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3-ketodihydrosphingosine reductase mutation induces steatosis and hepatic injury in zebrafish.

3-ketodihydrosphingosine reductase (KDSR) is the key enzyme in the de novo sphingolipid synthesis. We identified a novel missense kdsrI105R mutation in zebrafish that led to a loss of function, and resulted in progression of hepatomegaly to steatosis, then hepatic injury phenotype. Lipidomics analysis of the kdsrI105R mutant revealed compensatory activation of the sphingolipid salvage pathway, resulting in significant accumulation of sphingolipids including ceramides, sphingosine and sphingosine 1-phosphate (S1P). Ultrastructural analysis revealed swollen mitochondria with cristae damage in th…

Aberrant sphingolipid metabolism in the human fallopian tube with ectopic pregnancy.

Sphingosine 1-phosphate (S1P), a product of sphingomyelin metabolism, is generated via phosphorylation of sphingosine by sphingosine kinases (SphK). It acts via a family of G protein-coupled receptors or as an intracellular second messenger for agonists acting through the S1P receptors (S1P1-5). In our study, the expression of SphK1 and S1P1 was identified by immunohistochemistry and immunoblot. The concentration of S1P was measured using ELISA. The spontaneous contraction of isolated fallopian tube strips was determined by tension recording. Our results showed that SphK1 and S1P1 were localiz…

S1PR1-Overexpressing Membrane-Coated Nanoparticles Inhibit Dedifferentiation Progression for the Treatment of Anaplastic Thyroid Carcinoma by Targeting the ACER3/SPHK1/S1P Pathway.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with a poor prognosis, characterized by dedifferentiation and aberrant angiogenesis. Through integrated analysis of TCGA and GEO transcriptomic data and single-cell RNA sequencing, this study identified significant enrichment of angiogenesis-related genes (ARGs), particularly sphingosine kinase 1 (SPHK1), in malignant cell subpopulations of ATC. Functional investigations revealed that alkaline ceramidase 3 (ACER3) cooperates with SPHK1 within the sphingolipid metabolic pathway to promote ATC progression. The SPHK1-specific in…

Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1.

Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disea…

The role of the sphingolipid pathway in liver fibrosis: an emerging new potential target for novel therapies.

Sphingolipids (SL) are a family of bioactive lipids and a major cellular membrane structural component. SLs include three main compounds: ceramide (Cer), sphingosine (Sp), and sphingosine-1-phosphate (S-1P), all of which have emerging roles in biological functions in cells, especially in the liver. They are under investigation in various liver diseases, including cirrhosis and end-stage liver disease. In this review, we provide an overview on the role of SLs in liver pathobiology and focus on their potential role in the development of hepatic fibrosis. We describe recent evidence and suggest S…

Fingolimod modulates microglial activation to augment markers of remyelination.

INTRODUCTION: Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells. METHODS: In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate…

Intracellular S1P Levels Dictate Fate of Different Regions of the Hippocampus following Transient Global Cerebral Ischemia.

Sphingosine-1-phosphate (S1P) is a sphingolipid molecule produced by the action of sphingosine kinases (SphK) on sphingosine. It possesses various intracellular functions through its interactions with intracellular proteins or via its action on five G-protein-coupled cell membrane receptors. Following transient global cerebral ischemia (tGCI), only the CA1 subregion of the hippocampus undergoes apoptosis. In this study, we evaluated S1P levels and S1P-processing enzyme expression in different hippocampal areas following tGCI in rats. We found that S1P was upregulated earlier in CA3 than in CA1…

Sphingolipids in Lung Pathology in the Coronavirus Disease Era: A Review of Sphingolipid Involvement in the Pathogenesis of Lung Damage.

Sphingolipids are bioactive lipids involved in the regulation of cell survival, proliferation, and the inflammatory response. The SphK/S1P/S1PR pathway (S1P pathway) is a driver of many anti-apoptotic and proliferative processes. Pro-survival sphingolipid sphingosine-1-phosphate (S1P) initiates its signaling cascade by interacting with various sphingosine-1-phosphate receptors (S1PR) through which it is able to exert its pro-survival or inflammatory effects. Whereas sphingolipids, including ceramides and sphingosines are pro-apoptotic. The pro-apoptotic lipid, ceramide, can be produced de novo…

Role of ceramide as a lipid mediator of 1 alpha,25-dihydroxyvitamin D3-induced HL-60 cell differentiation.

The treatment of HL-60 myelocytic leukemia cells with 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) resulted in the activation of a neutral … d HL-60 cell differentiation independent of 1,25-(OH)2D3. A 2-h exposure of HL-60 cells to N-acetyl-sphingosine was sufficient to cause differentiation. Morphologically, N-acetylsphingosine caused a similar monocytic differentiation of HL-60 cells as did 1,25-(OH)2D3. Exogenous ceramide was further metabolized to sphingomyelin and other sphingolipids, but no …

Sphingolipids as multifaceted mediators in ovarian cancer.

