Sphingosine-1-phosphate Receptor Research Articles

Progressive Multifocal Leukoencephalopathy Associated with Sphingosine-1-Phosphate Receptor Modulators: A Large Case Series

Risk factors for progressive multifocal leukoencephalopathy (PML) associated with sphingosine-1-phosphate receptor (S1PR) modulators are not as well-characterized as for natalizumab. We characterized S1PR modulator-associated PML cases and risk factors for PML using spontaneous adverse event reports. We reviewed case reports from the FDA Adverse Event Reporting System database and the medical literature. We identified 57 PML cases encompassing all marketed S1PR modulators approved for multiple sclerosis, the majority (n = 53) associated with fingolimod. Ten cases reported a fatal outcome. Length of S1PR modulator exposure (≥18 months) appears to be a robust risk factor for PML. Patient age ≥50 years was identified as a potential risk factor, although this may be the result of several biases. We propose that prior immunosuppressant exposure should be considered as a potential risk factor for further validation. No conclusions could be drawn regarding JC virus serology and lymphopenia severity. Spontaneous adverse event reports support the observation that extended S1PR modulator exposure appears to be a robust PML risk factor. As a result, the U.S. Prescribing Information for each product in the S1PR modulator class was updated. Validation of other potential risk factors would support efforts to stratify and mitigate the risk of S1PR modulator-associated PML.

The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases.

Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct ac-tions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the ap-proval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clini-cal trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are af-fected, and the structural characteristics of several small molecule S1P modulators, with a particu-lar focus on their structure-activity connections.

Characterisation and Clinical Relevance of Tertiary Lymphoid Structures in Primary Biliary Cholangitis

ABSTRACTBackground and AimsThe pathological characteristics of lymphocyte infiltration in the hepatic portal tracts of patients with primary biliary cholangitis (PBC) remain unclear. Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues associated with the exacerbation of autoimmune reactions. Here, we evaluate the role of TLSs in PBC and investigate their potential therapeutic value.MethodsWe recruited 75 patients with PBC and 53 control patients with liver biopsies who were followed more than 2 years. TLSs and their maturity were identified by the amount and spatial distribution of immune cells. Bulk RNA sequencing of liver was performed in PBC patients with different TLS maturity. The sphingosine‐1‐phosphate receptor (S1PRs) modulator FTY720 was administered to dnTGFβRII mice to assess the role of TLSs on cholangitis.ResultsTLSs presented in 61.3% (46/75) of liver tissues from patients with PBC, including 26 patients with mature TLS (mTLS) and 20 patients with immature TLS (imTLS). The proportion of mTLS was higher in PBC compared with chronic hepatitis B and autoimmune hepatitis. PBC patients with mTLS exhibited the highest serum levels of biochemical indicators, immune globulin and proportions of liver cirrhosis. Gene sets for lymphocyte migration and chemokine signalling pathways were enriched in patients with PBC presenting with TLS. FTY720 inhibited TLS formation and relieved cholangitis and fibrosis in dnTGFβRII mice.ConclusionTLSs are characteristics of lymphocyte accumulation in the portal tracts of PBC, of which the maturity of TLSs correlates with the inflammation and fibrosis of PBC. Targeting TLSs formation is a potential treatment of PBC.

Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis.

Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis in vitro and in vivo. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury in vivo. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.

Abstract 4120623: Sphingosine Kinase 1 Is Integral For Elastin Deficiency-induced Arterial Hypermuscularization

