Sphingosine-1-phosphate (S1P)/S1P receptor signalling exerts cardioprotective effects. However, the effect of the selective S1P1 receptor agonist SEW2871 on myocyte necroptosis in heart failure and the underlying mechanisms are unknown. In the present study, we tested the hypothesis that SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines.

Eight-week-old male C57BL/6J mice underwent myocardial infarction (MI) or sham operation. The animals were randomized to receive SEW2871 (5 mg·kg-1·day-1, i.p) or placebo for 4 weeks.

MI mice exhibited the increases in left ventricular (LV) end-diastolic dimension, LV end-systolic dimension, LV mass and lung weight and a decrease in LV ejection fraction, indicating LV dilation, LV systolic dysfunction and lung congestion, and these alterations were attenuated by the SEW2871 treatment. Myocardial expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-1β and interleukin-6, and phosphorylated RIPK1 (p-RIPK1), p-RIPK3 and p-MLKL, reflective of their respective kinase activities, markers of necroptosis, was markedly increased in the MI placebo group, and the increase was abolished by the SEW2871 treatment. Similarly, intracellular levels of reactive oxygen species, inflammatory cytokines, p-RIPK1, p-RIPK3 and p-MLKL protein expression were increased in H9C2 cardiomyocytes under mimic ischaemia and the increases were prevented by the SEW2871 treatment.

The selective S1P1 receptor agonist SEW2871 attenuates myocyte necroptosis through inhibition of oxidative stress and inflammatory cytokines, leading to improvement of LV remodelling and function in heart failure.

Medial vascular calcification is common in chronic kidney disease patients and linked to hyperphosphatemia. Upon phosphate exposure, intricate signaling events orchestrate pro-calcific effects in the vasculature mediated by vascular smooth muscle cells (VSMCs). Sphingosine kinase 1 (SPHK1) produces sphingosine-1-phosphate (S1P) and is associated with complex effects in the vascular system. The present study investigated a possible involvement of SPHK1 in VSMC calcification. Experiments were performed in primary human aortic VSMCs under pro-calcific conditions, with pharmacological inhibition or knockdown of SPHK1 or SPNS2 (a lysolipid transporter involved in cellular S1P export), as well as in Sphk1-deficient and wild-type mice treated with cholecalciferol. In VSMCs, SPHK1 expression was up-regulated by pro-calcific conditions. Calcification medium up-regulated osteogenic marker mRNA expression and activity as well as calcification of VSMCs, effects significantly augmented by co-treatment with the SPHK1 inhibitor SK1-IN-1. SK1-IN-1 alone was sufficient to up-regulate osteogenic signaling in VSMCs during control conditions. Similarly, the SPHK1 inhibitor PF-543 and SPHK1 knockdown up-regulated osteogenic signaling in VSMCs and aggravated VSMC calcification. In contrast, co-treatment with the SPNS2 inhibitor SLF1081851 suppressed osteogenic signaling and calcification of VSMCs, effects abolished by silencing of SPHK1. In addition, Sphk1 deficiency aggravated vascular calcification and aortic osteogenic marker expression in mice after cholecalciferol overload. In conclusion, SPHK1 inhibition, knockdown, or deficiency aggravates vascular pro-calcific signaling and calcification. The reduced calcification after inhibition of S1P export suggests a possible involvement of intracellular S1P, but further studies are required to elucidate the complex roles of SPHKs and S1P signaling in calcifying VSMCs.

Safflower extract (SE) has been reported to treat acute myocardial ischemia (AMI); however, its underlying mechanism remains unclear.

To investigate the ameliorative effects of SE on rats with AMI and the underlying mechanism.

UPLC-Q-TOF-MS/MS method was used to analyze the drug-derived components in the serum of rats following SE administration. We treated the ISO-induced rat model of AMI with different doses. Echocardiography and histopathology (HE staining) were used to evaluate the effect, alongside biochemical parameters. SE medicinal serum (SEMS) was used to assess its protective effect on H9C2 cells against hypoxic reoxygenation injury in vitro. We explored the mechanism of SE in improving AMI through non-targeted metabolomics combined with network pharmacological analysis based on in vivo components, and further integrated with targeted sphingolipomics. RT-qPCR was used to evaluate the gene expression levels of the key enzymes involved in ceramide synthesis (CERS1 and CERS4).

Nineteen compounds were identified following oral administration of SE. Echocardiography showed that different doses of SE significantly improved cardiac function in AMI rats. The serum levels of CK, HBDH, AST, LDH, and SOD were significantly reduced in AMI rats. HE staining results showed that SE significantly improved pathological injury in AMI rats. In vitro experiments results showed that SEMS protects against OGD/R injury in H9C2 cells. Non-targeted metabolomics and network pharmacology results indicated that SE regulates glycosphingolipid and glycerophospholipid metabolism to improve acute myocardial ischemic injury. Targeted sphingolipomics have shown that SE had significant regulatory effects on 18:0 acyl-chain ceramides, dihydroceramides, 1-phosphorylated ceramides, glycosylated ceramides, Sph and S1P. RT-qPCR results showed that SE significantly down-regulates the expression of mCERS4.

SE significantly improves AMI in rats, with the mechanism related to the regulation of CERS4 and then the modulation of C18:0 sphingolipid metabolism.

