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Apolipoprotein M (ApoM) Ameliorates Acute Alcohol Intoxication (AAI)-Hemorrhagic Shock and Resuscitation (HSR)-Induced Microvascular Leakage.

OBJECTIVE: Microvascular hyperpermeability is a serious complication that occurs from hemorrhagic shock and resuscitation (HSR), especially when combined with acute alcohol intoxication (AAI). We tested the hypothesis that administration of Apolipoprotein M (ApoM), a lipocalin that normally resides in plasma high-density lipoproteins (HDL) and a carrier of sphingosine-1-phosphate (S1P), reduces combined AAI and HSR-induced microvascular leakage. METHODS: An established rat model of AAI/HSR was combined with intravital microscopy to study whether the administration of ApoM in resuscitative flu…

Time Course of Plasma Proteomic and Oxylipin Changes Induced by LPS Challenge and Modulated by Antioxidant Supplementation in a Randomized Controlled Trial.

Systemic molecular responses to pathogen-associated molecular patterns and their modulation by antioxidants are poorly understood in humans. … lenge had no detectable effect on protein kinetics but significantly downregulated pro-inflammatory sphingosine-1-phosphate and increased levels of oxylipins, 20-HEPE, and 22-HDoHE, which have been described to facilitate the resolution of inflammation. The present study identified a complex network of lipid mediators deregulated in plasma upon lipopolysaccha …

Therapeutic targets for fibro-inflammation in Graves' orbitopathy.

Graves' orbitopathy (GO), a complex autoimmune disorder, remains the most common extrathyroidal manifestation of Graves' disease. Its pathog … g, yes-associated protein 1/transcriptional coactivator with PDZ-binding motif mechanotransduction, sphingosine-1-phosphate (S1P)/S1P receptor axis, bone morphogenic protein 7, IL-11, IL-17 and microRNAs as well as, IGF-1R/thyroid-stimulating hormone receptor crosstalk, and IL-6 trans-signaling. Most studies focus on exploring the potential of therapeutic age …

Concomitant Use of Etrasimod With Opioids or Antidepressants in Patients With Ulcerative Colitis-A Safety Analysis.

BACKGROUND: Etrasimod is an oral, once-daily (q.d.), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Unlike the S1P receptor modulator ozanimod, etrasimod does not have a molecular structure to inhibit monoamine oxidase (MAO). Coadministration of drugs that inhibit MAO with opioids and antidepressants may increase the risk of adverse events (AEs). AIMS: This post hoc analysis evaluated the incidence of AEs potentially related to serotonin syndrome in patients taking etrasimod and concomitant opioids or…

Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures.

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long … s to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together …

Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactions.

Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although mole … signaling. Concurrently, metabolic and signaling pathways in endothelial cells-such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription-indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as tr …

Metabolomics of cerebrospinal fluid following traumatic brain injury: Exploration of biomarkers for secondary injuries and severity.

Traumatic brain injury (TBI) constitutes a major global public health concern associated with substantial mortality and long-term disability … owing TBI. Early-phase changes (day 1) predominantly involved energy-related metabolites, including sphingosine, glucose, and dl-lactate. More pronounced metabolic shifts were observed by day 3, characterized by marked variations in amino acids (l-glutamine, l-histidine) and medium-chain fatty acids (caprylic acid, octanoic acid), suggesting the transition fr …

Causal Relationships Between Plasma Metabolites and Risk of Dermatomyositis.

PURPOSE: This exploratory study aimed to investigate the potential causal relationships between plasma metabolites and dermatomyositis using … r false discovery rate (FDR) correction. Notable heterogeneity was observed in Lactosyl-N-palmitoyl-sphingosine levels, and pleiotropy was evident with 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (3-CMPFP). Robustness was confirmed through MR-PRESSO and leave-one-out analyses. CONCLUSION: This study conducted the first exploratory Mendelian randomization a …

Immune cells in dorsal root ganglia are associated with pruritus in a mouse model of allergic contact dermatitis and co-culture study.

The interaction between the neuroimmune system plays a crucial role in itch sensation, yet most research has focused on immune cells within … ed in immune responses, inflammation, and itch, with notable upregulation of Cathepsin S (Ctss) and sphingosine-1-phosphate (S1P) phosphatase 2 (Sgpp2). Subsequent functional experiments targeting CTSS in co-culture studies validated suppressed response to pruritogen and agonists of TRPA1 and TRPV1, indicating a potential role in peripheral sensitization. Add …

Real-world comparison of lymphopenia profiles in S1P receptor modulators for multiple sclerosis: a multicenter retrospective study.

INTRODUCTION: Sphingosine-1-phosphate (S1P) receptor modulators, regulating the S1P/S1PR pathway, lead to lymphocyte sequestration in lymphoid organs, which results in peripheral lymphopenia. This study evaluates the degree of lymphopenia induced by S1P modulators in people with Multiple Sclerosis (MS): Ozanimod, Siponimod, Ponesimod, and Fingolimod. METHODS: We conducted a retrospective multicenter study across thirteen MS centers in Italy, including 191 MS patients (mean age 46.4 years; 61.3% women). Of these, 28.8% received Siponimod, 26.2% Ozanimod, 24.1% Fingolimod, and 20.9% Ponesimod. …

A Randomized Trial on the Combined Effect of Ponesimod and Propranolol on Heart Rate, Cardiac Safety, and Pharmacokinetics in Healthy Adults.

