kinase 1 Phosphorylation and Activity in Plasmodium-Infected Erythrocytes.

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator is involved in an array of biological processes and linked to pathological manifestations. Erythrocyte is known as the major reservoir for S1P as they lack S1P-degrading enzymes (S1P lyase and S1P phosphohydrolase) and harbor sphingosine kinase-1 (SphK-1) essential for sphingosine conversion to S1P. Reduced S1P concentration in serum was correlated with disease severity in patients with Plasmodium falciparum and Plasmodium vivax infections. Herein, we aimed to identify the underlying mechanism and contribution of host erythrocytes towar…

Serum sphingosine negatively correlates with albumin predicting the risk of hepatocellular carcinoma.

BACKGROUND: The roles of sphingosine in various cancers have not been fully investigated. Our aim was to identify the relationship between serum sphingosine and the risk of hepatocellular carcinoma (HCC). METHODS: Serum sphingosine in 34 normal people and 73 HCC patients were reviewed retrospectively. Receiver operating characteristic curve analysis was performed to determine the cut-off values of sphingosine in the serum. Chi-square test, t test and regression analysis were used to test the association between serum sphingosine and individual clinicopathologic parameters. RESULTS: Serum sph…