Sphingosine-1-phosphate activates ICl,swell in ventricular myocytes via mitochondrial reactive oxygen production.

Efferocytosis is a critical physiological process in which phagocytes clear apoptotic cells to maintain tissue homeostasis. However, within the tumour microenvironment (TME), this process is systematically hijacked by tumour cells, transforming it into a key pathological mechanism that drives immunosuppression, tumour progression and therapeutic resistance. This review systematically elucidates the central role of metabolic reprogramming in this functional reversal, emphasising that efferocytosis is essentially an immunometabolic intersection process precisely regulated by metabolism. By releasing various metabolites such as ATP, lactate, adenosine and sphingosine-1-phosphate (S1P), apoptotic tumour cells not only recruit tumour-associated macrophages (TAMs) but also metabolically pre-program their functions, inducing polarisation towards a pro-tumourigenic M2-like phenotype. During the recognition stage, tumour cells exploit metabolic abnormalities, such as glycosylation and lipid oxidation, to modify surface 'eat-me/don't-eat-me' signals, thereby hijacking macrophage recognition and engulfment programs. Upon completion of engulfment, systemic reprogramming of amino acid, lipid and glucose metabolism occurs within macrophages. These metabolic alterations synergistically lock their immunosuppressive phenotype and establish a metabolic symbiosis between the tumour and stromal cells. Based on these mechanisms, this review further explores translational strategies targeting the efferocytic-metabolic axis, aiming to reprogram the immunosuppressive efferocytosis into immune-activating events to overcome TME-mediated immunosuppression and enhance current therapeutic efficacy. By deeply dissecting the metabolic regulatory networks of efferocytosis, we aim to pave new directions for cancer immunotherapy, achieving a paradigm shift from 'metabolic hijacking' to 'metabolic interventional therapy'.

Ozanimod is a second-generation sphingosine 1-phosphate receptor (S1PR) modulator approved for treatment of relapsing multiple sclerosis (MS). Data are lacking for ozanimod use in real-world clinical practice. This study aims to determine characteristics of people with MS (pwMS) prescribed ozanimod as well as ozanimod persistence, tolerability, safety, and effectiveness over one year. Data were retrospectively collected for adults with MS or clinically isolated syndrome who received ozanimod at two tertiary MS centers. We identified 206 pwMS for inclusion. Many (n = 146, 71%) had prior disease-modifying therapy (DMT) experience. The most common reasons for switching to ozanimod were cost (n = 48, 33%) and prior DMT intolerance (n = 29, 20%). Most individuals (n = 149, 72%) remained on ozanimod at last data collection. The most frequent reason for discontinuation was side effects (n = 21, 37% of discontinuers, 10.2% of total cohort). Few pwMS reported tolerability concerns (7.5% at 12 months). When comparing pre-ozanimod baseline to 12-month data, the annualized relapse rate was reduced by 56% (p = 0.034), and fewer pwMS had new/enlarging brain MRI T2 lesions (6.6% versus 40%, p < 0.001) and gadolinium-enhancing lesions (3.9% versus 27%, p = 0.027). Ozanimod was well-tolerated with good treatment persistence, a favorable safety profile, and reductions in clinical and radiographic disease.

