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TLR-Induced SMPD3 Defects Enhance Inflammatory Response of B Cell and Macrophage in the Pathogenesis of SLE.

B lymphocyte and macrophages may contribute to SLE pathogenesis through cytokine production after TLR stimulation. Emerging evidences sugges … d that TLR signalling induced the abnormal expression of sphingomyelin phosphodiesterase 3 (SMPD3), sphingosine-1-phosphate phosphatase 2 (SGPP2), ceramide kinase (CERK) and UDP glycosyltransferase 8 (UGT8), which were involved in sphingolipid metabolism. TLR signalling also induced the transportation of SMPD3 from Golgi apparatus. Furthermore, the dysfunctio …

Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance.

The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient…

Tandem Mass Spectrometry Quantitation of Lyso-Gb3 and Six Related Analogs in Plasma for Fabry Disease Patients.

Fabry disease is an X-linked lysosomal storage disorder, caused by a deficit in α-galactosidase A enzyme activity, leading to the storage of sphingolipids such as globotriaosylsphingosine (lyso-Gb3 ), globotriaosylceramide (Gb3 ), and galabiosylceramide (Ga2 ) in organs, tissues and biological fluids. A recent metabolomic study performed in plasma revealed lyso-Gb3 analogs as novel Fabry disease biomarkers. These molecules correspond to lyso-Gb3 with different chemical modifications on the sphingosine chain (-C2 H4 , -H2 , +O, +H2 O, +H2 O2, and +H2 O3 ). An ultra-performance liquid chromatogr…

Serum metabolic fingerprinting after exposure of rats to quinolinic acid.

Quinolinic acid (QUIN), one of the end metabolites in the kynurenine pathway, plays an important role in the pathogenesis of several disease … ntadecanoic amide, palmitic amide, oleamide, and stearamide), polyamines (spermine and spermidine), sphingosine, and deoxy-prostaglandin; caused alterations in phospholipids. This is the first report of comprehensive metabolites analysis after chronic intraperitoneal administration of QUIN. Further studies could develop new therapeutics for patients with diso …

Emerging Strategies to Enhance Homing and Engraftment of Hematopoietic Stem Cells.

Successful clinical outcomes from transplantation of hematopoietic stem cells (HSCs) depend upon efficient HSC homing to bone marrow (BM), s … ic factors include α-chemokine stromal-derived factor 1 (SDF-1), the bioactive phosphosphingolipids sphingosine-1-phosphate (S1P) and ceramid-1-phosphate (C1P), and the extracellular nucleotides ATP and UTP. Stem cells may also respond to a Ca(2+) or H(+) gradient by employing calcium- or proton-sensing receptors, respectively. In this review, we will present …

Small Molecules in the Treatment of Psoriasis.

Preclinical Research Psoriasis is an inflammatory systemic skin disease that affects various parts of the body requiring long-term managemen … ated protein kinase inhibitors, spleen protein kinase inhibitors, other tyrosine kinase inhibitors, sphingosine 1-phosphate receptor agonists, and A3 adenosine receptor agonists. These new treatment options represent important advances in the development of specific drugs to respond to the goals of treatment and improve patient quality of life.

The effects of fetal and perinatal asphyxia on neuronal cytokine levels and ceramide metabolism in adulthood.

In a rat model of global fetal and perinatal asphyxia, we investigated if asphyxia and long-lasting brain tolerance to asphyxia (preconditioning) are mediated by modifications in inflammatory cytokines and ceramide metabolism genes in prefrontal cortex, hippocampus and caudate-putamen at the age of 8months. Most significant changes were found in prefrontal cortex, with reduced LAG1 homolog ceramide synthase 1 expression after both types of asphyxia. Additionally, sphingosine kinase 1 was upregulated in those animals that experienced the combination of fetal and perinatal asphyxia (precondition…

Huntington's disease vasculopathy is barrier-type-selective and arteriolar-dominant with spatially-coupled astrogliosis and reversible by S1pr1 stimulation.