Introduction: Defective elastic lamellae and smooth muscle cell (SMC) accumulation are characteristics of diverse obstructive arterial diseases (e.g., atherosclerosis, pulmonary hypertension, and supravalvular aortic stenosis [SVAS]) as well as physiological closure of the ductus arteriosus (DA). Mechanistic links between defective elastin and SMC proliferation are not well elucidated. Methods: Immunostaining for proliferation marker Ki67 was performed on wild-type (WT) and Eln (-/-) mouse aortas at embryonic day (E) 13.5 and E15.5 because elastin (ELN) is expressed in the mouse aorta from E14. Bulk RNA-seq was conducted on mouse aortic SMCs isolated from WT or Eln (-/-) embryos at E15.5. As sphingosine kinase 1 (SPHK1) was found as a highly promising candidate, its expression was evaluated in human SVAS patient aortas and in mouse Eln (-/-) aortas and WT DA. S1P receptor 1 (S1PR1) activity was assessed in aortic SMCs from S1pr1 (knock-in/knock-in) , H2B-GFP mice. Genetic deletion of Sphk1 in SMCs was performed on the elastin mutant background. Pharmacological SPHK1 inhibition was evaluated on both elastin mutants and WT embryos. Regulatory mechanisms of SPHK1 were assessed by mRNA stability assay and TRANSFAC database analysis. Results: SMC hyperproliferation was first observed in Eln (-/-) aorta at E15.5, prior to morphological differences. Bulk RNA-seq revealed that Sphk1 is the most upregulated transcript in Eln (-/-) aortic SMCs at E15.5. Reduced ELN increases SPHK1 levels in SMCs of human patient aortas and mouse aorta and DA. S1PR1 expression and activity are increased by elastin insufficiency. SMC Sphk1 deletion attenuates SMC proliferation and muscularization in the elastin-defective aorta, leading to extended viability of Eln (-/-) mice. Similarly, pharmacological SPHK1 inhibition ameliorates elastin aortopathy but leads to patent DA in WT mice. mRNA stability assay indicated Sphk1 is upregulated by enhanced transcription. TRANSFAC and bulk RNA-seq data suggested that transcription factor early growth response 1 (Egr1) induces Sphk1 transcription. Indeed, EGR1 was upregulated in elastin mutant aortas and DA. Conclusions: Elastin deficiency upregulates SPHK1 transcription, leading to SMC proliferation and hypermuscularization in elastin aortopathy as well as during physiological DA closure. Inhibiting SPHK1 is a promising therapeutic strategy for elastin aortopathy and for select congenital heart diseases in which patent DA maintains circulation.

Sphingosine-1-phosphate (S1P) receptor type 1 signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice.

Sphingosine 1-phosphate (S1P) is a lysosphingolipid with anti-atherogenic 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 type 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, IRF8, and LXR and were skewed towards a M2-distinct phenotype characterized by enhanced production of IL-10, IL-1RA, and IL-5, increased ATP-binding cassette transporter A1- and G1-dependent cholesterol efflux, increased expression of MerTK and efferocytosis, and reduced apoptosis due to elevated Bcl6 and MafB. A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203. Mechanistically, the enhanced PU.1, IRF8, and LXR activity in S1P1-overexpressing macrophages led to down-regulation of the cAMP-dependent protein kinase A and activation of the signaling cascade encompassing protein kinases Akt and mTOR complex 1 (mTORC1) as well as the late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (Lamtor-1). Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages towards an anti-atherogenic functional phenotype and countervails the development of atherosclerosis in mice.

TMIC-57. EFFECT OF HYPOXIA ON SPHINGOSINE-1-PHOSPHATE (S1P) METABOLIZING ENZYMES IN DIFFUSE INTRINSIC PONTINE GLIOMA CELL LINES

Abstract Diffuse Midline Glioma H3K27 altered (DMG) is a devastating and incurable paediatric brain tumour. Previously a bioinformatic approach was taken to evaluate genes involved in the sphingosine-1-phosphate (S1P) biosynthesis pathway in diffuse intrinsic pontine gliomas (DIPG). S1P is known to interact with epigenetic partners (HDAC1) as well as play a role in proliferation, immune cell trafficking, angiogenesis and apoptosis. As a part of a broad bioinformatic approach evaluating the expression of genes associated with the sphingomyelin (SM) biosynthesis pathway, S1P metabolism, S1P receptors and downstream targets, 14 of 25 genes were found to be dysregulated in DIPG relative to normal brain (p<0.0002). Herein we focus on the imbalance of the S1P metabolic enzymes sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate lyase (SGPL1). Bioinformatic data revealed higher levels of SGPL1 and lower levels of SPHK2 compared with normal brain. DIPG cell lines (SU-DIPG-IV, VUMC-DIPG-08, VUMC-DIPG-A) were used to validate gene and protein expression and to evaluate changes following exposure to hypoxic conditions. Confocal images reveal an increase in nuclear SPHK2 staining in cells cultured for 24- and 48-hours under hypoxic conditions. HDAC1 immunostaining was localised in the nucleus. SGPL1 immunostaining, while mostly cytoplasmic, nuclear staining was observed. qRT-PCR assays were used to evaluate changes in mRNA expression in SPHK2, SGPL1 and HDAC1 in DIPG cell lines incubated under hypoxic conditions. The Pfaffl method was used to analyse gene expression relative to the housekeeping gene TBP. Under hypoxic conditions, the levels of SPHK2 and HDAC1 were higher in DIPG cells cultured in hypoxic conditions for 48 hours compared to DIPG cells cultured in normoxic conditions, whereas SGPL1 expression was lower in hypoxic treated cells. Current experiments targeting the modulation of these S1P-metabolizing enzymes are underway to determine the role of the S1P signalling pathway and determine the potential advantage of targeting this pathway in DIPG.

Involvement of sphingosine-1-phosphate receptor 1 in pain insensitivity in a BTBR mouse model of autism spectrum disorder

BackgroundAbnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear.MethodsThe pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR.ResultsThrough integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD.ConclusionsS1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD.

Computational Analysis of S1PR1 SNPs Reveals Drug Binding Modes Relevant to Multiple Sclerosis Treatment

Background/Objectives: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by myelin and axonal damage with a globally rising incidence. While there is no known cure for MS, various disease-modifying treatments (DMTs) exist, including those targeting Sphingosine-1-Phosphate Receptors (S1PRs), which play important roles in immune response, CNS function, and cardiovascular regulation. This study focuses on understanding how nonsynonymous single nucleotide polymorphisms (rs1299231517, rs1323297044, rs1223284736, rs1202284551, rs1209378712, rs201200746, and rs1461490142) in the S1PR1’s active site affect the binding of endogenous ligands, as well as different drugs used in MS management. Methods: Extensive molecular dynamics simulations and linear interaction energy (LIE) calculations were employed to predict binding affinities and potentially guide future personalized medicinal therapies. The empirical parameters of the LIE method were optimized using the binding free energies calculated from experimentally determined IC50 values. These optimized parameters were then applied to calculate the binding free energies of S1P to mutated S1PR1, which correlated well with experimental values, confirming their validity for assessing the impact of SNPs on S1PR1 binding affinities. Results: The binding free energies varied from the least favorable −8.2 kcal/mol for the wild type with ozanimod to the most favorable −16.7 kcal/mol for the combination of siponimod with the receptor carrying the F2055.42L mutation. Conclusions: We successfully demonstrated the differences in the binding modes, interactions, and affinities of investigated MS drugs in connection with SNPs in the S1PR1 binding site, resulting in several viable options for personalized therapies depending on the present mutations.

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Clinicians' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

Four sphingosine-1-phosphate receptor (S1PR) modulators are currently available in the USA for treating relapsing forms of multiple sclerosis (MS). These S1PR modulators have similar efficacy. Clinicians may therefore consider other factors, such as clinical management considerations, when distinguishing among treatments. This study estimated which S1PR modulator clinicians would choose on the basis of a treatment's clinical management and quantified how individual aspects of clinical management might drive this choice. A multi-criteria decision analysis (MCDA) was conducted on the basis of clinical management preferences elicited in a discrete choice experiment (DCE) and real-world clinical management profiles of the S1PR modulators currently available to treat relapsing forms of MS (fingolimod, ozanimod, ponesimod, siponimod). The DCE was completed by neurologists in the USA experienced in treating MS and included eight clinical management attributes: first-dose observations, genotyping, liver function tests, eye exams, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Attribute levels were selected on the basis of S1PR modulator product labels. In the MCDA, partial MCDA scores were created for each attribute and summed to produce an overall MCDA score for each S1PR modulator. The DCE was completed by 200 neurologists. The overall MCDA score was highest for ponesimod (4.78 points), followed by siponimod (4.10 points), fingolimod (3.61 points), and ozanimod (2.38 points). Having fewer drug-drug interactions contributed most to the overall scores (up to 1.56 points), followed by having no first-dose observations (0.95 points), the shortest immune system recovery time (0.94 points), and not interacting with foods high in tyramine (0.86 points). When considering clinical management convenience, the average US-based neurologist treating MS is likely to choose ponesimod over siponimod, fingolimod, or ozanimod. The strongest driver of preferences was the number of drug-drug interactions. This information can help inform recommendations for the treatment of MS and facilitate shared decision-making between clinicians and patients.