The Major Facilitator Superfamily (MFS) comprises a large and diverse group of membrane transport proteins involved in the translocation of metabolites across cellular membranes. The genome of Toxoplasma gondii encodes approximately 60 putative MFS transporters, yet the functions of most remain poorly characterized. Conserved across the superphylum Alveolata, the inner membrane complex (IMC) is a specialized peripheral membrane system essential for parasite replication, structural integrity, motility, and host cell invasion. Here, we identify Toxoplasma gondii Daughter Cell Transporter 1 (TgDCT1), a previously uncharacterized MFS transporter, as a critical regulator of daughter cell formation. TgDCT1 localizes predominantly to the daughter cell IMC and contains a predicted spinster-like MFS domain. Phylogenetic and structural analyses reveal that TgDCT1 is conserved across Alveolata, shares a canonical MFS fold with its Plasmodium falciparum orthologue, and exhibits striking structural similarity to the human sphingosine-1-phosphate (S1P) transporter SPNS2, suggesting an evolutionarily conserved role in lipid transport. Conditional depletion of TgDCT1 results in severe defects in cytokinesis, including disrupted IMC architecture, aberrant daughter cell morphology, and failure of plasma membrane abscission. Although TgDCT1-depleted parasites retain the capacity for microneme secretion and egress, they display profoundly impaired motility and host cell invasion, ultimately leading to arrest of the lytic cycle. Notably, pharmacological inhibition of the S1P transporter SPNS2 using the compounds 11i and 33p phenocopies TgDCT1 depletion, impairing parasite morphogenesis, intracellular replication, and division synchrony. Furthermore, transgenic complementation demonstrates that the spinster-like domain of the P. falciparum DCT1 orthologue can functionally substitute for TgDCT1, indicating that these transporters likely recognize the same substrate. Together, these findings establish TgDCT1 as a central regulator of lipid homeostasis required for IMC maturation, endodyogeny, and parasite propagation in Toxoplasma gondii and likely other Apicomplexa.

Demyelinating diseases are heterogeneous in their etiology, clinical course, and manifestations. In the long run, however, they lead to irreversible dysfunction of the nervous system. Although myelin regeneration occurs in response to myelin damage in both animal models of demyelination and human patients, the outcome is usually less favorable in humans. This explains the interest in treatments that could improve the effectiveness of myelin regeneration. Among these, treatment with the monoclonal antibody rHIgM22 has been shown to effectively enhance myelin regeneration in both immune and non-immune mouse models of demyelination. Its administration to patients with multiple sclerosis was well tolerated, and it was detected in the cerebrospinal fluid, suggesting penetration of the central nervous system. Previously, we demonstrated that administering rHIgM22 to rat mixed glial cultures alters the balance between ceramide and sphingosine 1-phosphate (S1P), thereby inducing S1P release and astrocyte and oligodendrocyte precursor cell (OPC) proliferation. In this paper, we studied the effects of rHIgM22 treatment on the lipid composition of purified glial cultures from the rat brain, including astrocytes, OPC, and oligodendrocytes (OL) at various stages of in vitro differentiation. rHIgM22 did not affect the phospholipid composition of any of the analyzed cell types. A steady-state metabolic labeling procedure revealed that sphingolipid patterns were unaffected by rHIgM22 treatment in astrocytes. However, rHIgM22 treatment significantly increased the levels of GM3 and GD3 gangliosides in oligodendroglial cells. The increase in GM3 and GD3 versus controls was highest in fully differentiated OL. We also detected a slight but significant reduction in cholesterol levels and in vitro acid sphingomyelinase activity in these cells. Acid sphingomyelinase is a key enzyme in sphingolipid metabolism. Thus, the effect of rHIgM22 on lipid metabolism is cell-specific among different glial populations. We hypothesize that the myelin regeneration effects of rHIgM22 could result from alterations in lipid-dependent membrane organization in oligodendroglial cells.

Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Fingolimod (FTY720) is a sphingosine-1-phosphate (S1P) receptor agonist that prevents lymphocytes from egressing from lymphoid tissues and has shown a cytotoxic effect on T-cell ALL (T-ALL) cells. However, the mechanism of action of FTY720 cytotoxicity in hematological malignancies is still unclear, and cell-specific effects have been reported. Here, we investigated the mechanism of cytotoxicity of FTY720 in T-ALL cells using a CRISPR-Cas9 genomic screening. Our goal was to identify novel positive regulators for the cytotoxic effect of FTY720 in T-ALL. Cells treated with FTY720 were enriched for single-guide RNAs (sgRNAs) such as ZNF575, GPX3, FBXL15, DNAJB5, UBE2D1, ATXN7, C6orf201, RIC8A, RAB13, and C10orf12 when compared to the DMSO (vehicle control) samples. Altogether, our study identified novel genes that, when silenced, were positively correlated with the survival of T-ALL cells treated with FTY720.

Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (RMS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Contraindications for ozanimod include patients who, in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure, or have a presence of Mobitz Type II second-degree or third-degree atrioventricular block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker; patients with severe untreated sleep apnea; or patients taking a monoamine oxidase (MAO) inhibitor. The molecular structure of ozanimod is distinct from that of earlier S1P receptor modulators, such as fingolimod, and binds with high affinity to S1P1 and S1P5. Experts Regina Berkovich, Founder and Director of the Berkovich MS Center and Research Institute and nationally recognized multiple sclerosis (MS) specialist based in West Hollywood, California, USA; and Robert Shin, Professor of Neurology and Ophthalmology at the University of Virginia, Charlottesville, and Director of the UVA Multiple Sclerosis and Clinical Neuroimmunology Center, USA, discussed several aspects of ozanimod therapy. They discussed ozanimod’s molecular structure, which distinguishes it from earlier S1P modulators, and reviewed long-term safety data (up to 7 years) from the DAYBREAK open-label extension (OLE) study and real-world evidence (RWE), including rates of serious adverse events (AE), infections, and treatment discontinuations. Finally, they described ozanimod’s efficacy in reducing annualized relapse rates (ARR) and MRI lesion activity in patients with early relapsing MS, and data on 3- and 6-month confirmed disability progression (CDP). Shin and Berkovich note how, taken together, these findings show that ozanimod as an oral disease-modifying therapy (DMT) may be suitable for early intervention in adults with relapsing MS.

Abstract BACKGROUND Mirikizumab (miri), an anti-interleukin (IL)-23p19 monoclonal antibody approved for ulcerative colitis (UC) and Crohn’s disease, demonstrated sustained efficacy and safety in patients with moderately to severely active UC in LUCENT clinical trials.1,2 However, real-world data on utilization of miri in the United States (US) are limited. METHODS This retrospective observational study used administrative claims from HealthVerity, a database that merges and deduplicates pharmacy and medical claims and enrollment information from closed claims data suppliers participating in the HealthVerity Marketplace. We described baseline demographic, clinical characteristics, and treatment history of UC patients in the US initiating miri and at 3 months follow-up. Adults diagnosed with UC who initiated miri between October 26, 2023 (post-US Food and Drug Administration approval) and July 2025 with at least 3-month follow-up available were included. The index date was defined as the date of the first medical or pharmacy claim for intravenous (IV) miri. Baseline was defined as 12 months prior to the index date (pre-index period), and outcomes were assessed 3 months after baseline. Descriptive statistics were used to report patient characteristics and outcomes. RESULTS A total of 233 patients initiating IV miri for UC were identified, of whom 142 (60.9%) had 3 months of follow-up and were included in this analysis. Patients had a mean (standard deviation [SD]) age of 41.8(14.6) years, 51.4% were female. Most commonly reported baseline comorbidities were anemia (26.1%), abdominal pain (20.4%), hypertension (18.3%). Baseline immunomodulator use was reported in 10 (7.0%) patients, 5-aminosalicylate use in 64 (45.1%), oral corticosteroid use in 96 (67.6%, Figure 1A). Baseline advanced UC therapy use was observed in 104 (73.2%) patients: 77 (54.2%) received one advanced therapy; 23 (16.2%) received two; and 4 (2.8%) received three or more advanced therapies. Within baseline advanced therapies, 84 (59.2%) patients used biologics, 33 (23.2%) used Janus Kinase Inhibitors (JAKi), and 4 (2.8%) used Sphingosine-1-Phosphate (S1P) receptor modulators. The most recent baseline advanced therapy before miri was approximately equally distributed between anti-integrin, JAKi, and IL12-23 (Figure 1B). Oral corticosteroid prescriptions declined from 67.6% at baseline to 28.2% in the 3 months after initiation. CONCLUSION Most patients initiating mirikizumab were previously exposed to biologics and failed one prior advanced therapy. Even so, more than 25% of the early initiators of mirikizumab included patients with no advanced therapy at baseline. Further research will evaluate follow-up treatment patterns with mirikizumab use.