Walnut oil (WO) and peanut oil (PO) are common vegetable oils rich in unsaturated fatty acids, known to alleviate atherosclerosis (AS) and reduce the risk of cardiovascular diseases (CVD). WO contains a higher proportion of polyunsaturated fatty acids (PUFAs) compared to PO. This study aimed to explore the influence of WO on AS and elucidate its potential mechanisms, providing a theoretical basis for enhancing the application of WO in functional foods and pharmaceuticals.

AS was established in rats using a high-fat diet and vitamin D3 injections. Rats with AS were administered WO or PO via gavage at a dose of 1.2 g/kg for 4 weeks. Serum lipid levels and arterial injury were assessed, and transcriptomic and metabolomic analyses of the rat vasculature were performed.

Both WO and PO significantly lowered serum lipid levels and the atherogenic index (AI) in rats, reducing arterial wall injury and plaque formation. WO exhibited a more pronounced effect, particularly in decreasing serum levels of TG, TC, HDLC, and LDL-C. Transcriptomic analysis indicated that fatty acid, amino acid metabolism were crucial in AS development due to a high-fat diet. Metabolomic analysis indicated significant changes in the metabolism of arginine, proline, cysteine, methionine, glycine, serine and threonine in rats treated with WO.

WO and PO help alleviate AS by regulating lipid metabolism and influencing pivotal metabolic pathways like TCA cycle and cysteine-methionine metabolism. The more significant impact of WO indicates its potential as a dietary supplement for preventing and treating AS.

Abnormal component changes of gut microbiota are related to the pathogenesis and progression of coronary heart disease (CHD), and gut microbiota-derived metabolites are key factors in host-microbiome interactions. This study aimed to explore the key gut microbiota and metabolites, as well as their relationships in CHD.

Feces samples and blood samples were collected from CHD patients and healthy controls. Then, the obtained feces samples were sent for 16s rRNA gene sequencing, and the blood samples were submitted for metabolomics analysis. Finally, conjoint analysis of 16s rRNA gene sequencing and metabolomics data was performed.

After sequencing, there were no significant differences in Chao 1, observed species, Simpson, Shannon, Pielou's evenness and Faith's PD between the CHD patients and controls. At phylum level, the dominant phyla were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. At genus level, the abundance of Sphingomonas, Prevotella, Streptococcus, Desulfovibrio, and Shigella was relatively higher in CHD patients; whereas Roseburia, Corprococcus, and Bifidobacterium was relatively lower. Randomforest analysis showed that Sphingomonas was more important for CHD. Through metabolomic analysis, a total of 155 differential metabolites were identified, and were enriched in many signaling pathways. Additionally, the AUC of the conjoint analysis (0.908) was higher than that of gut microbiota species (0.742).

In CHD patients, the intestinal flora was disordered, as well as Sphingomonas and the identified differential metabolites may serve as was candidate biomarkers for CHD occurrence and progression.

Cardiovascular disease remains a leading cause of mortality worldwide, driven by factors such as dysregulated lipid metabolism, oxidative stress, and inflammation. Recent studies highlight the critical roles of both glycerophospholipid and sphingosine- 1-phosphate metabolism in the pathogenesis of cardiovascular disorders. However, the contributions of glycerophospholipid-derived metabolites remain underappreciated. Glycerophospholipid metabolism generates bioactive molecules that contribute to endothelial dysfunction, lipid accumulation, and cardiac cell injury while also modulating inflammatory and oxidative stress responses. Meanwhile, sphingosine- 1-phosphate is a bioactive lipid mediator that regulates vascular integrity, inflammation, and cardiac remodeling through its G-protein-coupled receptors. The convergence of these pathways presents novel therapeutic opportunities, where dietary interventions such as omega- 3 polyunsaturated fatty acids and pharmacological targeting of sphingosine- 1-phosphate receptors could synergistically mitigate cardiovascular risk. This review underscores the need for further investigation into the interplay between glycerophospholipid metabolism and sphingosine- 1-phosphate signaling to advance targeted therapies for the prevention and management of cardiovascular disease.

We aimed to assess currently unexplained effects of isometric exercise on central hemodynamic, arterial, and cardiac cycle parameters. Twenty-three young physically active males performed 5-min forearm sustained exercise at 20% of maximum voluntary contraction. The pulse wave analysis (SphygmoCor) was conducted at baseline (BL) and at 1, 5, 10, 15, and 20 min of post-load recovery. The General Linear Model repeated measures analysis with post hoc test was used to compare the BL values, 1-min, and 15-min recovery states. Exercise immediately elevated central and peripheral systolic blood pressure (BP), augmentation index, left ventricular contractility, and its relative relaxation time. These prompt reactions were followed by a hypotensive response and positive lusitropic effect with shortening relaxation in 15 min after the contraction ceased. The diastolic BP decrement was inversely correlated with the amount of body lean mass and body muscle but not fat mass measured by the bioelectrical impedance method. It is hypothesized that (1) the body lean mass-dependent BP-lowering effect of exercise is due to the arterial distending influence of metabolites accumulated in the muscle during exercise-induced occlusion and then washed out into general circulation, and (2) muscle arteries are more sensitive to these effects than vessels of fat tissue.

