Search Results (542)

Stage-specific embryonic antigen-3-positive pluripotent-like/macrophage-like multilineage-differentiating stress-enduring (Muse) cells are a distinct subpopulation of mesenchymal stromal cells (MSCs), accounting for 1% to several percent of MSCs. Although stem cell therapy for spinal cord injury (SCI) typically targets the subacute phase to avoid the hostile acute environment, the therapeutic window for Muse cells remains unclear. C57BL/6J mice with severe T9 contusion SCI received a single tail vein injection of human bone marrow-derived (BM) Muse cells, BM-MSCs (both 5 × 10⁴ cells), or vehicle at 2, 8, 14, or 28 days post-injury (DPI) without immunosuppressants. Among the different administration time points, the 2-DPI Muse cell group exhibited significantly higher Basso Mouse Scale scores than the BM-MSC and vehicle groups from 14 days after injection, while no significant differences were observed at the other administration time points. The 2-DPI Muse cell group showed significantly greater homing to the injured spinal cord than the BM-MSC group, with persistent engraftment and neural-lineage marker expression at day 42. Ablation of engrafted Muse cells at day 42 partially reversed locomotor recovery, suggesting that engrafted Muse cells contributed to functional recovery. These findings suggest that intravenous Muse cell therapy exerts timing-dependent therapeutic effects after SCI, with greater efficacy during the early post-injury phase. Full article

Background/Objectives: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM). Methods: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen’s d, and sample-level coupling as Spearman ρ. Results: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs. Conclusions: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation. Full article

Endothelial dysfunction underlies many cardiovascular and metabolic diseases. Lysosomal storage disorders, particularly sphingolipidoses, cause intracellular accumulation of specific sphingolipids due to inherited enzyme defects. This review focuses on Gaucher, Niemann–Pick (types A, B, A/B) and Fabry diseases, selected because they exhibit clinically significant cardiovascular manifestations and each accumulates a distinct sphingolipid—glucocerebroside, sphingomyelin, or globotriaosylceramide—allowing comparative analysis of how different metabolic defects converge on similar endothelial phenotypes. We summarize current knowledge on how substrate accumulation disrupts the ceramide/sphingosine-1-phosphate (S1P) rheostat, affecting NO synthase, vascular permeability, inflammation, angiogenesis, autophagy and cell death. Common and disease-specific changes in endothelial morphology and barrier function are discussed. Importantly, direct experimental evidence for endothelial involvement in Gaucher and Niemann–Pick diseases remains scarce; most mechanistic insights derive from non-endothelial cell models, highlighting a significant gap that underscores the need for targeted endothelial studies. Deficiencies of GBA1, SMPD1, and GLA each modulate S1P and ceramide production through distinct pathways, yet all three conditions share similar functional endothelial alterations driven by disrupted sphingolipid homeostasis. Understanding these common mechanisms opens new perspectives for diagnostic biomarkers and therapeutic strategies aimed at restoring sphingolipid balance in the endothelium, though further research is required to validate these findings in endothelial-specific contexts. Full article

Background: Organ-preservation strategies in locally advanced rectal cancer (LARC) increasingly require accurate assessment of response to neoadjuvant therapy, yet magnetic resonance imaging poorly distinguishes complete from near-complete responses. We investigated plasma sphingolipid dynamics across multiple treatment timepoints as monitoring biomarkers for pathological response. Methods: This single-centre cohort study included 86 patients with histologically confirmed LARC; 58 received neoadjuvant treatment followed by surgical resection with an evaluable Mandard tumour regression grade (TRG) and formed the response-evaluable cohort (19 good responders [TRG 1–2], 39 poor [TRG 3–5]). Plasma sphingomyelin (SM), sphingosine-1-phosphate and glucosylceramide were quantified by UPLC–MS/MS at baseline (M0), post-chemoradiotherapy (M1) and post-surgery (M2). Discrimination was assessed by receiver operating characteristic analysis and odds ratios, longitudinal trajectories by a linear mixed-effects model, and SM was compared head-to-head with serum carcinoembryonic antigen (CEA). Results: SM did not discriminate response at baseline (M0 AUC = 0.53) but did after treatment (M1 AUC = 0.750, p = 0.024; M2 AUC = 0.786, p = 0.010; pooled AUC = 0.767; odds ratio 10.67 at a 164.0 mg/L cutoff; negative predictive value 84%). SM correlated inversely with TRG grade (Spearman ρ = −0.43, p = 0.016) and outperformed serum CEA (AUC 0.74 vs. 0.60). Trajectories diverged over time (mixed-model time × group interaction p = 0.023) with no baseline difference (p = 0.96): good responders increased SM by +22.5% from M0 to M2, whereas poor responders declined by −8.4%. Conclusions: Plasma SM is not a pre-treatment predictor but emerges as a post-treatment monitoring biomarker for pathological response in LARC, supporting its integration into multimodal response assessment for organ-preservation decision-making. External validation in independent cohorts is warranted. Full article