Background: The management of pediatric inflammatory bowel disease (PIBD) has evolved significantly over the past two decades, transitioning from corticosteroids and immunomodulators to biologic and small-molecule therapies. These advances have aimed not only to control inflammation but also to promote mucosal healing, improve growth, and enhance long-term quality of life. Objectives: This narrative review summarizes current evidence on the efficacy, safety, and clinical applications of biologic and novel small-molecule therapies in PIBD, highlighting emerging trends in personalized and precision-based management. Methods: A literature search was performed across PubMed, Embase, and the Cochrane Library, focusing on studies published within the last five years. Additional data were retrieved from key guidelines and position papers issued by ECCO-ESPGHAN, SIGENP, the FDA, and the EMA. Results: Anti-tumor necrosis factor (TNF) agents such as infliximab and adalimumab remain first-line biologics with proven efficacy in remission induction and maintenance. Newer biologics-vedolizumab, ustekinumab, risankizumab, and mirikizumab-offer alternatives for anti-TNF-refractory cases, showing encouraging short-term results and favorable safety profiles. Although many are approved only for adults with limited pediatric evidence, emerging small molecules-including Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) and sphingosine-1-phosphate (S1P) modulators (etrasimod)-provide oral, rapidly acting, and non-immunogenic treatment options for refractory disease. Furthermore, the gut microbiome is increasingly recognized as an emerging therapeutic target in PIBD, with growing evidence that host-microbiome interactions can influence both the efficacy and safety of biologics and small-molecule therapies. Conclusions: While biologics and small molecules have transformed PIBD management, challenges remain, including high treatment costs, limited pediatric trial data, and variable access worldwide. Future directions include multicenter pediatric studies, integration of pharmacogenomics, and biomarker-guided precision medicine to optimize early, individualized treatment and improve long-term outcomes.

BACKGROUNDExosomes (Exos) derived from mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for diabetic wound healing owing to their strong pro-angiogenic potential. Nevertheless, their relatively low bioactivity remains a major barrier to successful clinical application. Fractional CO2 laser therapy offers a precise and controllable form of photothermal stimulation that may potentiate exosome activity without the need for additional exogenous agents, possibly promoting more effective diabetic wound repair.AIMTo investigate the mechanisms through which low-energy fractional Exos derived from CO2 laser-preconditioned adipose-derived MSCs (Ad-MSCs) (CO2 laser-Exos) promote the healing of diabetic wounds.METHODSAd-MSCs were subjected to a single exposure of fractional CO2 laser at energy densities of 30 mJ/cm2, 40 mJ/cm2, or 50 mJ/cm2. Infrared thermography was employed to monitor temperature fluctuations in the culture medium. To determine the optimal energy level, western blotting was performed to assess heat shock protein 90 expression, while apoptosis was analyzed by flow cytometry. Exos were subsequently isolated through ultracentrifugation, and sphingosine-1-phosphate (S1P) concentrations within the Exos were measured using enzyme-linked immunosorbent assay. The therapeutic efficacy and underlying mechanisms of CO2 laser-Exos were further investigated through a series of in vitro and in vivo experiments.RESULTSFollowing a single exposure to fractional CO2 laser, the culture medium temperature increased rapidly and then gradually declined. Among the tested groups, Ad-MSCs treated with 40 mJ/cm2 demonstrated the highest heat shock protein 90 expression and exhibited reduced apoptosis. in vitro, CO2 laser-Exos markedly promoted the proliferation, migration, and tube formation of human umbilical vein endothelial cells, while their S1P content was higher than that of unconditioned Exos. Under high-glucose conditions, human umbilical vein endothelial cells showed increased expression of S1P receptor 1 (S1PR1). Silencing S1PR1 significantly impaired the pro-angiogenic activity of CO2 laser-Exos and suppressed the expression of phosphorylated protein kinase B, hypoxia-inducible factor 1 alpha, and vascular endothelial growth factor-A. In vivo, compared with Exos, CO2 laser-Exos substantially accelerated diabetic wound healing by promoting neovascularization within the wound bed.CONCLUSIONLow-energy fractional CO2 laser irradiation augments the biological activity of MSC-derived Exos through photothermal stimulation. These Exos, in turn, enhance endothelial cell functions by activating the S1PR1/protein kinase B/hypoxia-inducible factor 1 alpha signaling pathway, ultimately accelerating the repair of diabetic wounds.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates in plasma bound to high-density lipoproteins (HDL) and albumin. Circulating S1P levels correlate positively with systolic blood pressure (BP) in hypertension and negatively with severity in septic shock and with left ventricular function in heart disease. In mice, isolated deficiency in HDL-S1P and endothelial cell S1P receptor (R)-1 both trigger hypertension, supporting an essential role for HDL-S1P in endothelial function. Physiological roles of albumin-S1P and myocyte S1PRs in the cardiovascular system remain incompletely defined. We report that mice lacking all circulating S1P pools display hypotension and lack of BP increase with age, which contrasts with HDL-S1P deficiency and suggests an essential role for albumin-S1P in cardiovascular homeostasis. Although cardiac output was preserved in a basal state, left ventricular systolic function and contractile reserve were reduced in the absence of circulating S1P. Cardiac function and BP were partially or fully normalized by transfusion of erythrocytes capable of S1P production. Hypotension was accompanied by reduced peripheral resistance, and albumin-S1P, but not S1P complexed to an HDL-like chaperone, dose-dependently increased vascular resistance in isolated perfused kidneys via S1PR3 and S1PR2. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent BP maintenance and pointed to a distinct origin of the cardiac phenotype. We thus uncover an essential role for circulating S1P in maintaining BP and left ventricular systolic function in mice. Our results also highlight distinct functions for the pools of S1P bound to HDL and to albumin, carrying both diagnostic and therapeutic implications.