Brain vascular barriers are dysfunctional in many neurological disorders, including Huntington's disease (HD), but which vessels are affecte … te activation pattern localized to affected vessels both in R6/2 mice and in brains of HD patients. Sphingosine-1-phosphate receptor 1 (S1pr1) agonist treatment reversed BCSFB leakage and partially restored BBB function, selectively reducing AMT in arterioles, with no effect in capillaries and venules. These findings redefine HD vascular pathology, demonstrat …

Enhancement of a nuclear factor of activated T cells (NFAT) reporter for the study of G protein-coupled receptors.

Cell-based assays are fundamental to G protein-coupled receptor (GPCRs) drug discovery. As the field strives to increase the use of physiolo … s in a panel of immortalised cell lines (HEK293, HeLa, A549, and HEK293T) and allowed us to observe Sphingosine-1-Phosphate (S1P)-mediated signalling in primary human CD8+ T cells via CRISPR/Cas9 knock-in. Our NFAT-reporter T cells demonstrate the reporters potential for use in bi-allelic expression systems and primary cell types.

Discovery of Novel Selective Dual Agonists Targeting S1PR1 and S1PR5 for the Treatment of Inflammatory Bowel Disease.

Sphingosine-1-phosphate (S1P) receptor agonists have emerged as promising therapeutics for autoimmune diseases, due to their crucial roles in regulating lymphocyte migration, differentiation, and cytokine secretion. Here, a series of novel 3-(naphthalene-1-yl)-1,2,4-oxadiazol derivatives are designed and synthesized as orally bioavailable, selective dual agonists of S1PR1 and S1PR5. Compounds 19 and 37 were identified, exhibiting excellent in vitro agonistic activity and more than 1000-fold selectivity over S1PR2, S1PR3, and S1PR4. Neither compound 19 and 37 displayed detectable agonistic acti…

Dual-Interface Hierarchical Assembly of Asymmetric ICG-Lipid Conjugates Enables Finite J-type Aggregation and Two-Stage NIR-II Fluorescence Enhancement.

Aggregation-induced quenching severely limits the imaging properties of indocyanine green (ICG), despite its FDA approval and its emission in the near-infrared II (NIR-II) region. Herein, we introduce a dual-interface assembly strategy that orchestrates the sequential assembly of asymmetric ICG-lipid conjugates at lipid and liposome-protein interfaces to achieve two-stage NIR-II fluorescence enhancement. The ICG-sphingosine conjugates without sulfonate groups (ICG-C-Sp) form finite, weakly coupled J-type aggregates within lipid bilayers, producing markedly enhanced NIR-II fluorescence. Upon se…

Small Molecules as Advanced Therapy for the Treatment of Inflammatory Bowel Disease, Particularly Regarding Ulcerative Colitis.

Small molecules used to treat inflammatory bowel disease (IBD) are orally administered therapies that offer a rapid onset without immunogenicity. Currently, three Janus kinase (JAK) inhibitors (tofacitinib, filgotinib, and upadacitinib), two Sphingosine-1-phosphate receptor (S1PR) modulators (ozanimod and etrasimod), and one alpha4-integrin antagonist (carotegrast methyl) are available in Japan. Each JAK inhibitor has its own efficacy and safety profile: Upadacitinib is the most effective, despite its higher frequency of associated adverse events, whereas filgotinib has a weaker efficiency but…

A cell-free lipid sterosomal therapeutic enables bone regeneration via USP18-mediated noncanonical S1P signaling.

Effective treatment of critical-sized bone defects remains challenging due to impaired osteogenesis, insufficient vascularization and oxidative stress-induced cell loss. Here, we report a chemically defined, cell-free sterosomal nanoplatform composed of sphingosine-1-phosphate (S1P) and 20(S)-hydroxycholesterol (Oxy) that integrates cytoprotective, pro-angiogenic, and osteogenic functions. S1P/Oxy sterosomes simultaneously enhance osteogenic differentiation and endothelial angiogenic activity while protecting resident cells from oxidative stress. In a rat critical-sized calvarial defect model,…

Beyond the Colon: Acute Hemolysis Associated With Etrasimod Therapy.

