Результаты поиска

Treatment with a sphingosine-1-phosphate analog inhibits airway remodeling following repeated allergen exposure.

Sphingosine-1-phosphate (S1P) is an immunomodulatory lipid mediator that plays an important role in lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar lavage (BAL) fluid of patients with asthma; however, its role in disease is not known. FTY720, a synthetic analog of S1P, has been shown to abrogate allergic inflammation and airway hyperresponsiveness following acute allergen challenge. However, its effects on asthmatic airway remodeling induced by repeated allergen exposure are unknown. Ovalbumin (OVA)-sensitized rats were challenged on days 14, 19, and 24 after sensit…

Будущие клинические проблемы при множественном склерозе: актуальность для фингозина 1-фосфатной модуляторной терапии рецептора.

Ограничения установленных методов лечения множественного склероза (МС) хорошо известны и включают необходимость инъекции, соблюдения курса лечения и решения вопросов удобства, частичную эффективность и, в некоторых случаях, риск потенциально опасных для жизни негативных явлений, таких, как прогрессивная многофукальная лейкоэнцефалопатия. В последнее время внимание сосредоточено на разработке более эффективных методов лечения, которые применяются в устной форме и ориентированы на нейродегенерацию, а также на воспаление. В настоящем обзоре мы предлагаем перспективы будущих клинических задач в об

Совпадение в аннотации оригинала
The limitations of established therapies for multiple sclerosis (MS) are well-known and include the need for injections, treatment adherence … future clinical challenges for MS treatment and management, and focus specifically on the emerging sphingosine 1-phosphate receptor (S1PR) modulators. We highlight the importance of improving our understanding of the neurobiological basis of MS to develop well-tolerated targeted therapies and the need to include advanced MRI assessments that quantify neurode …

S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species.

AIMS: Sphingosine kinase 1 (SPHK1), its product sphingosine-1-phosphate (S1P), and S1P receptor subtypes have been suggested to play protective roles for cardiomyocytes in animal models of ischaemic preconditioning and cardiac ischaemia/reperfusion injury. To get more insight into roles for SPHK1 in vivo, we have generated SPHK1-transgenic (TG) mice and analysed the cardiac phenotype. METHODS AND RESULTS: SPHK1-TG mice overexpressed SPHK1 in diverse tissues, with a nearly 20-fold increase in enzymatic activity. The TG mice grew normally with normal blood chemistry, cell counts, heart rate, an…

Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin ligase PAM.

The signaling pathways that are regulated by sphingosine-1-phosphate (S1P) and mammalian target of rapamycin (mTOR) modulate cell growth, mitogenesis and apoptosis in various cell types and are of major interest for the development of new cancer therapeutics. Previous reports show that S1P can cross-activate the mTOR pathway although the mechanisms that connect both pathways are still unknown. We found that S1P-treatment activates mTOR in several cancer cell lines and primary cells. The activation was independent of ERK, Akt and PI3-kinase, but instead was mediated by the E3 ubiquitin ligase P…

Genome-wide Association Studies of the Pathogenic Sphingosine-1-Phosphate Gene in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can lead to malignancies over time. Sphingosine-1-phosphate (S1P) receptor signaling affects lymphocyte trafficking and vascular integrity, influencing intestinal inflammation. This study aimed to identify S1P-related key genes in UC. METHODS: Differentially expressed genes (DEGs) between the UC and control groups were analyzed in the GSE87473 (training) dataset. Genes overlapping between the DEGs and S1P-related genes were considered candidate genes. These genes were incorporated into machine learning algorithms…

Targeting sphingosine-1-phosphate receptor-2 attenuates spinal cord injury by preventing neuronal ferroptosis.

BACKGROUND AND PURPOSE: Spinal cord injury (SCI) imposes severe physiological and psychological burdens on patients. We investigated the role of sphingosine-1-phosphate receptor 2 (S1P2 receptor) in contusive spinal cord injury and evaluated the therapeutic effects of an S1P2 receptor antagonist S118 (C₁₉H₁₄Cl2FN₇O) in a rat model of SCI. EXPERIMENTAL APPROACH: The SCI model was established using a 10 g weight dropped onto the T10 vertebrae in female rats. After functional testing, spinal cords were harvested for biochemical and histopathological assays at different time points. Nissl and Pru…

Sphingosine-1-Phosphate Regulation to Alleviate Sickle Cell Disease Severity: A Promising Therapeutic Approach.

Although Yersinia pestis is classified as a "high-virulence" pathogen, some host species are variably susceptible to disease. Coyotes (Canis latrans) exhibit mild, if any, symptoms during infection, but antibody production occurs postinfection. This immune response has been reported to be against the F1 capsule, although little subsequent characterization has been conducted. To further define the nature of coyote humoral immunity to plague, qualitative serology was conducted to assess the antiplague antibody repertoire. Humoral responses to six plasmid-encoded Y. pestis virulence factors were

Curcumin attenuates ulcerative colitis via regulation of Sphingosine kinases 1/NF-κB signaling pathway.

Curcumin, a compound from Curcuma longa L., has significant anti-inflammatory properties. However, the mechanisms underlying its anti-inflam … bly, RNA-seq analysis demonstrated that curcumin significantly downregulated the mRNA expression of sphingosine kinase 1 (SphK1). Furthermore, molecular docking analysis showed that curcumin can bind to SphK1 and NF-κB. Additionally, curcumin was found to inhibit the activation of the SphK1/NF-κB signaling pathway in DSS-induced UC colon tissue. This study ad …

Prevotella copri facilitates wound healing in mice through the sphingosine-CerS1-ceramide metabolic pathway.