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. 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. Relevant English and Spanish language articles were extracted and evaluated. Sphingosine-1-phosphate receptors (S1PR) regulate both immunological and metabolic functions, representing a key therapeutic target in multiple sclerosis. Agents such as fingolimod, siponimod, ozanimod and ponesimod bind to these receptors, thereby preventing lymphocyte migration into the central nervous system. Preclinical evidence suggests that S1P signaling participates in insulin receptor and Akt pathways, affecting glycogen synthesis, glucose uptake and β-cell survival. Clinical experience, including a case of a patient with type 1 diabetes and multiple sclerosis treated with ponesimod, indicates potential increases in insulin requirements and hyperglycemia, although formal human studies are lacking. Clinicians should monitor glycemic control in patients with multiple sclerosis receiving S1PR modulators, especially those with pre-existing metabolic disorders. Awareness of potential insulin resistance may guide drug selection and metabolic management. Further prospective studies are warranted to clarify clinical implications. S1PR modulators are effective disease-modifying therapies in multiple sclerosis, but emerging evidence suggests a possible impact on insulin signaling and glucose metabolism. Vigilance in metabolic monitoring is recommended, particularly in patients with diabetes or other risk factors for insulin resistance.

Heparin decreases serum sphingosine-1-phosphate levels in patients with vascular diseases.

Sphingosine-1-phosphate attenuates seizures and cognitive deficits, associated with reduced hippocampal IL-1β in a PTZ-induced epilepsy model.

Cerebellar subregional atrophy in relapsing-remitting multiple sclerosis: Stage-dependent dynamics and pharmacological modulation.

This study aimed to investigate the effects of exercise preconditioning on rat myocardial Sphingosine1-phosphate(S1P) content and its potential mechanisms of heart protection. A rat model of exercise preconditioning followed by exhaustive exercise was established. Rats were randomized to four groups: control (C), exercise preconditioning (EP), EP plus the S1PR1-selective antagonist W146 (EP + W146), and EP plus the MEK1/2 inhibitor PD98059 (EP + PD98059). Following a final exhaustive swim, comparisons across groups revealed that EP attenuated myocardial injury and apoptosis, an effect which was abolished by both W146 and PD98059. 1. Exercise preconditioning (EP) significantly attenuated exhaustive exercise-induced myocardial injury and apoptosis (P < 0.001); 2. EP significantly elevated myocardial S1P levels (P = 0.002), and S1PR1-selective antagonist (W146) abolished this cardioprotective effect (P = 0.016 for apoptosis); 3. Most importantly, MAPK pathway inhibition (PD98059) abrogated the protective effect of EP, as evidenced by significantly increased apoptosis (P = 0.002), despite unaltered S1P levels. In summary, beyond confirming S1P elevation with exercise preconditioning, our findings propose the S1P→MAPK signaling axis as a novel mechanistic pathway warranting future validation.

