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Biologic and small-molecule therapies for inflammatory bowel disease: mechanisms, comparative evidence and the emerging pipeline.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a chronic immune-mediated disorder of rising global prevalence, with newly industrialised nations now entering the phase of most rapid growth. Its therapeutic landscape has transformed since 2020. Three selective interleukin (IL)-23p19 antagonists have been approved for both UC and CD; two sphingosine-1-phosphate receptor modulators and a second-generation Janus kinase (JAK) inhibitor have entered routine practice; subcutaneous formulations have altered delivery; and the first formal head-to-head …

Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study.

BACKGROUND/AIMS: There is limited evidence for ozanimod, an oral sphingosine 1-phosphate receptor modulator, in patients with ulcerative colitis (UC) before treatment is escalated to an immunomodulator (IM) or advanced therapy (AT), including biologics and Janus kinase inhibitors. METHODS: We performed post hoc analyses to examine the efficacy and safety of ozanimod 0.92 mg versus placebo in a subgroup of Japanese IM-/AT-naive patients with moderately to severely active UC, without concomitant corticosteroids (CS), enrolled in the randomized J-True North study. RESULTS: The analyses comprise…

Bowel urgency in ulcerative colitis is associated with clinical endpoints, health-related quality of life, and biomarkers: data from the etrasimod ELEVATE UC 52 trial.

BACKGROUND: Bowel urgency (BU) is a disruptive ulcerative colitis (UC) symptom. Etrasimod, a sphingosine 1-phosphate (S1P)1,4,5 receptor modulator, improved BU in the ELEVATE UC clinical program. METHODS: We assessed associations between BU and efficacy endpoints, health-related quality of life (HRQoL), and biomarkers (Weeks 12 and 52) in patients receiving etrasimod in ELEVATE UC 52. A patient-reported numerical rating scale (NRS; 0-10; none to worst BU) assessed BU at baseline, Week 12, and Week 52. Binary BU outcomes were BU remission (NRS ≤1), clinically meaningful improvement in BU (NRS …

The Efficacy and Safety of Etrasimod in Mildly to Moderately Active Ulcerative Colitis: Results From the Phase II GLADIATOR Trial.

BACKGROUND & AIMS: Etrasimod is an approved, oral, once-daily, selective sphingosine 1-phosphate receptor modulator with efficacy and safety in moderately to severely active ulcerative colitis demonstrated in the ELEVATE UC program. GLADIATOR evaluated etrasimod efficacy and safety in adults with mildly to moderately active ulcerative colitis. METHODS: GLADIATOR was a phase II, double-blind, treat-through trial. Patients with baseline modified Mayo score 4 to 6, endoscopic subscore ≥2, and rectal bleeding subscore ≥1 were randomized (2:1; stratified by biologic/Janus kinase inhibitor experien…

Emerging Therapeutics in Rheumatoid Arthritis.

PURPOSE OF REVIEW: Current rheumatoid arthritis (RA) treatment guidelines recommend a treat-to-target approach with a goal of remission or l … t rheumatoid arthritis. Multiple pathways targeting T-cells including PD-1, CD40-CD40L, OX40-OX40L, sphingosine-1-phosphate receptor-1, and C-X-C Chemokine Receptor Type 5 have been investigated in phase 1 and 2 trials. Recent advances in B-cell-directed therapy have included investigations into Bruton’s tyrosine kinase inhibitors and Anti-FcRn Monoclonal Ant …

Roles of Ceramide Glucosyltransferase in Controlling Cerebral Microvascular Endothelial Integrity and Angiogenesis Post-Ischemia/Reperfusion.

Sphingolipids critically regulate microvascular integrity and function, but the role of glycosphingolipids in endothelial survival and angio … ctivation near-completely suppressed hexosylceramide levels and at high dose increased ceramide and sphingosine-1-phosphate (S1P), a known pro-angiogenic sphingolipid, while UGCG knockdown moderately decreased mostly short (C16, C18) hexosylceramides. UGCG activation increased hexosylceramide without significantly altering ceramide and S1P. Pharmacological UG …

Fibroblast S1PR2 Amplifies NLRP3 Inflammasome Activation Under Pressure Overload.

