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Causal effects among hypertension, osteoporosis, and metabolites: A Mendelian randomization study.

BACKGROUND: Studies have examined the connection between blood metabolites, osteoporosis (OP), and hypertension; however, there is not enoug … paragine, adenosine 5'-diphosphate (ADP) to 5-oxoproline ratio, sphinganine-1-phosphate levels, and sphingosine-1-phosphate levels showed preliminary suggestive mediating effects on the association between hypertension and decreased bone mineral density in statistics. CONCLUSION: Our study revealed a positive correlation between hypertension and OP and sugge …

Lysosome-triggered nanotherapy packages osteoclast apoptotic bodies with pro-anabolic lipids to couple anti-resorption and bone formation.

Osteoporosis remains challenging to treat because no approved therapy can simultaneously suppress bone resorption and stimulate bone formation. Here we report a lysosome-triggered nanotherapy that converts osteoclast death into a regenerative signal. We first synthesized docosahexaenoyl ceramide (DHA-ceramide) by replacing the native fatty acid of ceramide with docosahexaenoic acid and encapsulated it in aspartate-modified liposomes (Asp-Lip@Cer) to target osteoclasts. After cellular uptake, lysosomal acid ceramidase cleaves DHA-ceramide to release sphingosine (SPH) and DHA. Asp-Lip@Cer select…

Low risk of severe COVID-19 in vaccinated people with multiple sclerosis: a nationwide Norwegian study.

BACKGROUND: We aimed to assess antibody responses and COVID-19 outcomes after vaccination in people with multiple sclerosis (pwMS) receiving … gistic regression. RESULTS: Among 3559 pwMS, 1201 received anti-CD20 monoclonal antibodies and 324 sphingosine-1-phosphate receptor (S1PR) modulators. After three vaccine doses, seroconversion was observed in 43.0% of anti-CD20-treated patients and 48.4% of S1PR-treated patients. In multivariable analysis, seroconversion was associated with lower risk of bre …

Assessment and Impact of Age on the Safety and Efficacy of Etrasimod in Patients With Ulcerative Colitis: A Post Hoc Analysis of Data From the ELEVATE UC Clinical Program.

BACKGROUND: Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program. METHODS: Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs…

An overview of small-molecule agents for the treatment of psoriasis.

Psoriasis is a prevalent, chronic inflammatory disease characterized by abnormal skin plaques. To date, physical therapy, topical therapy, s … AhR), Interleukin-1 receptor-associated kinase 4 (IRAK), chemoattractant-like receptor 1 (ChemR23), Sphingosine-1-phosphate receptor (S1P), A3 adenosine receptor (A3AR), Heat shock protein 90 (HSP90), The Rho-associated protein kinases (ROCK), The bromodomain and extra-terminal domain (BET), FMS-like tyrosine kinase 3 (FLT3), Tumor Necrosis Factor α Convertin …

Beyond High-density Lipoprotein-cholesterol: Unraveling the Complexity of High-density Lipoprotein Functionality.

High-density lipoprotein (HDL) levels have long been inversely associated with cardiovascular disease (CVD) and are traditionally evaluated … HDL also exhibits vasoprotective functions by enhancing nitric oxide (NO) production and modulating sphingosine-1-phosphate (S1P) signaling. Furthermore, it exerts anti-inflammatory effects by suppressing adhesion molecules, proinflammatory cytokines, and innate immune activation while modulating adaptive immune responses and attenuating tissue fibrosis. In a …

A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for etrasimod.

OBJECTIVE: To characterize the post-marketing safety profile of etrasimod using the latest data from the FDA Adverse Event Reporting System (FAERS), and to provide a comparative analysis versus other sphingosine-1-phosphate (S1P) receptor modulators. METHODS: AE reports associated with etrasimod were retrieved from FAERS (Q1 2004 - Q2 2025). Disproportionality analyses were conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) methods. A comparative analysis again…

Overall and Comparative Risk of Shingles With Advanced Therapies in Patients With Inflammatory Bowel Diseases.

BACKGROUND: Advanced therapies increase the risk of shingles in inflammatory bowel diseases (IBD). AIM: To compare the risk of shingles with different advanced therapies in patients with IBD. METHODS: We identified patients with IBD who initiated treatment with tumour necrosis factor (TNF) antagonists, anti-integrins, anti-interleukins, Janus kinase (JAK) inhibitors, or sphingosine-1 phosphate receptor (S1PR) modulators between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation. We estimated the incidence rate (IR per 100 person-year [PY]) of shingles (…

BAF312 Inhibits the Growth of Glioma and Promotes the Normalization of Tumor Blood Vessels.

This study investigates the repurposing of BAF312 (Siponimod), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist for multiple sclerosis, as a dual-targeting therapeutic agent for glioma by inhibiting tumor growth and normalizing aberrant tumor vasculature. The clinical correlations between S1PR1/5 expression and glioma prognosis were analyzed using the GEPIA and HPA databases. The effects of BAF312 on tumor growth, cell cycle progression, apoptosis, and vascular remodeling were evaluated using orthotopic GL261 glioma models and glioma cell lines (U118MG, T98G, GL261). Techniques s…

The janus face of astrocytes in multiple sclerosis: Balancing protection and pathology.

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination and neurodegeneration in the central nervous system … imethyl fumarate (DMF) and fingolimod modulate astrocyte reactivity, targeting oxidative stress and sphingosine-1-phosphate receptors to mitigate neuroinflammation. However, challenges persist in translating murine A1/A2 concepts to human MS, as human astrocytes display heterogeneous, context-dependent responses influenced by regional microenvironments and di …

Ингибиция AMPAR снижает S1P в человеческой крови и улучшает аутоиммунную нейроинфламму, блокируя выход Т клеток из лимфоузлов.