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1–S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer’s disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood–brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD. Full article

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8⁺ TILs exhibiting a progenitor stem-cell-like profile (CD39⁻ CD69⁻). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the “double-edged sword” nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome. Full article

Women living with HIV face an increased burden of spontaneous preterm birth (sPTB); however, the underlying immunological mechanisms of sPTB and its association with HIV infection are poorly understood. Although the limited earlier literature implicates sphingosine-1-phosphate (S1P), a lysosphingolipid signaling molecule, in reproductive biology, the association of S1P signaling with HIV and sPTB has not been investigated. We examined whether two S1P signaling components, S1P receptors and sphingosine kinases, are expressed in the female reproductive tract and whether levels are associated with HIV status or spontaneous preterm birth. We quantified the mRNA expression of sphingosine-1-phosphate receptors 1 and 3 (S1PR1/S1PR3) and sphingosine kinases 1 and 2 (SPHK1/SPHK2) in 167 banked vaginal swab specimens collected between 14 and 26 weeks of gestation in a longitudinal pregnancy cohort in Lusaka, Zambia. We evaluated the expression of S1PR1, S1PR3, SPHK1, and SPHK2 by real-time quantitative reverse transcription PCR (RT-qPCR) in four groups (n = 41–42 each): women without HIV (WWoH) with term birth (≥37 weeks of gestation; TB), WWoH with spontaneous preterm birth (<37 weeks of gestation, sPTB), women with HIV (WWH) with TB, and WWH with sPTB. We found that S1P receptors and sphingosine kinases are expressed in the female reproductive tract. SPHK1 and SPHK2 mRNA expression were generally comparable among women independent of HIV status or birth outcome, though SPHK2 trended toward higher expression in women with HIV and women with sPTB. In contrast, S1PR1 mRNA trended toward higher expression in WWH vs. WWoH overall, as well as in WWH vs. WWoH among women with sPTB. Similarly, S1PR3 mRNA expression was greater in women with HIV than in women without HIV, and WWH, both with TB and sPTB, had higher S1PR3 mRNA expression than WWoH with TB. Perturbations in S1PR1 and S1PR3 mRNA expression may be associated with inflammation related to HIV infection and spontaneous preterm birth, suggesting that further studies of S1P signaling in pregnancy, especially among women with HIV, are warranted. Full article

Alterations in sphingolipids (SLs), oxylipins (OLs) and cytokines (CKs) are central to neuroinflammation. However, the effects of low doses Fumonisins B (FBs) on these analytes in the avian brain remain unclear.This study investigated SLs, OLs, CKs, and the activities of phospholipase A2c (PLA2c) and cyclooxygenase 2 (COX2) in the brains of chickens exposed to FB at a nominally safe dose of 14.6 mg FB1 + FB2/kg for 14 and 21 days. Targeted LC-MS/MS analyses revealed that FB exposure increased brain concentrations of sphingosine, N-acetyl-sphingosine, sphingosine 1-phosphate (So1P), ceramides (Cers), and sphingomyelins (SM). The Cer:SM ratio was elevated at 14 days but normalized by 21 days, whereas the So1P:Cer ratio rose at 14 days and continued to increase at 21 days. These changes coincided with elevated PLA2c and COX2 activities. OL profiling indicated a modest rise in pro-inflammatory arachidonic acid-derived COX metabolites at 14 days, while anti-inflammatory OLs derived from COX and lipoxygenase (LOX) pathways, including PGE2, 15-HETE, and 17-HDHA, increased significantly at 21 days. In contrast, the levels of CKs changed only slightly. Brain concentrations of Fumonisin B1 (FB1) indicated increased blood–brain barrier permeability.These findings highlight a key role of Cers in modulating OL production in FB neurotoxicity. Full article

Background/Objectives: Sphingosine-1-phosphate (S1P) is implicated in glycemic control. However, its circulating levels and clinical significance in type 2 diabetes mellitus (T2DM) remain controversial. We assessed plasma S1P levels in T2DM patients, its associations with metabolic parameters and complications, and explored its biomarker potential and non-linear (U-/J-shaped) relationships. Methods: This cross-sectional study enrolled 140 patients with T2DM and 63 matching healthy controls. Plasma S1P was measured by competitive ELISA. Statistical analyses included comparisons, correlation, ROC analysis, multivariable logistic regression, and quadratic/spline regression for U-shaped relationships. Results: Plasma S1P was significantly elevated in T2DM patients [1256.7 (149.4–1510.0) ng/mL] compared to controls [1075.1 (202.0–1510.0) ng/mL; p < 0.001]. S1P correlated positively with age, disease duration, HbA1c, insulin resistance, TyG index, triglycerides, systolic blood pressure, and negatively with HDL-C. Patients with complications had higher S1P than those without (p = 0.001), with progressive increases from retinopathy to nephropathy to mixed complications. Insulin-treated patients exhibited the highest S1P levels (p < 0.001). ROC analysis showed moderate diagnostic accuracy (AUC = 0.724). S1P is an independent associated factor with complications (OR = 1.18 per 100 ng/mL, p = 0.003). Non-linear analysis revealed a U-shaped relationship with HDL-C (optimal S1P: 1100–1350 ng/mL) and a J-shaped relationship with complication risk (threshold ~1250 ng/mL). Conclusions: Plasma S1P is elevated in T2DM and correlates with disease severity, glycemic control, insulin resistance, and complications. S1P demonstrates moderate biomarker potential and exhibits non-linear U-/J-shaped relationships with metabolic parameters, suggesting an optimal therapeutic window of 1100–1280 ng/mL. These findings support S1P as a marker of cumulative disease burden and a potential therapeutic target. Full article

Corneal scarring is a result of unregulated fibrotic processes in wound healing, which causes visual impairment. Bioactive sphingolipids (SPLs) are known to modulate physiological processes that are central to wound healing. Of these bioactive SPLs, sphingosine-1-phosphate (S1P) is perhaps the most studied. Previous research has shown that knocking out sphingosine kinase 1 (Sphk1), which produces S1P, alters SPL species metabolism and improves wound healing in mice corneas. However, it is unknown how SphK1 knockout (SphK1^-/-) affects SPL metabolism during stages of corneal wound healing. Following an alkali burn procedure on wild-type (WT) and SphK1^-/- mice, corneal lipidomic profiles in unburned corneas at 1, 7, 14, and 28 days post-injury (DPI) were measured. Significant differences in SPL species between genotypes, both in uninjured mouse corneas and during distinct stages of corneal burn healing, were observed. WT mice expressed burn healing stage-dependent modulation of SPL species, with decreased expression of most SPL species observed at 1 and 14 DPI. Interestingly, this wild-type SPL modulation was absent in most measured SPL species in the SphK1^-/- corneas. These findings provide evidence for a previously unknown modulatory role of SphK1 and S1P on the expression of SPLs during corneal wound healing. Full article

Siponimod, a selective sphingosine 1-phosphate (S1P) receptor modulator, represents a next-generation therapeutic drug for active secondary progressive multiple sclerosis. This study conducted in-depth forced degradation studies of siponimod in solid state subjected to acidic, alkaline, oxidative, photolytic, and thermal conditions, in compliance with ICH guidelines Q1A (R2) and Q3A (R2). An HPLC method was developed to quantify siponimod and separate its degradation products (DPs). The DPs were characterized using LC-HRMS/MS and LC-MSⁿ techniques. Moreover, the toxicological profiles of siponimod and its DPs were evaluated through the in silico tools ProTox 3.0 and ADMETlab 3.0, with molecular docking and dynamics simulations assessing their binding to the S1P1 receptor. Siponimod was stable to light but degraded under acidic, alkaline, oxidative, and thermal stress, producing five products: DP-1 (acidic), DP-2/3 (oxidative), DP-4 (hydrolytic), and DP-5 (thermal). The toxicity prediction suggested that neither siponimod nor its DPs exhibited carcinogenic or mutagenic potential, and the molecular modeling analysis revealed that DP-2 and DP-3 demonstrated favorable binding affinities, with stable dynamic profiles and thermodynamic properties that closely resembled those of siponimod. As far as we know, this is the first study on the structural elucidation of the DPs of siponimod by LC-HRMS/MS and LC-MSⁿ. Full article