Skin wound repair constitutes a sophisticated biological process involving spatiotemporally coordinated molecular cascades, with emerging ev … al growth factor and epidermal growth factor. Metabolomic profiling revealed that P. copri-secreted sphingosine undergoes bioconversion to C18-ceramide via the non-canonical CerS1 pathway, driving keratinocyte hyperproliferation and neoangiogenesis. Pharmacological inhibition of CerS1 with P053 suppressed ceramide synthesis and delayed healing, mechanisticall …

Cell line engineering for enhanced measles virus production with sphingosine kinase 1 gene overexpression.

One challenge in utilizing the Measles virus (MV) for cancer therapy is the number of virus particles required, nearly a million times greater than the amount reported for vaccination. This study aims to design and develop a cell line with increased production capacity to supply the required amounts of MV in oncolytic virotherapy. The sphingosine kinase 1 (SphK1) gene was inserted into a pIRES2-EGFP plasmid and transiently transfected into four cell lines: MRC-5, HEK293, Vero, and A549. Fluorescent light intensity was measured using flow cytometry, and the MV production titer was determined us…

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

AIMS: We previously demonstrated that bacterial sphingomyelinase (SMase), which converts plasmalemmal sphingomyelin to long-chain ceramides, activates the swelling-activated chloride current (ICl,swell) in rabbit ventricular myocytes in a reactive oxygen (ROS)-dependent manner under isosmotic conditions. Ceramides can be converted to sphingosine by ceramidase and, in turn, phosphorylated by sphingosine kinase to yield sphingosine-1-phosphate (S1P), which binds to multiple cytoplasmic targets and activates S1P receptors via inside-out transport. This study was designed to determine the cellular…

Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.

Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by…

Reticulon 3 regulates sphingosine-1-phosphate synthesis in endothelial cells to control blood pressure.

The discovery of the endothelium as a major regulator of vascular tone triggered intense research among basic and clinical investigators to unravel the physiologic and pathophysiologic significance of this phenomenon. Sphingosine-l-phosphate (S1P), derived from the vascular endothelium, is a significant regulator of blood pressure. However, the mechanisms underlying the regulation of S1P biosynthetic pathways in arteries remain to be further clarified. Here, we reported that Reticulon 3 (RTN3) regulated endothelial sphingolipid biosynthesis and blood pressure. We employed public datasets, pati…

Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease.

Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P1), is coupled to Gi/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P1 constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P1 receptor-mediated activity in he…

PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [18F]TZ4877 in Nonhuman Primates.

PURPOSE: The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR1-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR1 radiotracer, [18F]TZ4877, in nonhuman primates. PROCEDURES: [18F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[18F]/F- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min followin…

Dissecting the Therapeutic Mechanisms of Sphingosine-1-Phosphate Receptor Agonism during Ischaemia and Reperfusion.

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PR) regulate many cellular processes, including lymphocyte migration and endothelial barrier function. As neutrophils are major mediators of inflammation, their transendothelial migration may be the target of therapeutic approaches to inflammatory conditions such as ischaemia-reperfusion injury (IRI). The aim of this project was to assess whether these therapeutic effects are mediated by S1P acting on neutrophils directly or indirectly through the endothelial cells. First, our murine model of peritoneum cell recruitment demonstrated the abilit…

Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor.

Lysosomes are catabolic organelles involved in macromolecular digestion, and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to common neurodegenerative diseases, many of which have lipid accumulation phenotypes. The mechanism of lipid efflux from lysosomes is well understood for cholesterol, while the export of other lipids, particularly sphingosine, is less well studied. To overcome this knowledge gap, we have developed functionalized sphingosine and cholesterol probes that allow us to follow their metabolism, protein interactions, and their subcellu…

Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells.

One of the common mechanisms responsible for obstetric complications, affecting millions of women every year, is abnormal uterine contractility. Despite the critical importance of this process for women's health, the mechanisms of uterine contraction regulation remain poorly understood. The initiation of uterine smooth muscle (myometrial) contraction is an inflammatory process, accompanied by upregulation of proinflammatory genes and cytokine release. In this study, we show that sphingolipid metabolism is activated during human labor and that sphingosine 1-phosphate (S1P), the main bioactive s…

S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin.

Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the skin barrier. However, the interaction between these two factors is still unclear. To investigate this, a study was conducted on healthy skin and allergic contact dermatitis (ACD) using 3,4-Dibutoxy-3-cyclobutene-1,2-dione (SADBE) on the ears of S1pr2fl/fl and S1pr2fl/flK14-Cre mice and using 1 × 106 CFU of S.…

Enhanced selective capture of phosphomonoester lipids enabling highly sensitive detection of sphingosine 1-phosphate.

Sphingolipids play crucial roles in cellular membranes, myelin stability, and signalling responses to physiological cues and stress. Among them, sphingosine 1-phosphate (S1P) has been recognized as a relevant biomarker for neurodegenerative diseases, and its analogue FTY-720 has been approved by the FDA for the treatment of relapsing-remitting multiple sclerosis. Focusing on these targets, we here report three novel polymeric capture phases for the selective extraction of the natural biomarker and its analogue drug. To enhance analytical performance, we employed different synthetic approaches …