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Second United Arab Emirates consensus guidance on the diagnosis and management of inflammatory bowel disease.

The second edition of the United Arab Emirates inflammatory bowel disease (IBD) consensus guidance provides updated recommendations for diag … . Key updates feature guidance on newer pharmacologic therapies - interleukin-23, Janus kinase, and sphingosine-1-phosphate receptor inhibitors - with refined therapeutic positioning informed by recent head-to-head trials. The consensus emphasizes early, effective treatment to prevent irreversible bowel damage, optimization strategies like therapeutic drug mo …

Exploratory analyses of leukocyte responses in hospitalized patients treated with ozanimod following a severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection.

Sphingosine-1-phosphate receptor 1 (S1P1) ligands effectively reduce immunopathological damage in viral pneumonia models. Specifically, S1P1 ligands inhibit cytokine storm and help preserve lung endothelial barrier integrity. We recently showed that the S1P receptor ligand ozanimod can be safely administered to hospitalized patients with coronavirus disease 2019 (COVID-19) exhibiting severe symptoms of viral pneumonia, with potential clinical benefits. Here, we extend on this study and investigate the impact of ozanimod on key features of the immune response in patients with severe COVID-19. W…

Mas Signaling Potentiates Neutrophil Extracellular Traps Formation Induced by Endothelial Cells Derived S1P in Mice with Acute Liver Failure.

Mas, a newly identified G-protein-coupled receptor, is prevalent in myeloid-derived immune cells and plays a key role in inflammation. This … xycholic acid (DCA) production in Mas1-/- activated hepatic farnesoid X receptor (FXR), suppressing sphingosine-1-phosphate (S1P)-dependent NETs. Additionally, Mas1-/- also activates the FXR-S1P-NETs axis in the liver by inhibiting SHP2. Single-cell sequencing shows decreased interaction between endothelial cells and Cldn1+CD177+ senescent neutrophils through …

Delineating the intricacies of polymorphisms, structures, functions and therapeutic applications of biological high-density lipoprotein-apolipoprotein M: A review.

Apolipoprotein-M (ApoM), primarily associated with high-density lipoproteins (HDL), plays a crucial role in lipid metabolism and cardiovascular health. It facilitates the transport of lipids such as cholesterol and sphingosine-1-phosphate (S1P), contributing to reverse cholesterol transport (RCT), which removes excess cholesterol from peripheral tissues to the liver for excretion. Through its association with HDL and S1P, ApoM exerts anti-inflammatory, anti-thrombotic, and anti-apoptotic effects. The ApoM-S1P complex regulates various cellular, immunological, and physiological processes via S1…

Sphingolipids and Male Reproductive Health: A Narrative Review of Their Roles in Spermatogenesis, Fertility, and Dysfunction.

Sphingolipids are bioactive lipids involved in cellular signaling and structural processes. Recent studies highlight their critical role in spermatogenesis, sperm functionality, and male infertility. Key sphingolipid metabolites, such as ceramide, ceramide-1-phosphate, and sphingosine-1-phosphate, mediate signaling pathways related to apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, aging, and differentiation. This review aims to summarize recent advancements in understanding the roles of sphingolipids in spermatogenesis, sperm motility, capacitation, the acrosome…

Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is primarily driven by the BCR::ABL1 oncoprotein, which has potent tyrosine kinase activity. BCR::ABL1 has be … d survival fate of K562 cells compared to thiamine metabolism inhibition. Furthermore, knockdown of sphingosine kinase 1 (SPHK1) resulted in extensive metabolic remodeling, affecting lipid, energy, and heme metabolism. Pharmacological targeting of sphingolipid metabolism appeared to attenuate the development of CML. Our study also demonstrated that BCR::ABL1 …

Активация S1PR1 Ponesimod for Multical Sclerosis Therapy: Unpening MAPK и PI3K Pathway Mechanisms и Repuring Potential.

Множественный склероз (МС), затрагивающий более 2 миллионов человек во всем мире, в первую очередь вызывает неврологические расстройства у лиц в возрасте до 40 лет. Это аутоиммунное расстройство включает в себя иммунную систему, атакующую миелиновую оболочку в центральной нервной системе. Сфингосин-1-фосфатный рецептор 1 (S1PR1) является многообещающей терапевтической целью, и утвержденные лекарства, такие как понизимод, выступают в качестве агонистов S1PR1. Однако точный механизм действий Понсимода в отношении S1PR1 и его терапевтических последствий в РС остается неясным. Наше исследование, с

Совпадение в аннотации оригинала
Multiple sclerosis (MS), affecting over 2 million people globally, primarily causes neurological disability in individuals under 40. This autoimmune disorder involves the immune system attacking the myelin sheath in the central nervous system. Sphingosine-1-phosphate receptor 1 (S1PR1) is a promising therapeutic target, with approved drugs like ponesimod act…

Case Report: Asymptomatic macular edema in ozanimod.

We report the case of a 61-year-old patient with relapsing-remitting multiple sclerosis (RRMS) who developed asymptomatic macular edema (ME) after initiation of ozanimod, a sphingosine-1-phosphate receptor (S1PR) modulator. The patient had a history of completely resolved central serous choroidopathy (CSC) in the right eye. Following a recent clinical worsening and a new brain lesion, ozanimod was started after appropriate screening, including ophthalmological evaluation. Three months into treatment, an OCT performed as part of routine monitoring revealed ME in the contralateral (left) eye, de…

Untargeted Metabolomic Study of Patients with Wet Age-Related Macular Degeneration in Aqueous Humor.

