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Sphingomyelin synthase 2 loss suppresses steatosis but exacerbates fibrosis in the liver of mice fed with choline-deficient, L-amino acid-defined, high-fat diet.

Sphingomyelin synthase 2 (SMS2) regulates sphingomyelin synthesis and contributes to obesity and hepatic steatosis. Here, we investigated the effect of SMS2 deficiency on liver fibrosis in mice fed with choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or injected with carbon tetrachloride (CCl4), respectively. SMS2 deficiency suppressed hepatic steatosis, but exacerbated fibrosis induced by CDAHFD feeding. Sphingosine 1-phosphate (S1P), which is a key lipid mediator induces fibrosis in various organs, was increased in the liver of mice fed with CDAHFD. The increase of S1P became…

Lipid⁻Protein Interactions in Niemann⁻Pick Type C Disease: Insights from Molecular Modeling.

The accumulation of lipids in the late endosomes and lysosomes of Niemann⁻Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel's voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that pho…

Emerging roles for lysophospholipid mediators in pregnancy.

Recent progress in lipid research has unveiled new biologic roles for lysophospholipids as mediators of intercellular signaling. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are representative lysophospholipids. Accumulating evidence suggests that, acting as intercellular mediators, these and other lysophospholipids may play important roles in physiological and pathological situations. This review discusses the possible involvement of LPA and S1P in reproductive processes, with a focus on the regulatory mechanisms of pregnancy maintenance. As LPA promotes prostaglandin synthes…

The ins and outs of hematopoietic stem cells: studies to improve transplantation outcomes.

Deciphering the mechanisms of hematopoietic stem/progenitor cell (HSPC) mobilization and homing is important for the development of strategi … oproteinases and carboxypeptidase M), complement proteins (C1q, C3a, C5a, membrane attack complex), sphingosine-1-phosphate, and pharmacologic agents such as the histone deacetylase inhibitor valproic acid and hyaluronic acid.

Characterization of monoclonal antibodies to galactolipids and uses in studies of dementia.

A panel of monoclonal antibodies was prepared from mice immunized with homogenates of ventral forebrain from patients with Alzheimer's disea … ids. Studies with a variety of purified lipids revealed that the antibodies reacted with galactosyl sphingosine, cerebrosides and sulfatides. These antibodies have been used to examine galactosphingolipids in brains with AD with both quantitative ELISA and immunocytochemical techniques. Additionally, the galactolipid composition of Pick's disease has also bee …

Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary ca…

RP001 hydrochloride improves neurological outcome after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) results in neurological damage, acute cardiac damage and has a high mortality rate. Immunoresponse in the acute phase after SAH plays a key role in mediating vasospasm, edema, inflammation and neuronal damage. The S1P/S1PR pathway impacts multiple cellular functions, exerts anti-inflammatory and anti-apoptotic effects, promotes remyelination, and improves outcome in several central nervous system (CNS) diseases. RP001 hydrochloride is a novel S1PR agonist, which sequesters lymphocytes within their secondary tissues and prevents infiltration of immune cells into th

SphK1/mitophagy axis in cementocytes drives orthodontic root resorption via mitochondrial transfer to osteoclasts.

Orthodontically induced inflammatory root resorption (OIIRR) is a prevalent complication driven by excessive mechanical force, yet the underlying mechanisms linking mechanotransduction to osteoclast activation remain elusive. Here, we identify a novel signaling axis wherein sphingosine kinase 1 (SphK1) in cementocytes translates heavy orthodontic force into a pro-osteoclastogenic signal via mitophagy-mediated mitochondrial transfer. In vivo, heavy force induced OIIRR and upregulated mitophagy markers in cementocytes. In vitro, heavy compression force triggered SphK1-dependent mitophagy in IDG-…

Dysregulated ceramide metabolism in mouse progressive dermatitis resulting from constitutive activation of Jak1.

Coordinated lipid metabolism contributes to maintaining skin homeostasis by regulating skin barrier formation, immune reactions, thermogenes … erythema. Among them, we found the levels of ceramides composed of nonhydroxy fatty acid and dihydrosphingosine containing very long-chain (C22 or more) fatty acids were significantly downregulated before AD onset. Furthermore, in vitro enzyme assays using the skin of Spade mice demonstrated the enhancement of ceramide desaturation. Finally, we revealed topic …

Profiling of bile acids and activated receptor S1PR2 in gingival tissues of periodontitis patients.

BACKGROUND: Bile acids, as a group of cholesterol metabolites, play important roles in inflammation and bone metabolism. However, the possible link between bile acids and periodontitis is still unclear. This study aimed to clarify the alterations of the bile acid profile and corresponding receptor expression levels in periodontitis patients, and evaluate their association with periodontitis severity. METHODS: The concentrations of 15 bile acids in gingival tissues from 16 periodontitis patients and 16 healthy individuals were tested by metabolomics. Sphingosine-1-phosphate receptor 2 (S1PR2) …

Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer.

Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure-activity relationship was investigated based on the S1PR2 binding assay. Representative compound 43 potently interacts with S1PR2 with a KD value of 0.73 nM. It displays potent 5-FU resensitizing activity in multiple…

[Chlorpromazine hydrochloride plays a tumor suppressive role in diffuse large B lymphoma by promoting the expression of S1PR2].