Etrasimod is an oral sphingosine 1-phosphate (S1P) receptor modulator used in the treatment of moderately to severely active ulcerative colitis (UC). Although its safety profile has been described in clinical studies, hematologic complications remain incompletely characterized. We report the case of a 31-year-old man with well-controlled UC who developed acute hemolytic anemia approximately two months after initiation of etrasimod therapy. Evaluation revealed macrocytic anemia with marked reticulocytosis, schistocytes on peripheral smear, elevated ferritin, and a positive direct antiglobulin t…

S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity.

G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by p…

The Role of Novel Small Molecule Drugs in the Management of Inflammatory Bowel Disease.

Treatment algorithms have traditionally been based on biological therapy when conventional therapy was not successful in controlling inflammatory bowel disease (IBD). Novel small molecule drugs (SMDs) for IBD include the Janus Kinase (JAK) inhibitors Tofacitinib, Filgotinib and Upadactinib and the sphingosine-1 phosphate (S1P) inhibitors Ozanimod and Etrasimod. SMDs have advantages over biologics, such as oral administration, lack of immunogenicity, and rapid onset of action. All agents are effective in treating ulcerative colitis, while Upadactinib is the only SMD for Crohn's disease. There i…

Alopecia areata: from immunopathogenesis to emerging therapeutic approaches.

Alopecia areata (AA) is a non-scarring inflammatory hair loss disorder characterized by a T-cell-mediated autoimmune disease that targets th … ovel therapeutic approaches such as neutralizing antibodies targeting cytokines and chemokines, and sphingosine-1-phosphate (S1P) receptor modulators have gained attention. Various molecular markers associated with AA have been identified as potential therapeutic targets. This review provides a comprehensive overview of the roles of immune cells in AA pathoge …

Colonic goblet cell-associated antigen passages mediate physiologic and beneficial translocation of live gut bacteria in preweaning mice.

Gut-resident microorganisms have time-limited effects in distant tissues during early life. However, the reasons behind this phenomenon are … response and required host goblet cells, the formation of goblet cell-associated antigen passages, sphingosine-1-phosphate receptor-dependent leukocyte trafficking and phagocytic cells. One translocating strain, Lactobacillus animalisWU, showed antimicrobial activity against the late-onset sepsis pathogen Escherichia coli ST69 in vitro, and its translocation …

Спасение гиппокампальной синаптической пластичности и эффективности памяти Финголимода (FTY720) в модели APP/PS1 болезни Альцгеймера сопровождается коррекцией метаболизма финголипидов, полиаминов и фосфолипидного насыщенного состава.

Ранее, наши метаболомические, транскриптомные и геномные исследования характеризовали путь церамида/шфингомилена как терапевтическую цель в болезни Альцгеймера, и мы показали, что FTY720, фингозин-1-фосфахатный рецептор, утвержденный для лечения множественных склерозов, восстанавливает синаптическая пластичность и память в мышах APP/PS1. Для дальнейшего изучения того, как FTY720 спасает патологию, мы провели метаболический анализ мозга, плазмы и печени обученных APP/PS1 и диких мышей. APP/PS1 мыши продемонстрировали локальные нарушения мозга в полиаминах, фосфолипидах и сфинголипидах. Большинс

Совпадение в аннотации оригинала
Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further inves…

Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory programs.

Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes … am fostering cell growth and a Myc-independent program controlling cell-movement regulators such as sphingosine-1 phosphate receptor 1 (S1PR1). S1pr1-deficient B cells experienced Notch signaling within B cell follicles without entering the MZ and were retained in the spleen upon Notch deprivation. Key elements of the mouse B cell Notch regulome were preserve …