Perivascular adipose tissues (PVATs) play a critical role in modulating vascular homeostasis and protecting against cardiovascular dysfunction-mediated blood pressure dysregulation. We demonstrated that the activating transcription factor-3 (Atf3) gene in the PVAT is crucial for improving vascular wall tension abnormalities; however, its protective mechanism remains unclear. Herein, we aim to determine whether ATF3 regulates PVAT-derived relaxing factor (PVDRF) biosynthesis and if its secretion contributes to vasorelaxation.

This study employed an in vivo animal model using global Atf3-deficient mice, in vitro blood vessel myography, and biochemical analyses to evaluate ATF3-mediated PVDRF release and reactivity in the vasculature.

Wild-type (WT) mouse thoracic aortic PVAT extracts significantly induced resting tone dilation and attenuated vasoconstrictor-induced contractile responses compared to Atf3-/- mice. Heat-stable PVAT extracts from WT mice caused sustained and reproducible vasodilation without tachyphylaxis in control aortic rings. Biochemical evaluation of PVDRF release revealed that Atf3-/- mice had lower sphingosine-1-phosphate (S1P) and HDL cholesterol (HDL-C) levels than WT mice. Furthermore, PVAT extracts from WT mice induced long-lasting vasorelaxation, which was significantly inhibited by the S1P3 receptor antagonist TY52156 and scavenger receptor class B type 1 receptor antagonist glyburide.

ATF3 within the PVAT can modulate vascular function by strengthening sphingosine kinase 1 (sphk1)-S1P-S1P3 receptor lipid signalling and stimulating S1P binding to HDL to form the vasodilator HDL-S1P. ATF3 is an essential modulator for maintaining the physiological function of PVAT, providing a novel target for treatment of obesity-related cardiovascular diseases.

Cardiomyocyte hypertrophy (CDH) is a critical factor in heart disease, leading to heart failure and increased mortality. Despite extensive research, the precise molecular mechanisms underlying CDH remain unclear. In our study, we conducted total RNA sequencing on blood-derived exosomes from 11 CDH patients and 8 healthy donors. This analysis identified differentially expressed genes (DEGs), which we further validated using real-time qPCR and ROC analysis to demonstrate their diagnostic potential in clinical samples. To explore the functional role of CA3 in CDH, we manipulated its expression using the AAV9 vector in TAC (transverse aortic constriction) rat models(N = 6). We observed a significant increase in CA3 expression in both the blood of CDH patients and TAC rat models. Knockdown of Ca3 using the AAV9 vector resulted in improved cardiac function in TAC rats (N = 6), as evidenced by a ∼30 % reduction in LVEF% (left ventricular ejection fraction) and LVFS% (left ventricular fractional shortening) compared to Sham-operated controls. Additionally, LV (left ventricular) mass and the HW/BW (heart weight to body weight ratio) were significantly higher in the TAC groups. Mechanistically, we identified miR-138-5p as a direct regulator of CA3 through the StarBase bioinformatics tool. This interaction was experimentally validated using a dual-luciferase reporter assay and real-time qPCR. We found that miR-138-5p expression was down-regulated in both CDH patients and TAC rat models. Restoration of miR-138-5p expression mitigated the phenotypes induced by Ca3 overexpression. Our findings reveal a novel miR-138-5p/CA3 axis involved in the pathogenesis of CDH, suggesting potential therapeutic avenues for this heart disease.

High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD.

Artemisinin (ART), a natural product isolated from the traditional Chinese plant Artemisia annua L., has shown neuroprotective properties in addition to its well-established antimalarial activities. This study investigates the therapeutic effect of ART in ischemic stroke (IS) and delves into its functional mechanism. Bioinformatics analyses revealed lysine demethylase 1A (KDM1A) as a promising target of ART aberrantly overexpressed in the context of IS. Increased KDM1A expression was detected in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons and transient middle cerebral artery occlusion (tMCAO)-challenged mice. Treatment with ART reduced KDM1A protein level, thus protecting mouse hippocampal neurons from OGD/R-induced oxidative stress and apoptosis. In vivo, ART reduced infarct size, reduced brain content, enhanced neurological function, and enhanced neuronal survival in tMCAO. Regarding the downstream cascade, KDM1A was found to repress transcription of sphingosine kinase 2 (SPHK2) by removing H3K4me2 modification near the SPHK2 promoter. Either KDM1A overexpression or SPHK2 knockdown abrogated the neuroprotective effects of ART. The ample evidence of this study suggests that ART fulfills neuroprotective functions in the context of IS by protecting SPHK2 from KDM1A-mediated transcription repression, highlighting ART as a promising regimen for the treatment of IS.

Atherosclerosis, with its complex pathogenesis, is a leading underlying cause of many cardiovascular diseases, which are increasingly prevalent in the population. Sphingolipids play an important role in the development of atherosclerosis. Key metabolites and enzymes in sphingolipid metabolism influence the pathogenesis of atherosclerosis in a variety of ways, including inflammatory responses and oxidative stress. Thus, an investigation of sphingolipid metabolism-related metabolites and key enzymes may provide novel insights and treatment targets for atherosclerosis. This review discusses various mechanisms and research progress on the relationship between various sphingolipid metabolites, related enzymes, and atherosclerosis. Finally, we look into the future research direction of phytosphingolipids.

Cadmium (Cd) is a toxic heavy metal that has been extensively implicated in disordered folliculogenesis, but the mechanisms underlying the ovarian toxicity of Cd remain to be explored fully. Granulosa cells are key players in ovarian follicular development and are the primary cells affected by Cd exposure-induced damage and dysfunction. In this study, we investigated how various levels of exposure of Cd (3 and 10 μM) to human granulosa cells (KGN cells) impacted the metabolism of the KGN cells utilizing a non-targeted metabolomics methodology. In vitro cell experiments revealed that Cd exposure dose-dependently diminished the viability of KGN cells. Metabolomics analysis revealed the presence of 296 (182 elevated and 114 reduced) and 397 (244 elevated and 153 reduced) differentially expressed metabolites after exposure to 3 and 10 μM, respectively. Cd exposure was found to significantly enrich nucleotide metabolism, sphingolipid metabolism, and ABC transporters in both groups. Although amino acid metabolic pathways exhibited significant enrichment across all groups, only glutathione, cysteine, and methionine metabolism were notably enriched in KGN cells exposed to 3 μM Cd, while glutathione and tryptophan metabolism were significantly enriched in the 10 μM Cd exposure cohort. The outcomes of this study provide mechanistic clues for elucidating Cd's cytotoxic impact on granulosa cells, and deepen our understanding of the ovarian toxicity of Cd.

Epidemiological studies have revealed that patients with higher levels of high-density lipoprotein cholesterol (HDL-C) were more resistant to cardiovascular diseases (CVD), and yet targeting HDL for CVD prevention, risk assessment, and pharmacological management has not proven to be very effective. The mechanistic investigations have demonstrated that HDL exerts anti-atherogenic functions via mediating reverse cholesterol transport, antioxidant action, anti-inflammatory activity, and anti-thrombotic activity. Contrary to expectations, however, adverse cardiovascular events were reported in clinical trials of drugs that raised HDL levels. This has sparked a debate between HDL quantity and quality. Patients with atherosclerotic CVD are associated with dysfunctional HDL, and the degree of HDL dysfunction is correlated with the severity of the disease, independent of HDL-C levels. This growing body of evidence has underscored the need for integrating HDL functional assays in clinical practice for CVD risk management. Because HDL exerts diverse athero-protective functions, there is no single method for capturing HDL functionality. This review critically evaluates the various techniques currently being used for monitoring HDL functionality and discusses key structural changes in HDL indicative of dysfunctional HDL and the technical challenges that need to be addressed to enable the integration of HDL function-based metrics in clinical practice for CVD risk estimation and the development of newer therapies targeting HDL function.

As an immune and metabolic organ, the liver affects the progression and prognosis of sepsis. Despite the severe adverse effects of sepsis liver injury on the body, treatment options remain limited. Sphingosine-1-phosphate (S1P) is a widely distributed lipid signaling molecule that binds to five sphingosine-1-phosphate receptors (S1PR) to regulate downstream signaling pathways involved in the pathophysiological processes of sepsis, including endothelial permeability, cytokine release, and vascular tone. This review summarizes current research on the role of S1P in normal liver biology and describes the mechanisms by which changes in S1P/S1PR affect the development of liver-related diseases. At the same time, the pathological processes underlying liver injury, as evidenced by clinical manifestations during sepsis, were comprehensively reviewed. This paper focused on the mechanistic pathways through which S1P and its receptors modulate immunity, bile acid metabolism, and liver-intestinal circulation in septic liver injury. Finally, the relationships between S1P and its receptors with liver inflammation and metabolism and the use of related drugs for the treatment of liver injury were examined. By elucidating the role of S1P and its receptor in the pathogenesis of sepsis liver injury, this review established a molecular targeting framework, providing novel insights into clinical and drug development.

Cholelithiasis is a common biliary system disease with a high incidence worldwide. Abnormal lipid metabolism has been shown to play a key role in the mechanism of gallstones. Therefore, recent research literature on the genes, proteins, and molecular substances involved in lipid metabolism during the pathogenesis of gallstones has been conducted. This study aimed to determine the role of lipid metabolism in the pathogenesis of gallstones and provide insights for future studies using previous research in genomics, metabolomics, transcriptomics, and other fields.

Endothelial injury is a key factor initiating in-stent restenosis (ISR) following peripheral artery stent implantation. Genetically modified endothelial progenitor cells (EPCs) can promote reendothelialization of injured arteries and inhibit neointimal hyperplasia. However, the role of engineered EPCs overexpressing lncRNA H19 in these processes remains unclear. We constructed EPCs overexpressing lncRNA H19 and investigated their effects and mechanisms in promoting reendothelialization and inhibiting neointimal hyperplasia both in vitro and in vivo. Compared to the normal control group, ISR patients exhibited a significant reduction in circulating EPCs. Engineered EPCs overexpressing lncRNA H19 promoted reendothelialization and inhibited neointimal hyperplasia in injured arteries. Exogenous overexpression of lncRNA H19 significantly upregulated the endothelial repair-related gene S1PR3 in EPCs, while the opposite was also observed. Additionally, engineered EPCs overexpressing S1PR3 promoted reendothelialization and inhibited neointimal hyperplasia in injured arteries. S1PR3 overexpression enhanced EPCs proliferation, migration, and tube formation in vitro; these effects were lost with S1PR3 inhibition. Binding sites for H3K27 acetylation were identified on the S1PR3 promoter. Mechanistically, we found that lncRNA H19 directly interacted with HDAC2, a known H3K27ac deacetylase, disrupting its binding to H3K27 acetylation. Our findings suggest that lncRNA H19 positively regulates S1PR3 expression by disrupting HDAC2 / H3K27ac binding, thereby promoting reendothelialization of injured arteries and inhibiting neointimal hyperplasia.

Diabetes is a significant global health issue, causing extensive morbidity and mortality, and represents a serious threat to human health. Recently, the bioactive lipid molecule Sphingosine-1-Phosphate has garnered considerable attention in the field of diabetes research. The aim of this study is to comprehensively understand the mechanisms by which Sphingosine-1-Phosphate regulates diabetes. Through comprehensive bibliometric analysis and an in-depth review of relevant studies, we investigated and summarized various mechanisms through which Sphingosine-1-Phosphate acts in prediabetes, type 1 diabetes, type 2 diabetes, and their complications (such as diabetic nephropathy, retinopathy, cardiovascular disease, neuropathy, etc.), including but not limited to regulating lipid metabolism, insulin sensitivity, and inflammatory responses. This scholarly work not only unveils new possibilities for using Sphingosine-1-Phosphate in diabetes treatment but also offers fresh insights and recommendations for future research directions to researchers.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and limited therapeutic options. The blood-brain barrier (BBB) breakdown post-ICH exacerbates secondary brain injury, highlighting the need for targeted therapies to preserve the BBB integrity. We aim to investigate the role of the Sphk1/S1P pathway in BBB breakdown following ICH and to evaluate the therapeutic potential of Sphk1 inhibition in mitigating this breakdown. Using a combination of human patient samples, mouse models of ICH, and in vitro cellular assays, we assessed the expression levels of Sphk1/S1P after ICH and changes of the BBB after ICH. The Sphk1 inhibitor PF543 and siRNAs were utilized to explore the pathway's impact on BBB integrity and the underlying mechanisms. The results indicate significant upregulation of Sphk1/S1P in the peri-hematomal brain tissue after ICH, which correlates with increased BBB leakage. Pharmacological inhibition of Sphk1 with PF543 attenuates BBB leakage, reduces hematoma volume, and improves neurological outcomes in mice. At the molecular and ultrastructural level, Sphk1 inhibition protects the BBB integrity by preserving tight junction proteins and suppressing endothelial transcytosis. Furthermore, mechanistic studies reveal that Sphk1 promotes Nlrp3-mediated pyroptosis of brain endothelial cells through the ERK1/2 signaling pathway. Taken together, the Sphk1/S1P pathway plays a critical role in ICH-induced BBB breakdown, and its inhibition represents a promising therapeutic strategy for ICH management.

Hypertension-induced myocardial remodelling encompasses both structural and functional changes in cardiac muscle tissue, such as myocardial hypertrophy, fibrosis, and inflammation. These alterations not only impair the systolic and diastolic functions of the heart but also elevate the risk of cardiovascular events and heart failure. One of the primary contributors to hypertensive cardiomyopathy (HTN-CM) is the over-activation of the renin-angiotensin-aldosterone system (RAAS), which subsequently induces myocardial remodeling. Although conventional therapeutic strategies aim to suppress RAAS and slow the progression of heart failure, the primary challenge in treating HTN-CM remains the lack of sensitive and specific biomarkers for early detection of myocardial remodelling. Combined multi-omics analyses, complemented by experimental validation, offer a systematic understanding of the landscape of gene/protein/metabolite expression in HTN-CM, revealing the underlying mechanisms of angiotensin II (Ang II)-induced myocardial remodeling in HTN-CM. Transcriptomic analysis revealed that differentially expressed genes (DEGs) are implicated in sphingolipid metabolic processes and are associated with collagen synthesis and inflammatory responses, collectively contributing to myocardial remodeling in HTN-CM. Proteomic analysis demonstrated that differentially expressed proteins (DEPs) are also involved in inflammatory and fibrotic processes, with associations to sphingolipid signaling pathways, particularly manifested through elevated expression of IL6, COL4A1, FGG, FGB, CREBBP and SPHK2 proteins. Metabolomic profiling further elucidated the increased expression of bioactive sphingolipid metabolites S1P and Sa1P in the myocardium of HTN-CM. Integrative multi-omics analysis revealed that HTN-CM is primarily influenced by the sphingolipid signaling pathway, with additional associations to the HIF-1α and FoxO signaling pathways. Correlation analysis has highlighted strong associations between sphingolipids and genes/proteins related to fibrosis and inflammation, as well as their connection to the HIF-1α and FoxO signalling pathways. Furthermore, certain key indicators were validated through ELISA and Western blot analyses in both plasma and myocardial tissue. In conclusion, the findings of this study suggest that excessive Ang II may induce abnormalities in sphingolipid metabolism, resulting in increased levels of S1P in both circulating and myocardial tissues. This elevation in S1P is implicated in myocardial inflammatory and fibrotic alterations, highlighting its pivotal role in myocardial remodeling. The specific mechanism underlying the sphingolipid signaling pathway in myocardial remodeling may involve downstream biological processes, including oxidative stress and excessive mitochondrial autophagy, mediated by HIF-1α and FoxO.