BACKGROUND: Although NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation has been implicated in pressure over … tenuated cardiac hypertrophy and inflammation under pressure overload. We further found that S1PR2 (sphingosine-1-phosphate receptor 2) is a critical upstream regulator of fibroblast NLRP3 inflammasome activation. Fibroblast-specific S1PR2 deletion suppressed inflammasome activation, mitigated hypertrophy, and preserved cardiac function, whereas S1PR2 overexp …

A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder.

Disruption of the photoreceptor-retinal pigment epithelium (RPE) interface, with loss of photoreceptor outer segments (POSs) in the retina, … common disease-causing CLN3 mutation (CLN3Δex7-8) leads to reduced levels of acid ceramidase (AC), sphingosine 1 phosphate, and POS loss. Furthermore, by analyzing control versus CLN3 mutant (CLN3Δex7-8) hPSC-derived RPE monoculture and hPSC-RO-RPE model, (i) we identified a pathogenic role of AC-mediated lysosomal sphingolipid metabolism in promoting CLN3 d …

Efficacy of Etrasimod in Ulcerative Colitis: Analysis of ELEVATE UC 52 and ELEVATE UC 12 by Baseline Endoscopic Severity.

BACKGROUND & AIMS: Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. In this post hoc analysis, induction and maintenance efficacy of etrasimod 2 mg versus placebo were assessed by baseline Mayo endoscopic subscore in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Moderate and severe endoscopic disease were defined as a centrally read endoscopic subscore of 2 and 3, respectively. Efficacy end points were evaluated at Weeks 12 (pooled population) and 52 (ELEVATE UC 52). Subgroup an…

Inhibition of advanced glycation end-products by the vitamin B6 vitamer pyridoxamine prevents systemic and skeletal muscle diet-induced metaflammation through modulation of S1P/RhoA/ROCK signalling.

The typical western diet contributes to the accumulation of Advanced Glycation End-products (AGEs), reactive compounds involved in metabolic alterations and low-grade inflammation, referred as metaflammation. AGEs affect sphingolipid metabolism increasing sphingosine-1-phosphate (S1P). S1P is in turn induces pro-inflammatory M1 macrophage polarization through activation of RhoA/ROCK. The current study seeks to determine whether inhibition of AGEs by the antiglycating vitamin B6 analog pyridoxamine prevents metaflammation via modulation of S1P/RhoA/ROCK signalling. Gastrocnemius muscle was obta…

Unveiling gastric precancerous stages: metabolomic insights for early detection and intervention.

BACKGROUND: Gastric precancerous lesions (GPL) represent a heterogeneous, multi-stage process that involves transition from a benign to a ma … us tissues than in normal tissues. A combination of glycerophosphocholine, tiglylcarnitine, malate, sphingosine, and γ-glutamylglutamic acid may serve as powerful biomarkers to distinguish normal tissue from GPL. CONCLUSION: We used ultra-high-performance liquid chromatography with tandem mass spectrometry to effectively characterize metabolomic profiles in …

The Effect of Etrasimod on Fecal Calprotectin and High-sensitivity C-reactive Protein: Results From the ELEVATE UC Clinical Program.

BACKGROUND: Biomarkers offer potential alternatives to endoscopies in monitoring ulcerative colitis (UC) progression and therapeutic response. This post hoc analysis of the ELEVATE UC clinical program assessed potential predictive values of fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) as biomarkers and associated responses to etrasimod, an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC, in 2 phase 3 clinical trials. METHODS: In ELEVATE UC 52 and ELEVATE UC 12, patients were ra…

The miR-29a/c-3p/HMCCR pathway is a potential mechanism by which chicken bursa of Fabricius responds to stress affecting immune response.

The bursa of Fabricius (BF), a central immune organ of birds, plays a critical role in immune regulation. Cholesterol metabolism is an impor … dynamic expression patterns and interrelationships of B cell receptor signaling subunit β (CD79B), sphingosine 1-phosphate receptor 1 (S1PR1), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genes in chicken BF were analyzed, and the miRNA regulatory mechanisms of cholesterol metabolism were further identified. The results showed that, under stress cond …

Evaluation and Characterization of Acute respiratory distress syndrome in tree shrews through TMT proteomic method.

Acute respiratory distress syndrome (ARDS), a common cause of acute fatal respiratory, is characterized by severe inflammatory lung injury a … atients also detail investigated for further analysis, such as ceruloplasmin (CP), hemopexin (HPX), sphingosine kinase 1 (SphK1), lactotransferrin (LTF), and myeloperoxidase (MPO) were upregulated in induced tissues and confirmed by western blot analysis. Overall, this study not only reveals a comprehensive proteomic analysis of the ARDS tree shrew model but …

Endoplasmic Reticulum Stress-Induced triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Downregulation Exacerbates Platelet Activation and Myocardial Infarction in Patients With Coronary Artery Disease.