Effect of Hepatic Lipid Overload on Accelerated Hepatocyte Proliferation Promoted by HGF Expression via the SphK1/S1PR2 Pathway in MCD-diet Mouse Partial Hepatectomy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming a major health problem worldwide. Liver regeneration is crucial for restoring liver function, and is regulated by extraordinary complex process, involving numerous factors under both physiologic and pathologic conditions. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid synthesized by sphingosine kinase 1 (SphK1), plays an important role in liver function through S1P receptors (S1PRs)-expressing cells. In this study, we investigated the effect of lipid overload on hepatocyte proliferation in a mouse hepatic steatosis model induced by feeding a methionine- and choline-deficient (MCD) diet. After 50% partial hepatectomy (PHx), liver tissues were sampled at various timepoints and then analyzed by immunohistochemistry, oil Red-O staining, quantitative-polymerase chain reaction (qPCR), and flow cytometry. In mice fed the MCD-diet, significantly exacerbated hepatic steatosis and accelerated liver regeneration were observed. After PHx, hepatocyte proliferation peaked at 48 and 36 hr in the liver of chow- and MCD-diet fed mice, respectively. By contrast, increased expression of S1PR2 was observed in hepatic neutrophils and macrophages of MCD-diet fed mice. Flow cytometry and qPCR experiments demonstrated that levels of HGF and FGF2 released by neutrophils and macrophages were significantly higher in MCD-diet fed mice. In conclusion, hepatic lipid overload recruits Kupffer cells and neutrophils that release HGF and FGF2 via SphK1/S1PR2 activation to accelerate hepatocyte proliferation.

The effect of immunosuppressive agent FTY-720 on coagulation, nitroxidergic lung activity and water balance in experimental antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic acquired autoimmune thrombophilia that leads to impaired non-respiratory lung functions due to the circulation of antiphospholipid antibodies, shifting the balance between the coagulation link of hemostasis and the anti-coagulation system towards hypercoagulation. The research examines the modulating effect of FTY-720 on the water balance, coagulation and NO-activity of the lungs under conditions of experimental APS. The functional activity of FTY-720 is largely due to its ability to bind to S1P1 receptors and block signaling pathways mediated by the interaction of the mediator sphingosine-1-phosphate with them. The main effect of FTY-720 is immunosuppression, which develops as a result of the drug’s receptor interaction predominantly with S1P1 receptors, resulting in the retention of autoreactive lymphocytes in lymph nodes, and prevents further spread of inflammation and damage. The experiments were conducted on 85 male rats, divided into groups as follows: The first group of animals (n = 30) was injected with cardiolipin antigen every other day for three weeks for APS modeling; the rats of the second group (n = 25), which served as a control group, were similarly injected with 0.9% NaCl; APS modeling and FTY-720 injection were combined on the remaining animals (n = 30). Three weeks later, arterial (art) and venous (ven) blood was taken, in which APTT and PT were determined using a hemocoagulometer CGL 2110 “Solar” and the corresponding coefficients of APPT of ven/art, PT of ven/ art were calculated. NO-activity was assessed by the content of plasma NO and NO bronchoalveolar lavage obtained by washing the extraction of the bronchopulmonary complex in anesthetized animals. To study the water balance of the lungs, the mass of moist and dried lungs was measured, were determined the total, extra- and intravascular fluid of the lungs. In APS, an increase in APTT and PT of arterial and venous blood was observed, an increase in the level of NO in bronchoalveolar lavages against the background of worsening nitroxidergic activity of the lungs – the NO index of ven/art decreased. There was a positive effect of FTY- 720 on the restoration of non-respiratory lung functions in APS.

Role of Sphingosine-1-Phosphate Signaling Pathway in Pancreatic Diseases.