Cardioprotection is a well-established term in the scientific world. It describes the protection of various mediators on the cardiovascular system. These protective effects can also be provided by certain lipids. Since lipids are a very specific and clearly definable class of substances, we define the term lipoprotection as lipid-mediated cardioprotection. In this review, we highlight high-density lipoprotein (HDL), sphingosine-1-phosphate (S1P) and omega-3 polyunsaturated fatty acids (n-3 PUFA) as the most important lipoprotective mediators and show their beneficial impact on coronary artery disease (CAD), acute myocardial infarction (AMI) and heart failure (HF).

The fungal pathogen Setosphaeria turcica (S. turcica) causes northern corn leaf blight (NCLB), resulting in significant yield and economic losses in maize. To elucidate the metabolic pathways essential for its pathogenicity, we investigated the metabolome of S. turcica during appressorium development, a critical stage for host infection. Our analysis indicated a substantial enrichment of sphingosine and related compounds during this phase. The application of chemical inhibitors to disrupt sphingolipid metabolism confirmed their pivotal role in appressorium formation and pathogenicity. Additionally, silencing of the serine palmitoyl transferase (Spt) core subunit gene StLCB2 led to significant alterations in fungal morphology and growth, accompanied by changes in cell membrane integrity, surface hydrophobicity, melanin, and sphingosine synthesis. These findings underscore the importance of sphingolipids in the pathogenicity of S. turcica and suggest that targeting specific components of the sphingolipid pathway could aid in developing novel fungicides or genetically engineered maize varieties with increased resistance to NCLB.

Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that arises during the neonatal period, and its underlying mechanisms are still not fully understood. The disorder of microvascular development plays a significant role in the development of BPD. This article presents a comprehensive review of the advancements made in understanding the mechanisms and treatment approaches related to microvascular development in the pathogenesis of BPD.

Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for the endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet, as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC autonomous S1P production, it is unclear if relative reductions in circulating S1P can cause endothelial dysfunction. It is also unclear how EC S1PR1 insufficiency, whether induced by deficiency in circulating ligand or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets.

We here fine map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell-type-specific and relative deficiencies in S1P production to define ligand source and dose dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries, and a subset of high-endothelial venules (HEVs). Similar zonation was observed for albumin extravasation in EC S1PR1-deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic ECs, S1PR1 engagement was high in collecting vessels and lymph nodes and low in blind-ended capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signalling in lymphatics and HEV, haematopoietic cells provided ∼90% of plasma S1P and sustained signalling in resistance arteries and lung capillaries. S1PR1 signalling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages.

This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and often debilitating condition requiring complex and individualized management. Over the past few decades, advancements in understanding IBD pathophysiology have led to a transformative shift in therapeutic approaches. This article provides a comprehensive overview of the evolution of IBD treatments, from early symptom-focused therapies to modern biologics, small molecule agents, and emerging treatment strategies. We discuss therapeutic goals centered on achieving clinical remission, endoscopic/mucosal healing, and enhancing patient quality of life. Additionally, we explore the rationale for the early and personalized use of biologic therapies in moderate-to-severe cases, review the current FDA-approved agents as of 2024, and highlight the advantages and limitations of these treatments. Special attention is given to the evolving role of novel oral therapies, including Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators, and future new directions. This paper aims to guide clinicians in navigating the expanding therapeutic landscape of IBD, emphasizing patient-centered decision-making and addressing ongoing challenges in achieving optimal disease control.

The impact of ionizing radiation on the male reproductive system is gaining increasing attention, particularly when it comes to testicular damage, which may result in decreased sperm quality and hormonal imbalances. Finding effective protective measures to mitigate testicular damage caused by radiation has become a focal point in the biomedical field. S1P, an essential biological signaling molecule, has garnered significant interest due to its multiple roles in regulating cellular functions and its protective effects against radiation-induced testicular injury. S1P not only effectively reduces the generation of ROS induced by radiation but also alleviates oxidative stress by enhancing the activity of antioxidant enzymes. Furthermore, S1P inhibits radiation-induced cell apoptosis by regulating the expression of anti-apoptotic and pro-apoptotic proteins. Additionally, S1P alleviates radiation-induced inflammation by inhibiting the production of inflammatory factors, thereby further protecting testicular tissue. In summary, S1P effectively reduces radiation-induced testicular damage through multiple mechanisms, offering a promising therapeutic approach to safeguard male reproductive health. Future research should explore the specific mechanisms of action and clinical application potential of S1P, aiming to contribute significantly to the prevention and treatment of radiation damage.

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.