Sphingosine 1-phosphate (S1P) is a potent bioactive sphingolipid that plays essential roles in regulating various immune responses, including lymphocyte trafficking, immune cell differentiation, and immunosurveillance. Different immune responses to S1P arise from the diverse Sphingosine 1-phosphate receptors (S1PRs) expressed on the cell surface, shaping unique, context-dependent responses to S1P. Beyond surface receptor engagement, intracellular S1P signaling is also being recognized as a crucial modulator of immune cell responses. Furthermore, the multifaceted S1P signaling axis has emerged as a key regulator of immune responses within the tumor microenvironment (TME), influencing both innate and adaptive immune cell behavior to facilitate tumor progression. A deeper mechanistic understanding of S1P signaling and its impact on immune cell fate is essential for developing novel therapeutic strategies to enhance anti-tumor responses. This review summarizes our current knowledge of how S1P influences immune cell function, with a specific focus on S1PR-dependent and S1PR-independent cellular signaling pathways. We also examine the alterations in immune cell responses that occur within the TME and current therapeutic strategies targeting S1P signaling. Full article

Abnormal intestinal mucosal immunity plays a crucial role in ulcerative colitis (UC). Autotaxin (ATX) can promote T cell migration and was reported to have a regulatory effect on Th17 cells, while sphingosine-1-phosphate (S1P) and its receptors (S1PRs) modulate Th17/Treg balance and inflammation, with S1PR modulators approved for UC. ATX can catalyze sphingosylphosphorylcholine (SPC) to produce S1P; however, the relationship between ATX and S1P/S1PRs in UC is unclear. Understanding the role of ATX-S1P/S1PRs in intestinal immunity can provide new treatment strategies for intestinal inflammatory diseases. Both UC patients and DSS-induced colitic mice showed significantly increased levels of ATX and S1P compared with healthy controls. ATX inhibitor PF8380 treatment led to reduced levels of S1P/S1PRs in colitic mice. Consistent with this, the S1PR antagonist etrasimod was able to alleviate ATX-induced intestinal inflammation, as well as partially restore ATX-induced Th17/Treg imbalance in MLNs and the spleen. In HT-29 and Raw246.7 cells, ATX treatment led to enhanced expression of S1P/S1PRs, with S1PR1 being the most significant. Furthermore, S1PR1 mediates the effect of ATX on Th17/Treg cell differentiation and function in vivo. Therefore, ATX affects the differentiation and function of Th17/Treg cells through S1P/S1PR1 signaling, increased ATX expression leading to Th17/Treg cell imbalance, intestinal mucosal immune dysfunction, and exacerbating intestinal inflammation. Full article

Sphingolipids, first discovered in 1874 by Johann Thudicum, are among the eight recognized classes of lipids and are present in essentially all plants, animals, and fungi, as well as some viruses and prokaryotes. In mammals, sphingolipids are enriched in the central nervous system (CNS), where they play vital roles in tissue development; membrane structure; cell adhesion and recognition; and, importantly, signaling. A subset of sphingolipids including ceramide, glucosylceramide, and sphingosine has been shown to have bioactive properties, but two sphingolipids in particular (ceramide-1-phosphate and sphingosine-1-phosphate) have been shown to exert their effects at least in part due to the activation of cell surface-expressed G protein-coupled receptors. In the CNS, sphingosine-1-phosphate signaling has specifically emerged as a productive therapeutic target for the treatment of neurodegenerative disease, with the first small molecule targeting sphingosine-1-phosphate receptors approved roughly 15 years ago for the treatment of multiple sclerosis. As more specific activators and inhibitors of these receptors have been developed and entered the clinical trial pipeline, now is an appropriate time to examine the current state of our knowledge of the role that these receptors play in the CNS and highlight the current landscape of available modulators targeting these pathways. Full article