Ozanimod hydrochloride (Product name: ZEPOZIA® Capsule Starter Pack, ZEPOZIA® Capsules 0.92 mg; Nonproprietary name: ozanimod hydrochloride, hereinafter referred to as ozanimod) is an orally available receptor modulator that acts on the sphingosine 1-phosphate (S1P) receptor and selectively binds with high affinity to S1P1 and S1P5 receptors. Following binding to and activation of S1P1 receptors, ozanimod acts as a functional S1P1 receptor antagonist by inducing internalization of S1P1 receptors expressed on the surface of cells such as lymphocytes through agonism of S1P1 receptors. These effects may ameliorate the pathologic changes of the autoimmune disease ulcerative colitis (UC). The Japanese phase II/III study (Study RPC01-3103) demonstrated the efficacy and safety of this drug in Japanese patients with moderate to severe ulcerative colitis. In Japan, it was approved by the Ministry of Health, Labour and Welfare (MHLW) in December 2024 for the treatment of moderate to severe UC in patients who have had an inadequate response to conventional therapies, and was launched in March 2025. Existing UC treatments show significant therapeutic effects, but medications for moderate to severe UC have respective advantages and disadvantages in efficacy, safety, and administration routes. No treatment meets all criteria. Ozanimod, with a novel mechanism, offers sustained high efficacy in improving clinical symptoms and mucosal damage in moderate to severe UC patients. It has a favorable safety profile, high medication compliance, and is a convenient oral treatment for long-term use. Thus, providing Ozanimod as a new UC treatment option is of high clinical significance.

Plasma ceramides decreased in Gilbert's syndrome associated with healthy blood lipid phenotypes: A cross-sectional study.

Study on the mechanism of anti-pulmonary fibrosis action of amygdalin based on transcriptomics and metabolomics.

Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain (CIPN) is a major neurotoxicity of cisplatin, a platinum-based drug widely used for lung, ovarian, and testicular cancer treatment. Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain causes drug discontinuation and severely affects life quality with no FDA-approved interventions. We previously reported that platinum-based drugs increase levels of sphingosine 1-phosphate (S1P) in the spinal cord and drive CIPN through activating the S1P receptor subtype 1 (S1PR1). However, the mechanisms engaged downstream of S1PR1 remain poorly understood. Using single-cell transcriptomics on male mouse spinal cord, our findings uncovered subpopulation-specific responses to cisplatin associated with CIPN. Particularly, cisplatin increased the proportion of astrocytes with high expression levels of S1pr1 ( S1pr1high astrocytes), specific to which a Wnt signaling pathway was identified. To this end, several genes involved in Wnt signaling, such as the fibroblast growth factor receptor 3 gene ( Fgfr3 ), were highly expressed in S1pr1high astrocytes. The functional S1PR1 antagonist, ozanimod, prevented cisplatin-induced neuropathic pain and astrocytic upregulation of the Wnt signaling pathway genes. Fibroblast growth factor receptor 3 gene belongs to the FGF/FGFR family which often signals to activate Wnt signaling. Intrathecal injection of the FGFR3 antagonist, PD173074, prevented the development of CIPN in male mice. These data not only highlight FGFR3 as one of the astrocytic targets of S1PR1 but raise the possibility that S1PR1-induced engagement of Wnt signaling in S1pr1high astrocytes may contribute to CIPN. Overall, our results provide a comprehensive mapping of cellular and molecular changes engaged in cisplatin-induced neuropathic pain and decipher novel S1PR1-based mechanisms of action.