Multiple sclerosis (MS) is a chronic, progressive demyelinating disease with a most likely autoimmune background and a neurodegenerative component. Besides the demyelinating process caused by autoreactive antibodies, an increased permeability in the blood-brain barrier (BBB) also plays a key role. Recently, there has been growing interest in assessing lipid profile alterations in patients with MS. As a result of myelin destruction, there is an increase in the level of cholesterol released from cells, which in turn causes disruptions in lipid metabolism homeostasis both in the central nervous system (CNS) and peripheral tissues. Currently, there is a growing body of evidence suggesting a protective role of HDL in MS through its effect on the BBB by decreasing its permeability. This follows from the impact of HDL on the endothelium and its anti-inflammatory effect, mostly by interacting with adhesion molecules like vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin. HDL, through its action via sphingosine-1-phosphate, exerts an inhibitory effect on leukocyte migration, and its antioxidant properties contribute to the improvement of the BBB function. In this review, we want to summarize these studies and focus on HDL as a mediator of the anti-inflammatory response in MS.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis.

Cardiovascular disease is a leading cause of morbidity and mortality. New research elucidates increasingly complex relationships between cardiac and metabolic health, giving rise to new possible therapeutic targets. Sphingolipids are a heterogeneous class of bioactive lipids with critical roles in normal human physiology. They have also been shown to play both protective and deleterious roles in the pathogenesis of cardiovascular disease. Ceramides are implicated in dysregulating insulin signalling, vascular endothelial function, inflammation, oxidative stress, and lipoprotein aggregation, thereby promoting atherosclerosis and vascular disease. Ceramides also advance myocardial disease by enhancing pathological cardiac remodelling and cardiomyocyte death. Glucosylceramides similarly contribute to insulin resistance and vascular inflammation, thus playing a role in atherogenesis and cardiometabolic dysfunction. Sphingosing-1-phosphate, on the other hand, may ameliorate some of the pathological functions of ceramide by protecting endothelial barrier integrity and promoting cell survival. Sphingosine-1-phosphate is, however, implicated in the development of cardiac fibrosis. This review will explore the roles of sphingolipids in vascular, cardiac, and metabolic pathologies and will evaluate the therapeutic potential in targeting sphingolipids with the aim of prevention and reversal of cardiovascular disease in order to improve long-term cardiovascular outcomes.

Siponimod, a second-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, represents an important therapeutic choice for active secondary progressive multiple sclerosis (SPMS). Besides the beneficial immunomodulatory effects, siponimod impacts cardiovascular function through S1PR1 modulation. Short-term vagomimetic effects on cardiac activity have proved to be mitigated by dose titration. However, long-term consequences are less known.

This study aimed to investigate the long-term impact of siponimod on cardiac autonomic modulation in people with SPMS (pwSPMS).

Heart rate variability (HRV) and vascular hemodynamic parameters were evaluated using Multiple Trigonometric Regressive Spectral analysis in 47 pwSPMS before siponimod therapy and after one, three, six and 12 months of treatment. Autonomic activation tests (tilt test for the sympathetic and deep breathing test for the parasympathetic cardiac modulation) were performed at each examination.

pwSPMS preserved regular cardiovascular modulation responses during the autonomic tests reflected in the variation of several HRV parameters, such as RMSSD, pNN50, total power of HRV, high-frequency and low-frequency bands of the spectral domain or hemodynamic vascular parameters (Cwk, Zao, TPR, MAP) and baroreflex sensitivity (BRS). In the long-term follow-up, RMSSD, pNN50, total power, BRS and CwK presented a significant decrease, underlining a reduction of the parasympathetic and a shift towards sympathetic predominance in cardiac autonomic modulation that tends to stabilise after 1 year of treatment.

Due to dose titration, the short-term effects of siponimod on cardiac autonomic modulation are mitigated. The long-term impact on cardiac autonomic modulation is similar to fingolimod. The autonomic activation tests showed normal cardiovascular responses during 1-year follow-up in pwSPMS, confirming the safety profile of siponimod. Further research on autonomic function could reveal whether the observed sympathetic activation is a compensatory response to S1P signaling intervention or a feature of the disease, while also shedding light on the role of S1PR modulation in MS.

Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R injury are not fully understood. Plasma lipidomics analysis by mass spectrometry revealed that sphingosine lipids, including sphingosine 1-phosphate (S1P), were significantly down-regulated following cardiac I/R injury in mice. The reduced S1P levels were also observed in the plasma of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI) compared with those without PCI. We found that S1P exerted a cardioprotective effect via endothelial cell (EC)-S1PR1, whereas EC-S1PR2 displayed a detrimental effect on cardiac I/R. Our data showed that EC-specific S1pr2 loss-of-function significantly lessened inflammatory responses and diminished cardiac I/R injury, while EC-specific S1pr2 gain-of-function aggravated cardiac I/R injury. Mechanistically, EC-S1PR2 initiated excessive mitochondrial fission and elevated ROS production via RHO/ROCK1/DRP1 pathway, leading to NLRP3 inflammasome activation and subsequent cell pyroptosis, thereby exacerbating inflammation and I/R injuries. Furthermore, RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA to specifically knockdown S1PR2 in endothelial cells significantly ameliorated cardiac I/R injury. Taken together, our investigations demonstrate that EC-S1PR2 induces excessive mitochondrial fission, which results in NLRP3 inflammasome activation and subsequently triggers cell pyroptosis, ultimately exacerbating inflammatory responses and aggravating heart injuries following I/R.