Глутаматергический α-амино-3-гидрокси-5-метил-4-изоксазолпропионовый рецептор кислоты (АМПАР) с помощью сигнала, сигнализирующего в нейронах, действует посредством регулирования ионовых каналов. В Т клетках мы обнаружили неканоническую медицину AMPAR с метаботропиком Gi с протеиновой связью. Избирательная блокада AMPAR повысила остроту заболеваний в экспериментальном аутоиммунном энцефаломиелите (EAE) как в мышах SJL, которые обычно демонстрируют курс релапсирующих заболеваний, так и в мышах C57BL/6, представляющих хронические заболевания. Блокада AMPAR привела к сохранению Т клеток в лимфатич

Совпадение в аннотации оригинала
Glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated signaling in neurons acts through regulation of … modifying transcription programs, including CD69. CD69+ T cells showed down-regulated expression of sphingosine 1-phosphate (S1P) receptor, a key regulator of T cell egress. Reduced T cell egress from lymph nodes upon AMPAR blockade was rescued by anti-CD69 antibody treatment or addition of S1P. Perampanel treatment additionally reduced S1P blood concentratio …

PAR1, a therapeutic target for remote lung injury associated with hind limb ischemia/reperfusion: ERK5/KLF2-dependent lung capillary barrier preservation.

Protease-activated receptor 1 (PAR1) is expressed in pneumocytes and endothelial cells of the alveolar barrier. Its activation by thrombin d … adherin, and connexin 37 levels. Such improvements are downstream targets of the ERK5/KLF2-mediated sphingosine-1-phosphate receptor 1 (S1PR1) upregulated expression and pS536-nuclear factor-κB (NF-κB) p65 inhibition. SCH79797 effectively impedes the evoked inflammatory response and oxidative burst by suppressing vascular endothelial growth factor, tumor necr …

Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFα-dependent inflammation and apoptosis.

Acute liver failure (ALF) causes severe liver dysfunction that can lead to multi-organ failure and death. Previous studies suggest that sphingosine kinase 1 (SphK1) protects against hepatocyte injury, yet not much is still known about its involvement in ALF. This study examines the role of SphK1 in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF, which is a well-established experimental mouse model that mimics the fulminant hepatitis. Here we report that deletion of SphK1, but not SphK2, dramatically decreased GalN/LPS-induced liver damage, hepatic apoptosis, serum alanine aminotra…

Beyond biologics: advanced therapies in inflammatory bowel diseases.

INTRODUCTION: Inflammatory bowel diseases (IBDs) are conditions affecting the gut at different levels characterized by an abnormal activatio … studies have identified new strategies, different from the TNF-α blockade, and new molecules, e.g. sphingosine-1-phosphate agonists and the JAK kinase inhibitors, have been proposed as potential therapeutic options for IBDs. CONCLUSIONS: With the availability of novel approaches reviewed in this article, physicians and especially gastroenterologists will in …

Vagal-α7nAChR signaling attenuates allergic asthma responses and facilitates asthma tolerance by regulating inflammatory group 2 innate lymphoid cells.

Disorders of immune tolerance may lead to allergic asthma. Group 2 innate lymphoid cells (ILC2s) and inflammatory ILC2s (iILC2s) are key pla … n of Chrna7 in asthma-tolerant conditions upregulated T helper 2 cytokine- (Il4, Il13 and Il25) and sphingosine-1-phosphate (S1P)-related genes (S1pr1 and Sphk1). Blockade of S1P reduced iILC2 recruitment into asthmatic lungs. Our work is the first to demonstrate that vagal-α7nAChR signaling engaging with iILC2s and S1P not only alleviates asthma but also fac …

Sphingolipids in Genetic and Acquired Forms of Chronic Kidney Diseases.

Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs. A balancing role of apoptotic SLs and anti-apoptotic S1P is crucial in the regulat…

Cancer and mental disorders in a national community sample: findings from the national comorbidity survey.

MicroRNA-155 (miR155) is overexpressed in various inflammatory diseases and cancer, in which bone resorption and osteolysis are frequently o … ifferentiation potential, supporting the results from Mir155-KO mice. TargetScan analysis predicted sphingosine 1-phosphate receptor-1 (S1pr1) as a target gene of Mir155, which was further confirmed by luciferase assay and Mir155 knockdown. S1pr1 overexpression in BMSCs robustly promoted osteogenic differentiation without affecting cell viability and prolifer …

Higher disease reactivation risk in women after fingolimod withdrawal.

BACKGROUND: Disease reactivation following cessation of sphingosine 1-phosphate receptor modulators (S1PRM) occurs in ~ 10% of multiple sclerosis (MS) patients. The biological factors underlying this phenomenon remain incompletely understood, including the potential contribution of sex-specific differences. METHODS: We performed a systematic review on published literature and adverse event registries (FAERS, EudraVigilance), as of January 2024, focusing exclusively on fingolimod (FTY) withdrawal in individuals with MS. Disease severity after FTY withdrawal was assessed in the experimental aut…

GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation.

Modulating the equilibrium between glucose metabolism and fatty acid metabolism represents highly promising novel strategies for therapy of myocardial ischemia/reperfusion (I/R) injury. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, has shown cardioprotective roles during myocardial infarction by regulating the activities of various transcript factors. Gene microarray revealed that SPC significantly upregulated the expression of GATA zinc finger domain protein 1 (GATAD1), which is a vital transcript factor affecting heart development and various heart diseases.

Hybrid and vaccine-induced immunity against SAR-CoV-2 in MS patients on different disease-modifying therapies.

OBJECTIVE: To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patien … ale; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly …