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Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors.

The BA-responsive GPCRs S1PR2 and TGR5 are almost ubiquitously expressed in human and rodent tissues. In the liver, S1PR2 is expressed in all cell types, while TGR5 is predominately found in non-parenchymal cells. In contrast to S1PR2, which is mainly activated by conjugated bile acids (BAs), all BAs serve as ligands for TGR5 irrespective of their conjugation state and substitution pattern.Mice with targeted deletion of either S1PR2 or TGR5 are viable and develop no overt phenotype. In liver injury models, S1PR2 exerts pro-inflammatory and pro-fibrotic effects and thus aggravates liver damage,

Quantitative evaluation of sphingomyelin and glucosylceramide using matrix-assisted laser desorption ionization time-of-flight mass spectrometry with sphingosylphosphorylcholine as an internal standard. Practical application to tissues from patients with Niemann-Pick disease types A and C, and Gaucher disease.

Niemann-Pick disease types A and C, and Gaucher disease are glycolipid storage disorders characterized by the systemic deposition of glycosphingolipids, i.e., sphingomyelin in Niemann-Pick disease types A and C tissues and glucosylceramide in Gaucher disease ones, respectively. Using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS), we analyzed the sphingolipids in liver and spleen specimens from patients with Niemann-Pick disease types A and C, and Gaucher disease. Crude lipids were extracted from tissue containing 5mg protein with chloroform and met

Vasorelaxing effect of the Rho-kinase inhibitor, Y-27632, in isolated canine basilar arteries.

OBJECTIVES: Increased calcium sensitization mediated by Rho/Rho-kinase may be important in the pathogenesis of cerebral vasospasm. The effects of a highly selective Rho-kinase inhibitor, Y-27632, were investigated on spasmogen-induced contractions of canine basilar artery. METHODS: Typical spasmogenic substances present after subarachnoid hemorrhage (SAH), including prostaglandin F2a (PGF2a), 12-deoxyphorbol 13-isobutyrate (DPB), sphingosylpho-sphorylcholine (SPC) and high K+, were used in the study. Isometric tension was recorded in canine basilar artery rings in vitro. Intracellular calcium

Quantitative evaluation of sphingolipids using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry with sphingosylphosphorylcholine as an internal standard. Practical application to cardiac valves from a patient with Fabry disease.

Fabry disease is a glycolipid storage disorder caused by a defect of alpha-galactosidase A, and characterized by the systemic deposition of glycosphingolipids with terminal alpha-galactosyl moieties, mainly globotriaosylceramide, in tissues. Using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS), we analyzed the sphingolipids in the cardiac valves from a 49-year-old male patient with Fabry disease who suffered from congestive cardiac failure. Crude lipids were extracted from the cardiac valves with chloroform and methanol. After

Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup.

Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of manifestations. Although Gaucher … ic Gaucher disease. Brain autopsy samples from two patients demonstrated elevated levels of glucosylsphingosine, a toxic glycolipid, which could contribute to the development of myoclonus. Thus, although there were certain shared mutant alleles found in these patients, both the lack of a shared genotype and the variability in clinical presentations suggest th …

Clustering of distinct autoimmune diseases associated with functional abnormalities of T cell survival in children.

To ascertain whether alterations of lymphocyte switching off may be associated with clustering of autoimmune diseases in children, Fas- and C2-ceramide-induced cell death was evaluated on T cell lines derived from three patients affected by clustering of autoimmune disorders. Three patterns were found: patient 3 was resistant to Fas- and C2-ceramide, patient 1 was resistant to Fas, but sensitive to C2-ceramide, patient 2 was resistant to C2-ceramide, but sensitive to Fas. By contrast, Fas- and C2-ceramide-induced cell death was normal in five children with systemic juvenile rheumatoid arthriti

Lactosylsphingosine-reactive antibody and CEA in patients with colorectal cancer.

The sera of 71 patients with colorectal cancer were examined for lactosylsphingosine-reactive antibody and CEA. Fifteen of those patients were studied repeatedly over extensive periods of time. The antibody was determined by the semiquantitative radioimmunoabsorption technique using lactosylsphingosine-polyacrylamide conjugate and [125I]-labelled anti-human IgG. Excessive antibody levels were invariably found In serum samples of all 39-patients who were examined before or within 2 months after surgery. Serum samples of certain patients became negative for the presence of high antibody levels u…

Negative Emotions Induce Urticaria by Regulating Metabolites: A Two-Step Mendelian Randomization Study.

INTRODUCTION: Several studies have indicated a potential link between emotions and urticaria. However, the causal relationship between diffe … lings increase urticaria risk by decreasing mannose, mannonate, and glycosyl-N-(2-hydroxynervonoyl)-sphingosine (d18:1/24:1(2OH)) levels and by increasing the phosphate-to-mannose ratio and glucose-to-mannose ratio. However, the relationship between nervous feelings and urticaria is not mediated by metabolites. These findings provide new perspectives and pote …

Inflammation-fibrosis crosstalk in endometriosis: immune-stromal mechanisms linking lesion persistence to pain and infertility.

Endometriosis is an estrogen-dependent chronic inflammatory disorder in which ectopic endometrial-like tissue undergoes repeated injury, incomplete resolution, and progressive remodeling. Fibrosis is therefore not merely a terminal scar but an active component of lesion biology. Cyclic bleeding activates platelets and innate immune cells, generates iron-dependent oxidative stress and hypoxia, and sustains transforming growth factor-β, sphingosine-1-phosphate, Wnt/β-catenin, PI3K/AKT-ERK, and Notch-related signals. These cues promote fibroblast activation, myofibroblast differentiation, extrace…

CerS2 Overexpression Enhances Palmitoyl-CoA-Induced Cytotoxicity and Alters Ceramide Species Composition in Breast Cancer Cells.

Sphingolipid metabolism, particularly the balance between pro-apoptotic ceramide and pro-survival sphingosine-1-phosphate (S1P), has been associated with breast cancer progression. The aim of the present study was to examine whether ceramide synthase 2 (CerS2) overexpression is associated with changes in increased palmitoyl-CoA (PCA) based ceramide buildup and cell fate changes in MCF-7 breast cancer cells, a hormone receptor-positive model. CERS2 plasmid transfected cells were treated with PCA and/or the CerS inhibitor, fumonisin B1 (FB1). Cell viability, the proliferation marker proliferatin…

Metabolomic profiling of genotype-derived ABO blood group, secretor status, and Lewis antigens and association with pancreatic ductal adenocarcinoma risk.

The ABO locus is associated with pancreatic ductal adenocarcinoma (PDAC). Potential metabolic mechanisms underlying these associations have … tes, respectively, at false discovery rate <0.20, with 9 in common. The ABO-associated metabolites, sphingosine (non-O: β = 0.15), aspartate (A: β = -0.11), and aspartylphenylalanine (A: β = -0.16) were positively, and fibrinopeptide B (1-13) (non-O: β = 0.13; A: β = 0.21) was inversely associated with PDAC (OR = 0.96-1.07 per SD change log10-metabolite, P <. …

Comparative effectiveness of anti-CD20 therapies and S1P receptor modulators in late-onset multiple sclerosis: real-world evidence from the MSBase registry.

BACKGROUND: Late-onset multiple sclerosis (LOMS), defined by symptom onset after age 50, is increasingly recognised as a distinct clinical entity. Evidence comparing disease-modifying therapies (DMTs) in this subgroup remains limited. OBJECTIVES: To compare clinical outcomes of anti-CD20 monoclonal antibodies and sphingosine-1-phosphate receptor modulators (S1PRMs) in LOMS. DESIGN: Multicentre, observational cohort study based on real-world data from an international multiple sclerosis registry. METHODS: We analysed data from the MSBase registry, including relapsing-remitting LOMS patients …

Etrasimod for the symptomatic relief of ulcerative colitis: a post-hoc analysis from the ELEVATE UC clinical programme.

OBJECTIVE: Bothersome ulcerative colitis (UC) symptoms include stool frequency (SF), rectal bleeding (RB), abdominal pain and bowel urgency; symptomatic relief is a key treatment goal. Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. We assessed outcomes related to symptomatic relief among patients with moderately to severely active UC in the phase III ELEVATE UC clinical programme. METHODS: In both ELEVATE UC 52 and ELEVATE UC 12, adults were randomly assigned (2:1) to etrasimod 2 mg QD or …

Role of S1PR1 in VEGF-exosomes mediated resistance of hepatocellular carcinoma to anti-angiogenesis therapy.

BACKGROUND: Anti-angiogenesis therapy (AAT) triggers vascular endothelial growth factor (VEGF)-exosomes secretion from tumor-associated endothelial cells (TAECs) for hepatocellular carcinoma (HCC) tubulogenesis and metastasis. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in HCC progression, but it was targeted by microRNA-9 (miR-9) that might mediate the formation of TAECs. This study aims to investigate the role of miR-9 and VEGF-exosomes in S1PR1-mediated HCC progression and resistance to AAT. METHODS: The expression and distribution of miR-9 in HCC tissues were analyzed u…

SPHK2 inhibition alleviates chronic intermittent hypoxia-induced inflammation in adipose tissue by decreasing endoplasmic reticulum stress.