Sphingolipids are eighteen carbon alcohol lipids synthesized from non-sphingolipid precursors in the endoplasmic reticulum (ER). The sphingolipids serve as precursors for a vast range of moieties found in our cells that play a critical role in various cellular processes, including cell division, senescence, migration, differentiation, apoptosis, pyroptosis, autophagy, nutrition intake, metabolism, and protein synthesis. In CVDs, different subclasses of sphingolipids and other derived molecules such as sphingomyelin (SM), ceramides (CERs), and sphingosine-1-phosphate (S1P) are directly related to diabetic cardiomyopathy, dilated cardiomyopathy, myocarditis, ischemic heart disease (IHD), hypertension, and atherogenesis. Several genome-wide association studies showed an association between genetic variations in sphingolipid pathway genes and the risk of CVDs. The sphingolipid pathway plays an important role in the biogenesis and secretion of exosomes. Small extracellular vesicles (sEVs)/ exosomes have recently been found as possible indicators for the onset of CVDs, linking various cellular signaling pathways that contribute to the disease progression. Important features of EVs like biocompatibility, and crossing of biological barriers can improve the pharmacokinetics of drugs and will be exploited to develop next-generation drug delivery systems. In this review, we have comprehensively discussed the role of sphingolipids, and sphingolipid metabolites in the development of CVDs. In addition, concise deliberations were laid to discuss the role of sEVs/exosomes in regulating the pathophysiological processes of CVDs and the exosomes as therapeutic targets.

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non-small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.

Ilex pubescens Hook. et Arn (IP), traditionally known for its properties of promoting blood circulation, swelling and pain relief, heat clearing, and detoxification, has been used in the treatment of thromboangiitis obliterans (TAO). Despite its traditional applications, the specific mechanisms by which IP exerts its therapeutic effects on TAO remain unclear.

This study aims to uncover the underlying mechanisms in the therapeutic effects of IP on TAO, employing network pharmacology and metabolomic approaches.

In this study, a rat TAO model was established by injecting sodium laurate through the femoral artery, followed by the oral administration of IP for 7 days. Plasma coagulation parameters were measured to assess the therapeutic effects of IP. The potential influence on the femoral artery and gastrocnemius muscle was histopathologically evaluated. Network pharmacology was employed to predict relevant targets and model pathways for TAO. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was used for the metabolic profile analysis of rat plasma. Immunohistochemistry (IHC) was used to verify the mechanisms by which IP promotes blood circulation in TAO.

The study revealed that IP improved blood biochemical function in TAO and played a significant role in vascular protection and maintaining normal blood vessels and gastrocnemius morphologies. Network pharmacology showed that IP compounds play a therapeutic role in modulating lipids and atherosclerosis. Metabolomic analysis revealed that the pathways involved in sphingolipid metabolism and steroid biosynthesis were significantly disrupted. The joint analysis showed a strong correlation between lysophosphatidylcholine and IP components, including triterpenoid and iridoid components, which support the curative action of IP through the modulation of sphingolipid metabolism. Furthermore, decreased expression levels of SPHK1/S1PR1, TNF-α, IL-1β, and IL-6 were observed in the IP-treated group, suggesting that IP exerts a protective effect on the vasculature primarily by regulating of the SPHK1/S1PR1 signaling pathway.

In this study, we found that IP protects the vasculature against injury and treats TAO by regulating the steady-state disturbance of the sphingolipid pathway. These findings suggest that IP promotes vasculature by modulating sphingolipid metabolism and SPHK1/S1PR1 signaling pathway and reduce levels of inflammatory factors, offering new insights into its therapeutic potential.

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666.

Pain is a complex perception involving unpleasant somatosensory and emotional experiences. However, the underlying mechanisms that mediate its different components remain unclear. Sphingosine-1-phosphate (S1P), a metabolite of sphingomyelin and a potent lipid mediator, initiates signaling via G protein-coupled receptors (S1PRs) on cell surfaces. It serves as a second messenger in cellular processes such as proliferation and apoptosis. Nevertheless, the neuropharmacology of sphingolipid signaling in pain conditions within the central nervous system remains largely unexplored and controversial.

Chronic nociceptive pain models were induced in vivo by intraplantar injection of 20 μL complete Freund's adjuvant (CFA) into the left hind paws. We assessed S1P and S1PR1 expression in the spinal cords of CFA model mice. Functional antagonists of S1PR1 or S1PR1-specific siRNA were administered daily following CFA model establishment. Paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL) were measured to evaluate mechanical allodynia and thermal hyperalgesia, respectively. RT-PCR assessed interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels. Western blotting and immunofluorescence were used to analyze glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), STAT3, ERK, and p38 MAPK protein expression.

In the chronic nociceptive pain model induced by CFA, S1P and S1PR1 expression levels were significantly elevated, leading to activation of spinal cord glial cells. S1PR1 activation also promoted MMP2-mediated cleavage of mature IL-1β. Additionally, S1PR1 activation upregulated phosphorylation of STAT3, ERK, and p38 MAPK in glial cells, profoundly impacting downstream signaling pathways and contributing to chronic nociceptive pain.

The S1P/S1PR1 axis plays a pivotal role in the cellular and molecular mechanisms underlying nociceptive pain. This signaling pathway modulates glial cell activation and the expression of pain-related genes (STAT3, ERK, p38 MAPK) and inflammatory factors in the spinal dorsal horn. These findings underscore the potential of targeting the S1P system for developing novel analgesic therapies.