Objective: To investigate the effect of chlorpromazine hydrochloride on proliferation, apoptosis and cell cycle arrest of human diffuse large B lymphoma cells and its possible mechanism. Methods: In January 2019, OCI-LY3 and TMD8 cells were treated with different concentrations of chlorpromazine hydrochloride for 72 h, the proliferations were detected by Alamar Blue assay. The apoptosis and cell cycle arrest of OCI-LY3 and TMD8 cells were detected by flow cytometry with FITC annexin V/PI (propidium iodide) double staining and PI, respectively. The mRNA levels of cyclin-dependent kinase inhibit

Asymmetric synthesis of D-ribo-phytosphingosine from 1-tetradecyne and (4-methoxyphenoxy)acetaldehyde.

An asymmetric synthesis of d-ribo-phytosphingosine (1) was achieved by utilizing the ProPhenol (12)-catalyzed alkynylation of unsaturated aldehyde 8 to afford allylic propargylic alcohol (S)-6 followed by asymmetric epoxidation and opening of propargylic epoxy alcohol anti-5 with NaN(3)/NH(4)Cl. Deprotection and reduction of the resulting acyclic azide 3 then gave 1. Alkyne-azide 3 was subjected to an intramolecular click reaction, generating a bicyclic triazole, which was found to have unexpected vicinal coupling constants. Application of the advanced Mosher method verified the configurations…

Melanophilin inhibit the growth and lymph node metastasis of triple negative breast cancer via the NONO-SPHK1-S1P axis.

BACKGROUND: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis, and there are no tar … noprecipitation and quantitative real-time PCR (RIP qPCR) were utilized to verify the regulation of sphingosine kinase 1 (SPHK1) expression by MLPH through Non-POU domain-containing octamer-binding protein (NONO). Cell functional assays and in vivo models experiments further confirmed the effects of MLPH on proliferation and lymph node metastasis of TNBC thro …

Dual Mechanisms of Cognitive Function and Pathological Improvements by the Selective S1PR1/5 Modulator Siponimod in 3xTg-AD Mice.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, with neuroinflammation and myelin dysfunction as crucial pathological mechanisms. Siponimod, a selective S1PR1/5 modulator, shows promising therapeutic potential through enhanced brain penetration and improved pharmacokinetic properties compared to first-generation modulators. Network pharmacology and molecular docking analyses were utilized to comprehensively elucidate the underlying mechanisms of Siponimod in the context of AD. Specifically, network pharmacology identified key targets and pathways associated with Sip

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper-IgA mice.

Because the association between sphingosine 1-phosphate (S1P)/apolipoprotein M (ApoM) and chronic kidney diseases has not been established, we investigated the involvement of S1P/ApoM in the phenotypes of IgA nephropathy in hyper-IgA (HIGA) mice. The overexpression of ApoM in adenoviral gene transfer ameliorated the phenotypes of IgA nephropathy in HIGA mice, whereas the knockdown of ApoM with siRNA caused deterioration. When ApoM-overexpressing HIGA mice were treated with VPC23019, an antagonist against S1P receptor 1 (S1P1) and 3 (S1P3), we observed that the protective effects of ApoM were r…

FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease.

Huntington disease (HD) is a genetic neurodegenerative disorder for which there is currently no cure and no way to stop or even slow the brain changes it causes. In the present study, we aimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may be effective in HD models and eventually constitute an alternative therapeutic approach for the treatment of the disease. Here, we utilized preclinical target validation paradigms and examined the in vivo efficacy of chronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improved

Investigating FTY720-NF immunomodulation of key lipid, gene, and protein mediators to enhance oral tissue regeneration.

Oronasal fistula (ONF) formation following cleft palate repair remains a significant clinical challenge, often driven by persistent inflammation, fibrotic remodeling, and insufficient mucosal regeneration. Effective oral wound healing depends on precise immune regulation, particularly by macrophages that coordinate both inflammation resolution and tissue repair. The sphingosine-1-phosphate (S1P) pathway is a key regulator of immune cell function and trafficking, and its modulation through the S1P receptor agonist FTY720 (Fingolimod) offers a promising multifaceted strategy for tissue regenerat…

Irilone и Lupinisoflavone C как потенциальные методы регулирования на основе растений S1PR1 для нейроиммунной модуляции при мультипликационном склерозе: Отличения от молекулярного допинга и динамических процессов.

Ген S1PR1 кодирует рецептор 1 фингозина-1-фосфата, который является членом семейства G-белковых рецепторов (GCR), сильно выраженных в эндотелиальных клетках. Протеин S1PR1 играет ключевую роль в регулировании миграции клеток, поддержании сосудистой целостности и посредничении нейронных сигналов посредством активации нижних эффекторов, включая RAC1, SRC, PTK2/FAK1 и MAP cinases. Его важнейшая роль в нейроинфламмации и гомеостазисе центральной нервной системы (СНС) связывает S1PR1 с патофизиологией нейродегенеративных расстройств, в частности множественным склерозом (МС). Чрезмерная активация S1

Совпадение в аннотации оригинала
The S1PR1 gene encodes the sphingosine-1-phosphate receptor 1, a member of the G protein-coupled receptor (GPCR) family that is highly expressed in endothelial cells. S1PR1 protein plays a pivotal role in regulating cell migration, maintaining vascular integrity, and mediating neural signaling through the activation of downstream effectors, including RAC1, S…