Obstructive Sleep Apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent disorder that significantly elevates the risk of cardiovascular and metabolic complications. Lipid metabolism disturbances, a common comorbidity in OSA, are closely associated with CIH-induced adipose tissue inflammation, yet the underlying mechanisms remain poorly defined. In this study, we established a CIH mouse model to investigate the roles of Sphingosine Kinase 2 (SPHK2) and endoplasmic reticulum stress (ERS) in CIH-induced lipid metabolic disturbances. Mice were exposed to normal air (NA) …

Lipid Dysregulation in Sebaceous Gland Disorders and the Impact of Sphingolipid Metabolism on Acne Pathogenesis.

Lipid dysregulation within sebaceous glands is a critical factor underlying the pathogenesis of sebaceous gland disorders, particularly acne … nization, and an exaggerated inflammatory response. Furthermore, sphingolipid intermediates such as sphingosine-1-phosphate (S1P) influence sebocyte differentiation, lipid synthesis, and cytokine release, linking sphingolipid metabolism to sebaceous gland homeostasis. Emerging therapeutic strategies targeting sphingolipid pathways offer new opportunities for …

Демиэлизация в связи с психическими и неврологическими расстройствами: механизмы, клиническое воздействие и новые терапевтические стратегии.

Демиелинация, определяемая как потеря милиновых оболочек вокруг нейронных аксонов, все чаще признается в качестве ключевого фактора широкого спектра психических и неврологических расстройств, включая шизофрение, серьезное депрессивное расстройство, биполярное расстройство, посттравматическое стрессовое расстройство, расстройство аутистического спектра, расстройства, связанные с потреблением психоактивных веществ, болезнь Альцгеймера, болезнь Паркинсона и множественный склероз. В рамках этого обзора изучаются основные механизмы демиелинации, ее клиническое воздействие и новые терапевтические ст

Совпадение в аннотации оригинала
Demyelination, defined as the loss of myelin sheaths around neuronal axons, is increasingly recognized as a key factor in a broad range of p … ion, and alterations in the gut-brain axis mediated by the vagus nerve. Promising therapies include sphingosine 1-phosphate receptor modulators and muscarinic acetylcholine receptor antagonists, both of which diminish immune-related myelin damage and may enhance neuroprotection. In addition, the novel antidepressant arketamine appears to boost myelination thr …

GLP-1 receptor agonists alleviate colonic inflammation by modulating intestinal microbiota and the function of group 3 innate lymphoid cells.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are drugs used for treating type 2 diabetes, have been reported to exert anti-in … graphy (LC)-mass spectrometry (MS) of faecal metabolites further revealed enrichment of N,N-dimethylsphingosine (DMS), an endogenous metabolite derived from sphingosine, in the GLP-1RA-treated group. Strikingly, DMS ameliorates colitis while promoting intestinal IL-22-producing ILC3s. Taken together, our findings show that GLP-1RAs exert a therapeutic effect …

Immunity in digestive diseases: new drugs for inflammatory bowel disease treatment-insights from Phase II and III trials.

BACKGROUND: Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), continues to challenge treatment paradigms. Advancements in therapeutic options have been have been driven by Phase 2 and 3 clinical trials of new drug classes, particularly sphingosine-1-phosphate (S1P) modulators and interleukin-23 (IL-23) inhibitors. METHODS: This review synthesizes findings from Phase 2 and 3 clinical trials conducted up to early 2024, focusing on the impact of S1P modulators and IL-23 inhibitors on IBD management. Drugs such as ozanimod, etrasimod, risankizumab, m…

Microvascular Network Remodeling in the Ischemic Mouse Brain Defined by Light Sheet Microscopy.

BACKGROUND: Until now, the analysis of microvascular networks in the reperfused ischemic brain has been limited due to tissue transparency challenges. METHODS: Using light sheet microscopy, we assessed microvascular network remodeling in the striatum from 3 hours to 56 days post-ischemia in 2 mouse models of transient middle cerebral artery occlusion lasting 20 or 40 minutes, resulting in mild ischemic brain injury or brain infarction, respectively. We also examined the effect of a clinically applicable S1P (sphingosine-1-phosphate) analog, FTY720 (fingolimod), on microvascular network remode…