BACKGROUND: Coronary artery disease is characterized by chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platel … ough reducing phosphatidylinositol (3,4,5)-trisphosphate levels and inhibiting Akt phosphorylation. Sphingosine-1-phosphate was identified as a physiological TREM2 agonist. CONCLUSIONS: TREM2 integrates ER stress, immune inflammation, and platelet function. ER stress-induced TREM2 downregulation contributes to platelet hyperactivation in coronary artery dise …

SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines.

BACKGROUND AND PURPOSE: Sphingosine-1-phosphate (S1P)/S1P receptor signalling exerts cardioprotective effects. However, the effect of the selective S1P1 receptor agonist SEW2871 on myocyte necroptosis in heart failure and the underlying mechanisms are unknown. In the present study, we tested the hypothesis that SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines. EXPERIMENTAL APPROACH: Eight-week-old male C57BL/6J mice underwent myocardial infarction (MI) or sham operation. The animals were randomized to receive SEW2871 (5 …

Финголимод как неевропащитный агент в ишемической истерике: обзор доклинических и клинических доказательств.

UNLABELLED: Ишемический инсульт по-прежнему является одной из основных причин смертности и инвалидности во всем мире, при этом нынешние методы лечения, такие, как внутривенный тромболиз и механическая тромбектомия, приносят пользу лишь ограниченному числу пациентов. Нейроинфламмация является одним из ключевых факторов вторичной травмы мозга, создавая веские основания для адъюнктивной терапии, нацеленной на иммунную модуляцию. Fingolimod, модулятор ффингосин-1-фосфатного рецептора (S1PR), первоначально утвержденный для множественного склероза, продемонстрировал многообещающий эффект как доклини

Совпадение в аннотации оригинала
UNLABELLED: Ischemic stroke remains a leading cause of mortality and disability worldwide, with current therapies such as intravenous thromb … ry, creating a strong rationale for adjunctive therapies targeting immune modulation. Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator originally approved for multiple sclerosis, has shown promising effects in both preclinical and early clinical studies of acute ischemic stroke. METHODS: We conducted a structured narrative review of preclinica …

Pentoxifylline in patients with ulcerative colitis treated with mesalamine by modulation of IL-6/STAT3, ZO-1, and S1P pathways: a randomized controlled double-blinded study.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that lasts a long time and has a variety of causes. AIM: The pri … ssess disease activity index (DAI) and numeric pain rating scale (NRS). Also, interleukin-6 (IL-6), sphingosine 1 phosphate (S1P), tumor necrosis factor-alpha (TNF-α), and fecal myeloperoxidase (MPO) were measured before and after therapy. Zonula occuldin-1 (ZO-1) and signal transducer and activator of transcription factor-3 (STAT-3) expression was assessed b …

Anti-hyperuricemia effect of Clerodendranthus spicatus: a molecular biology study combined with metabolomics.

Hyperuricemia (HUA), a metabolic disease caused by excessive production or decreased excretion of uric acid (UA), has been reported to be cl … nents, including 1-Palmitoyl-2-Arachidonoyl-sn-glycero-3-PE, Tyr-Leu and N-cis-15-Tetracosenoyl-C18-sphingosine, were identified as potential biomarkers for the UA-lowering effect of C. spicatus. In addition, pathway enrichment analysis revealed that arginine biosynthesis, biosynthesis of amino acids, pyrimidine metabolism and other metabolic pathways might b …

A non-targeted metabolomics comparative study on plasma of pfizer and sinopharm COVID-19 vaccinated individuals, assessed by (TIMS-QTOF) mass spectrometry.

UNLABELLED: COVID-19 is a highly contagious infectious disease that has posed a global threat, leading to a widespread pandemic characterize … he Sinopharm-vaccinated group, significant alterations were observed in sphinganine, neopterin, and sphingosine. These metabolites hold potential as biomarkers for evaluating vaccine efficacy. Additionally, both Pfizer and Sinopharm vaccinations were found to influence sphingolipid and histidine metabolisms compared to the control group. The Sinopharm group a …