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolic product produced via the phosphorylation of sphingosine by sphingosine kinases (SPHKs), serving as a powerful modulator of various cellular processes through its interaction with S1P receptors (S1PRs). Currently, this incompletely understood mechanism in pancreatic diseases including pancreatitis and pancreatic cancer, largely limits therapeutic options for these disorders. Recent evidence indicates that S1P significantly contributes to pancreatic diseases by modulating inflammation, promoting pyroptosis in pancreatic acinar cells, regulating the activation of pancreatic stellate cells, and affecting organelle functions in pancreatic cancer cells. Nevertheless, no review has encapsulated these advancements. Thus, this review compiles information about the involvement of S1P signaling in exocrine pancreatic disorders, including acute pancreatitis, chronic pancreatitis, and pancreatic cancer, as well as prospective treatment strategies to target S1P signaling for these conditions. The insights presented here possess the potential to offer valuable guidance for the implementation of therapies targeting S1P signaling in various pancreatic diseases.

Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease

Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P1), is coupled to Gi/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P1 constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P1 receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P1 receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [35S]GTPγS binding stimulated by the S1P1 receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P1 receptors.S1P1 receptor-mediated activity, along with that of the cannabinoid CB1 receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P1 signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P1 receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P1 receptor activity and Braak stages, suggesting that S1P1 receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P1 receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P1 receptor-mediated responses in the human brain.

Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease.

Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS. Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knockout, and LacZ knockin mice

FAM19A5 is a novel secretory protein expressed primarily in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function through sphingosine-1-phosphate receptor 2 (S1PR2). In our study, we investigated FAM19A5 transcript and protein levels in peripheral tissues, including adipose tissues, from wild-type, FAM19A5 knockout, and FAM19A5 LacZ knockin mice. We found that the FAM19A5 transcript levels in the central nervous system were much greater than those in any of the peripheral tissues, including adipose tissues. Furthermore, the FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for Western blot analysis and ELISA. Additionally, we found that the FAM19A5 protein did not interact with S1PR2 in terms of G protein-mediated signal transduction, β-arrestin recruitment, or ligand-mediated internalization. Taken together, our findings revealed basal levels of FAM19A5 transcripts and proteins in peripheral tissues, confirming its primary expression in the central nervous system and lack of significant interaction with S1PR2.

Adipose tissue responds to stress-induced immunosuppression affecting immune response partially by miR-145-5p/S1PR1 pathway

Stress-induced immunosuppression (SIIS) is one of the most common problems in intensive poultry production, which can cause immunized chickens to still develop diseases and bring huge losses to production. Recently, adipose tissue, as an immunomodulatory organ, has become a hot topic of attention. However, the function and mechanism of adipose tissue involved in SIIS and its influence on the immune response are still unclear. In this study, we dynamically analyzed the correlations between the T cells migration and change of sphingosine-1-phosphate receptor 1(S1PR1) gene in adipose tissue using chicken models with different immune states, and further explored the regulatory mechanisms and application. The results showed that SIIS could significantly change the expressions of lymphocytes migration related S1PR1 gene, and SIIS could inhibit the Newcastle disease virus (NDV) immune response partially by affecting the migration and proliferation of TCRα+ T cells in adipose tissue. Moreover, the miR-145-5p/S1PR1 pathway was a potential key mechanism to regulate T cells migration in adipose tissue, and circulating miR-145-5p had potential value as a molecular marker. This research can provide innovative reference for in-depth studying the immunoregulatory function and mechanism of adipose tissue.

Ozanimod: A Review in Relapsing Forms of Multiple Sclerosis.

Ozanimod (Zeposia®), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P1 and S1P5 receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-β1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS.

Explore the Role of the Sphingosine-1-Phosphate Signalling as a Novel Promising Therapeutic Target for the Management of Parkinson's Disease.

Sphingosine-1-phosphate (S1P) is a cellular signalling molecule derived from sphingosine, which is a pro-apoptotic sphingolipid. Sphingolipids control various cellular actions like growth, homeostasis, and stress-related responses. The main sources of S1P in our body are erythrocytes. S1P controls both cellular mediators and other second messengers intracellularly. The S1P receptor also helps in inflammatory and neuroprotective effects (required to manage of Parkinson's). A large number of anti-Parkinson drugs are available, but still, there is a need for more effective and safer drugs. S1P and its receptors could be targeted as novel drugs due to their involvement in neuro-inflammation and Parkinson's. The present review effort to explore the biological role of S1P and related receptors, for their possible involvement in PD; furthermore. Overall, S1P and other related metabolizing enzymes have significant therapeutic opportunities for Parkinson's disease along with other neurological disorders.