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Pharmacodynamics of the S1P1 receptor modulator cenerimod in a phase 2b randomised clinical trial in patients with moderate to severe SLE.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoreactive T and B lymphocytes. Sphingosine-1- phosphate (S1P) is involved in lymphocyte egress from peripheral lymphoid organs into the circulation. In phase 2a clinical trial, the potent, selective S1P1 receptor modulator cenerimod reduced circulating antibody-secreting cells and interferon (IFN)-associated biomarkers. OBJECTIVES: Pharmacodynamic effects of 2 and 4 mg cenerimod were evaluated in the phase 2b clinical trial (CARE) in moderate to severe patients with SLE (NCT03742037). METHODS: …

Etrasimod reduces circulating and mucosal inflammatory lymphocyte populations and alters innate immune and non-immune cell signatures in intestinal mucosa: ELEVATE UC phase 3 clinical data.

BACKGROUND AND AIMS: Innate and adaptive immune cell dysregulation contributes to ulcerative colitis pathogenesis. The sphingosine 1-phosphate receptor modulator etrasimod showed efficacy in ulcerative colitis treatment in Phase 3 ELEVATE UC studies. Changes in circulating immune cells and mucosal cell types were characterized in etrasimod-treated patients with ulcerative colitis. METHODS: Blood (etrasimod n = 525, placebo n = 257 patients) and mucosal biopsies (etrasimod n = 411, placebo n = 200 patients) from patients in the ELEVATE UC trials were used to assess cellular and molecular chang…

Comparison of the Antimicrobial Properties of Nanoemulsions Made from Phytosphingosine and Chitosan with a Triple Antibiotic Paste Against Enterococcus faecalis in Endodontics: An in-vitro Study.

PURPOSE: Aerobic and facultative anaerobic bacteria are most commonly found in failed root canal cases. Among those, Enterococcus faecalis ( … . The purpose of the study is to compare the antimicrobial efficacy of intracanal medications, Phytosphingosine nano-emulsion (PHSN), Chitosan nano-emulsion (CHN), and Triple Antibiotic Paste (TAP) against E. faecalis in endodontics. PATIENTS AND METHODS: Assuming the Minimum Inhibitory Concentration (MIC) of 15.93 and SD 1.53 with estimated error of 1, 80% …

Лечение воспаления кишечника и обезвоживание болезней: практическое руководство по терапевтическим выгодам и рискам.

Демиелионирующие заболевания, особенно множественный склероз (МС), представляют собой уникальную терапевтическую проблему в борьбе с подстрекательским кишечным заболеванием (ИБД). Несмотря на свою редкость, совпадение IBD и демиелионирующих расстройств хорошо задокументировано и может отражать общие иммунные, генетические и экологические факторы риска. По мере расширения терапевтического ландшафта IBD, включая биологию и небольшие молекулы, которые нацелены на иммунные пути, также связанные с MS, растет озабоченность по поводу неврологической безопасности. В частности, противомоскитные некрозн

Совпадение в аннотации оригинала
Demyelinating diseases, particularly multiple sclerosis (MS), present a unique therapeutic challenge in the management of inflammatory bowel … consistently linked to new-onset or worsening demyelinating events, while other treatments such as sphingosine-1-phosphate receptor modulators and natali-zumab are licensed for both IBD and MS, though real-world data in patients with coexisting disease remain limited. This review synthesizes current evidence regarding the neurological safety and efficacy of …

Compression force regulates cementoblast mineralization via S1PR1/mitophagy axis.

Orthodontically induced inflammatory root resorption (OIIRR) poses a significant clinical challenge, as excessive orthodontic force shortens tooth longevity by impairing cementoblast-mediated cementum mineralization and promoting root resorption. Cementoblasts, essential for mineralized cementum formation and resistance to resorption, exhibit altered mechanosensitivity and mechanotransduction under orthodontic force, yet the role of mitophagy in this process remains poorly understood. In this study, we investigated how the S1PR1/mitophagy axis modulates cementoblast mineralization and OIIRR pr

Identification of a Specific Plasma Sphingolipid Profile in a Group of Normal-Weight and Obese Subjects: A Novel Approach for a "Biochemical" Diagnosis of Metabolic Syndrome?

Metabolic syndrome is nosographically defined by using clinical diagnostic criteria such as those of the International Diabetes Federation ( … amides (HexCer), lactosyl-ceramides (LacCer), sphingomyelins (SM) and GM3 ganglosides families, and sphingosine-1-phosphate (S1P) and its congeners, was performed in plasma. Only total DHCers and S1P were significantly higher in OB-SIMET+ than NW subjects (p < 0.05), while total Cers decreased in both obese groups, though statistical significance was reached …

Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF-β signaling pathway.

The hepatic vascular niche plays an important role in the pathological process of liver fibrosis. Liver sinusoidal endothelial cells (LSECs) predominantly compose hepatic vascular niches. Endothelial cell (EC)-expressing sphingosine 1-phosphate receptor 2 (S1pr2) plays an essential role in the regulation of vascular functions. Nevertheless, it remains unknown whether liver LSEC-S1pr2 might modulate pathological liver fibrosis. In this study, liver fibrosis was induced by hepatotoxin carbon tetrachloride (CCl4 ). The expression of S1pr2 is significantly downregulated in liver sinusoidal endothe…

Investigation of the Genotoxic Potential of the Marine Toxin C17-SAMT Using the In Vivo Comet and Micronucleus Assays.

The contaminant responsible for the atypical toxicity reported in mussels from Bizerte Lagoon (Northern Tunisia) during the last decade has been characterized as C17-sphinganine analog mycotoxin (C17-SAMT). This neurotoxin showed common mouse toxic symptoms, including flaccid paralysis and severe dyspnea, followed by rapid death. For hazard assessment on human health, in this work we aimed to evaluate the in vivo genotoxic effects of this marine biotoxin using the classical alkaline and modified Fpg comet assays performed to detect DNA breaks and alkali-labile sites as well as oxidized bases.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. OBJECTIVE: To characterize long-term safety and efficacy of ozanimod. METHODS: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. RESULTS: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DA…

Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses.

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has d…

Targeting synaptic pathology in multiple sclerosis: fingolimod to the rescue?

Multiple sclerosis (MS) is an inflammatory disorder affecting the brain and spinal cord. Major hallmarks of MS typically include inflammation, demyelination and axon degeneration, although recent studies have also implicated synaptic dysfunction and degeneration in disease pathogenesis. The discovery that treatment with the orally active immunomodulatory drug fingolimod (FTY720) confers benefits in animal models and human patients has opened up new avenues for the treatment of MS. In the present issue of the BJP, Rossi and colleagues used a mouse model of MS [experimental autoimmune encephalom

CEBPD-mediated SGPP2 upregulation via PERK/ER stress in endothelial cells disrupts S1P homeostasis and impairs angiogenesis in chronic endometritis.

BACKGROUND: Chronic endometritis (CE) is a persistent inflammatory condition associated with adverse pregnancy outcomes. Although impaired e … dicated dysregulation of sphingolipid metabolism in CE patients. ELISA revealed decreased levels of sphingosine-1-phosphate (S1P) in the endometrium of CE patients and in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). Functional assays including tube formation, wound healing, and transwell invasion were performed to evaluate …

Next generation sequencing and RNA-seq characterization of adipose tissue in the Nile crocodile (Crocodylus niloticus) in South Africa: Possible mechanism(s) of pathogenesis and pathophysiology of pansteatitis.

BACKGROUND: Concerted efforts to identify the pathogenesis and mechanism(s) involved in pansteatitis, (a generalized inflammation of the adi … ssociated with spinal and lower extremity muscle atrophy was also upregulated in pansteatitis while Sphingosine -1-phosphate phosphatase 2 (SGPP2) involved in Sphingosine -1- phosphate metabolism was downregulated. Futhermore, Doublesex-mab-related transcription factor 1 (DMRT1) responsible for sex gonad development and germ cell differentiation was also down …

Response of growing swine to dietary exposure to pure fumonisin B1 during an eight-week period: growth and clinical parameters.