The objective of this phase 1 study was to evaluate the pharmacokinetics (PK), pharmacodynamics, and cardiac effect following administration of ponesimod (a selective sphingosine-1-phosphate receptor modulator) and propranolol in healthy adults. In treatment period (TP) 1, participants received ponesimod (2 mg). In TP2, if resting heart rate (HR) was ≥ 55 bpm, the ponesimod up-titration regimen was initiated. Participants were randomized to TP2A (placebo plus ponesimod up-titration) or TP2B (80 mg propranolol plus ponesimod up-titration). Concomitant administration resulted in an increased bra…

Сипонимод поддерживает воспоминание в неподдерживающей среде.

Воспаление, характерное для множественных повреждений склероза (MS), приводит к функциональным повреждениям и постепенной потере аксона с течением времени. Хотя, как считается, ремилеляция защищает аксоны, внутренние регенерационные процессы часто являются неполными или полностью неэффективными у многих пациентов с синдромом MS. Хотя точные причины провала воспоминаний остаются неясными, неоднократное обезвоживание в ранее затронутых районах с белыми телами является признанным фактором, способствующим этому. В одном из предыдущих исследований мы продемонстрировали, что модификатор Siпонimod с

Совпадение в аннотации оригинала
Inflammatory demyelination, a hallmark of multiple sclerosis (MS) lesions, leads to functional impairments and progressive axonal loss over … e matter regions is a recognized contributing factor. In a previous study, we demonstrated that the sphingosine-1-phosphate modulator Siponimod ameliorates metabolic oligodendrocyte injury in an MS animal model. In this study, we explored the potential of Siponimod to enhance remyelination in a non-supportive environment. To this end, male mice were subjected …

Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials.

INTRODUCTION: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. METHODS: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their ba…

Exploring Microbial Metabolite Receptors in Inflammatory Bowel Disease: An In Silico Analysis of Their Potential Role in Inflammation and Fibrosis.

Metabolites produced by dysbiotic intestinal microbiota can influence disease pathophysiology by participating in ligand-receptor interactio … innate immune cells, while, in the non-inflamed CD ileum, the cannabinoid receptor 1 (CNR1) and the sphingosine-1-phospate receptor 4 (S1PR4) were downregulated and were involved in the regulation of B-cell activation. In inflamed UC, the upregulated receptors HCAR2 and HCAR3 were more closely associated with the process of TH-17 cell differentiation, while t …

CD36 deficiency protects lipopolysaccharide-induced sepsis via inhibiting CerS6-mediated endoplasmic reticulum stress.

The type 2 scavenger receptor CD36 functions not only as a long chain fatty acid transporter, but also as a pro-inflammatory mediator. Ceramide is the simple N-acylated form of sphingosine and exerts distinct biological activity depending on its acyl chain length. Six ceramide synthases (CerS) in mammals determine the chain length of ceramide species, and CerS6 mainly produces C16-ceramide. Endotoxin-induced septic shock shows high mortality, but the pathophysiologic role of sphingolipids involved in this process has been hardly investigated. This paper aims to highlight the different role of …

S1PR-1/5 modulator RP-101074 shows beneficial effects in a model of central nervous system degeneration.

INTRODUCTION: In multiple sclerosis (MS), chronic disability primarily stems from axonal and neuronal degeneration, a condition resistant to conventional immunosuppressive or immunomodulatory treatments. Recent research has indicated that selective sphingosine-1-phosphate receptor S1PR-1 and -5 modulators yield positive effects in progressive MS and mechanistic models of inflammation-driven neurodegeneration and demyelination. METHODS: In this study, the S1PR-1/-5 modulator RP-101074 was evaluated as a surrogate for ozanimod in the non-inflammatory, primary degenerative animal model of light-…

Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis.

OBJECTIVE: The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) accumulate with overnutrition and have been implicated in non-alcoholic steatohepatitis (NASH) development. ORMDL3, a negative regulator of the rate-limiting step in ceramide biosynthesis, has been identified as an obesity-related gene. Therefore, we assessed the role of ORMDL3 in diet-induced obesity and development of NASH. METHODS: Globally overexpressing Ormdl3-Flag transgenic mice (ORMDL3TG) were fed a western high-fat, carbohydrate and cholesterol enriched diet, with high fructose-glucose drinki…

Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome (SRNS) that predominantly affects the podocytes. While mutations in genes causing pediatric SRNS have enhanced our understanding of FSGS, the disease's etiology remains complex and poorly understood. METHODS: Whole exome sequencing (WES) was performed on a 9-year-old girl with SRNS associated with FSGS (SRNS-FSGS). We analyzed the expression of CRB2, slit diaphragm (SD)-associated proteins, and sphingosine 1-phosphate receptor 1 (S1PR1) in the proband and CRB2 knock-down podocytes.…

Adiponectin receptor agonist ameliorates cardiac lipotoxicity via enhancing ceramide metabolism in type 2 diabetic mice.

Accumulation of lipids and their metabolites induces lipotoxicity in diabetic cardiomyopathy. Lowering ceramide concentration could reduce t … ease in PP2A level. It also increased acid ceramidase activity which reduced ceramide and increased sphingosine-1 phosphate levels in the heart of db/db mice and cultured human cardiomyocytes. Consistent upregulation of AdipoRs and their downstream regulatory pathways involving pAMPK/PPARα/PGC-1α levels led to lipid metabolism enhancement, thereby improving l …

Immunomodulator FTY720 improves glucose homeostasis and diabetic complications by rejuvenation of β-cell function in nonhuman primate model of diabetes.

Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, sustainably normalized hyperglycemia by stimulating β-cell in vivo regeneration in db/db mice. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes. The male diabetic cynomolgus macaques of 18-19 year old were randomly divided into Vehicle (Purified water, n = 5) and FTY720 (5 mg/kg, n …