PURPOSE: The objective of this study was to ascertain metabolic biomarkers and investigate the metabolic alterations associated with aqueous … Ceramides (Cer) (d32:0), Cer (d34:0), Cer (d36:0), Monogalactosyldiacylglycerol (MGDG) (16:1_18:3), Sphingosine (SPH) (d18:0) and TG (16:0_10:4_16:0) was down regulated. CONCLUSION: Through metabolomics analysis of AH, this study successfully uncovered valuable metabolic biomarkers linked to wet AMD. These findings contribute to a more comprehensive understa …

Repurposing the multiple sclerosis drug Siponimod for osteoporosis treatment.

Osteoporosis is the most common bone disorder, in which an imbalance between osteoclastic bone resorption and osteoblastic bone formation disrupts bone homeostasis. Osteoporosis management using anti-osteoclastic agents is a promising strategy; however, this remains an unmet need. Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are essential for maintaining bone homeostasis. Here, we identified that Siponimod, a Food and Drug Administration-approved S1PR antagonist for the treatment of multiple sclerosis, shows promising therapeutic effects against osteoporosis by inhibiting osteoclast…

Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.

Sirtuin-3 (Sirt3) deacetylates several mitochondrial proteins implicated into cerebral ischemia/reperfusion (I/R) injury. The mitochondrial … dria against brain post-ischemic malfunction via eliciting the UPRmt by the forkhead box O3 (Foxo3)/sphingosine kinase 1 (Sphk1) pathway. Inhibiting either the UPRmt or the Foxo3/Sphk1 pathway relieved the favorable influence of Sirt3 on neural function and mitochondrial behavior. In contrast, Sphk1 overexpression was sufficient to reduce the infarction size, …

Dasatinib-induced spleen contraction leads to transient lymphocytosis.

The tyrosine kinase inhibitor dasatinib is approved for Philadelphia chromosome-positive leukemia, including chronic myeloid leukemia (CML). … ymphocytosis. Unexpectedly, dasatinib-induced lymphocyte egress occurred independently of canonical sphingosine-1-phosphate-mediated egress signals; instead, dasatinib treatment led to a decrease in spleen size, concomitant with increased splenic stromal cell contractility, as measured by myosin light chain phosphorylation. Accordingly, dasatinib-induced lymp …

Switching to ozanimod as a strategy to adjust fingolimod-related lymphopenia.

INTRODUCTION: Fingolimod is a disease-modifying therapy for multiple sclerosis (MS) that modulates sphingosine 1-phospate receptors, impeding the egress of lymphocytes from lymphnodes and thus causing lymphopenia. Severe lymphopenia should lead to fingolimod discontinuation. We aim to evaluate whether switching from fingolimod to ozanimod can adjust fingolimod-related lymphopenia while maintaining clinical efficacy. METHODS: In this real-world observational study, we included 18 people with MS (47.7 ± 7.6 years of age, 77.8 % of women, 13.9 ± 6.9 years of disease duration, median EDSS 3.0) at…

Characterization of the Sphingolipidome of the Peri-Infarct Tissue during Hemorrhagic Transformation in a Mouse Model of Cerebral Ischemia.

BACKGROUND: Cardiovascular diseases like stroke cause changes to sphingolipid mediators like sphingosine 1-phosphate (S1P) or its ceramide analogs, which bear the potential to either alleviate or exacerbate the neurological damage. Therefore, the precise identification of alterations within the sphingolipidome during ischemic stroke (IS) and hemorrhagic transformation (HT) harbors a putative therapeutic potential to orchestrate local and systemic immunomodulatory processes. Due to the scarcity of research in this field, we aimed to characterize the sphingolipidome in IS and HT. METHODS: C57BL…

Testosterone improved erectile function by upregulating transcriptional expression of growth factors in late androgen replacement therapy model rats.

We previously showed that castration of rats reduced erectile function over time; when testosterone replacement therapy was started 4 weeks … uscle actin (α-SMA), caveolae associated protein 1 (Cavin-1), Cavin-2, Cavin-3, sirtuin 1 (Sirt-1), sphingosine-1-phosphate 1 (S1P1), S1P2, and S1P3 and eNOS protein expression. Testosterone replacement therapy improved erectile function in castrated rats by increasing growth factors and eNOS protein.

Evaluation of Serologic Changes of IgG and IgM Antibodies Associated with SARS-COV-2 in Cancer Patients: A Cohort Seroprevalence Study.

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosph…

Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients.

Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects o … ent fails to alter blood-brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.

Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway.

Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1-phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post-TAC hearts. Endothelial-specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated…

Anti-epileptogenic and Anti-convulsive Effects of Fingolimod in Experimental Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) represents a devastating neurological condition, in which approximately 4/5 of patients remain refractory for anti-convulsive drugs. Epilepsy surgery biopsies often reveal the damage pattern of "hippocampal sclerosis" (HS) characterized not only by neuronal loss but also pronounced astrogliosis and inflammatory changes. Since TLE shares distinct pathogenetic aspects with multiple sclerosis (MS), we have here scrutinized therapeutic effects in experimental TLE of the immunmodulator fingolimod, which is established in MS therapy. Fingolimod targets sphingosine-phosph…

Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes.

When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distende … , allowing them to infect new neighboring cell targets. Dying macrophages also produced chemotactic sphingosine 1-phosphate, enhancing cell-to-cell contact, further promoting infection. This necroptosis-driven expansion of infected macrophages in buboes maximized the number of bacteria-bearing macrophages reaching secondary lymph nodes, leading to sepsis. In …