Consumption of corn or corn-based products contaminated with Fusarium moniliforme/fumonisins has been associated with a variety of animal an … re measured. Because fumonisins are potent inhibitors of sphingolipid biosynthesis, sphinganine and sphingosine concentrations were determined in the liver, lung, and kidney. Organ weights and carcass quality were measured at the end of the trial. In general, male pigs were more adversely affected by FB1 in the diet than females. The average daily gain for ma …

COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: There are limited data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine reactogenicity in … with more physical impairment and lower odds of reactions for PwMS on an alpha4-integrin blocker or sphingosine-1-phosphate receptor modulator. In 442 PwMS who received their second vaccination shot, 74% reported experiencing a reaction, whereas 22% reported a severe reaction. Reaction profiles after the second shot were similar to those reported after the fi …

Enzymatic hydrolysis of fumonisins in the gastrointestinal tract of broiler chickens.

Fumonisins (FB) are among the most frequently detected mycotoxins in feedstuffs and finished feed, and recent data suggest that the function … he degree of reduction of FB in the GIT, 2 characteristics were analyzed. First, the sphinganine-to-sphingosine ratio in the serum and liver was determined as a biomarker of effect for exposure to FB. Second, the concentration of fumonisin B1 and its hydrolyzed forms was evaluated in the gizzard, the proximal and distal parts of the small intestine, and the e …

In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis.

BACKGROUND: Strongyloidiasis is a parasitic disease widely present in tropical and subtropical areas. Strongyloides stercoralis represents the main species that infects human beings. Ivermectin is the current drug of choice; however, issues related with treatment failure in patients with diabetes or infected with T-lymphotropic virus-1 make the identification of new molecules for alternative treatment a priority. In the present study, the activity of sphingosine-related aminoalcohol and diamine were evaluated against Strongyloides venezuelensis third-stage larva (L3) cultures and experimental …

A genome-wide CRISPR/Cas9 screen reveals novel positive regulators of FTY720 sensitivity in acute lymphoblastic leukemia cells.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Fingolimod (FTY720) is a sphingosine-1-phosphate (S1P) receptor agonist that prevents lymphocytes from egressing from lymphoid tissues and has shown a cytotoxic effect on T-cell ALL (T-ALL) cells. However, the mechanism of action of FTY720 cytotoxicity in hematological malignancies is still unclear, and cell-specific effects have been reported. Here, we investigated the mechanism of cytotoxicity of FTY720 in T-ALL cells using a CRISPR-Cas9 genomic screening. Our goal was to identify novel positive regula…

Etrasimod: A Next-Generation S1P Receptor Modulator for Ulcerative Colitis - Mechanistic Insights and Clinical Progress.

Etrasimod, a next-generation oral selective sphingosine-1-phosphate (S1P) receptor modulator, has emerged as a promising treatment for immune-mediated inflammatory diseases (IMIDs), most notably moderate-to-severe ulcerative colitis (UC). Acting primarily on S1PR1, S1PR4, and S1PR5, etrasimod effectively reduces gastrointestinal inflammation by retaining lymphocytes in lymphoid tissues, thereby minimising systemic immunosuppression and associated risks. Etrasimod provides better safety, a favorable pharmacokinetic profile, and a short washout period when compared to first-generation modulators…

[11C]CS1P1 PET links T-cell-associated immune activation with endothelial and astrocytic responses.

Neuroimmune signaling across the peripheral-vascular-glial axis is increasingly recognized as a driver of both age-related brain vulnerability and the earliest stages of neurodegenerative disease, including Alzheimer disease. Evaluating this axis in vivo remains challenging due to limited neuroinflammatory imaging biomarkers. We utilized [11C]CS1P1 positron emission tomography (PET) to quantify sphingosine-1-phosphate receptor 1 (S1PR1) availability alongside plasma proteomics in 42 cognitively normal individuals (age 21-82). Through differential abundance analysis and structural equation mode…