Ovarian cancer is the most lethal gynaecological malignancy. It is commonly diagnosed at advanced stage when it has metastasised to the abdo … o promote chemoresistance and metastasis in a wide range of malignant neoplasms. In particular, the sphingosine kinase 1-sphingosine 1-phosphate receptor 1 axis has been shown to be altered in ovarian cancer in multiple ways and therefore represents an attractive therapeutic target. Here we review the roles of sphingolipids in ovarian cancer progression, meta …

Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.

Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofibe … on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle at …

Sphingosylphosphorylcholine is a substrate for the Pseudomonas aeruginosa phospholipase C/sphingomyelinase, PlcH.

Sphingolipids are critical to eukaryotic cell membrane structure and function and play important roles in a variety of host processes that i … erate phosphocholine and ceramide, and analogously, we demonstrate here that PlcH hydrolyzes SPC to sphingosine and, putatively, phosphocholine. We provide evidence that SPC induction of PlcH is primarily regulated by the sphingosine-responsive SphR regulator and that resultant sphingosine liberated from SPC induces transcription from the other genes in the S …

Isoliquiritin ameliorates rheumatoid arthritis by inhibiting S1P synthesis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation and pain, often leading to joint deformity and functional impairment. By comparing serum metabolic profiles between 50 pairs of RA patients and healthy controls, we identified aberrant expression of sphingosine-1-phosphate (S1P) in RA patient serum, which was closely associated with inflammatory and autoimmune responses. Through integrated bioinformatic analysis and in vitro/in vivo experiments, we demonstrated that isoliquiritin (ISL) binds to protein kinase C (PRKC), thereby inhibiting the activati…

Этрасимод: Обзор соображений безопасности и практического управления новой пероральной терапией для лечения язвительного колита.

Модуляция рецепторов фингозина-1-фосфата представляет собой относительно недавний подход к лечению подстрекательского кишечника, хотя эти модуляторы были утверждены с 2010 года для других подстрекательских заболеваний, таких, как множественный склероз. Etrasimod — модульный рецептор с фингозином-1-фосфатом (S1PR), связывающий его с рецепторами S1PR1, S1PR4 и S1PR5, и его эффективность была продемонстрирована при лечении умеренно-суперактивного язвительного колита. Это небольшая молекула и синтетический препарат, применяемый в устной форме, с надлежащей биодоступностью и быстрой скоростью уничт

Совпадение в аннотации оригинала
Modulation of sphingosine-1-phosphate receptors represents a relatively recent approach in the treatment of inflammatory bowel disease, although these modulators have been approved since 2010 for other inflammatory conditions such as multiple sclerosis. Etrasimod is a sphingosine-1-phosphate receptor (S1PR) modulator that binds to S1PR1, S1PR4 and S1PR5 rece…

Ceramide signaling in the gut.

Sphingolipids are essential lipid components in the intestinal epithelial cells (IEC) along the intestinal tract. They play crucial roles in maintaining barrier integrity, regulating nutrient absorption, and acting as signaling molecules to regulate regeneration and differentiation of intestinal mucosa (Kurek et al., 2012). Ceramide is the central sphingolipid species and the precursor of all complex sphingolipids and other downstream simple intermediates like sphingosine (SPH), ceramide-1-phosphate (C-1-P), and sphingosine-1-phosphate (S-1-P). It is also a critical signaling molecule regulati…

Targeting the SPHK1/S1P/S1PR2 axis ameliorates GH-secreted pituitary adenoma progression.

BACKGROUND: Growth hormone-secreted pituitary adenoma (GHPA) is a prominent subtype of pituitary adenoma (PA) associated with progressive somatic disfigurement, various complications, and elevated mortality rates. Existing treatment options have limited efficacy, highlighting the urgent need for novel pharmacological interventions. Previous studies have revealed that sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/S1P receptors (S1PRs) signalling have critical roles in the tumour microenvironment, but their role in GHPA remains unclear. METHODS: We performed integrative analyses in…

FTY720 alleviates HBV-mediated inflammatory liver injury through a dual role of inhibiting lymphocyte trafficking and viral replication.

BACKGROUND: The host immune response plays a critical role in clearing hepatitis B virus infection. However, in chronic hepatitis B, this response fails to eliminate the virus, leading to recurrent inflammation, liver tissue damage, and a gradual progression from hepatitis to fibrosis, and eventually, hepatocellular carcinoma. Reducing liver injury while enhancing antiviral efficacy remains a key objective in hepatitis B virus treatment development. Our previous research revealed a close association between hepatitis B virus infection and the sphingosine 1-phosphate signaling pathway. Conseque…

FAM46C Expression Sensitizes Multiple Myeloma Cells to PF-543-Induced Cytotoxicity.

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) are key regulators of sphingolipid signaling, a pathway essential for maintaining cell structure and function but frequently deregulated in tumors, making them promising targets for cancer therapy. Preliminary work from our laboratory showed that FAM46C expression synergizes with admini…

Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer's disease.

Lipid metabolism is abnormal in Alzheimer's disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1-3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here …

The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.

BACKGROUND: In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely. OBJECTIVE: A Xenopus tra … ocytes per optic nerve. RESULTS: Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 gene editing showed that the promyelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5. CONCLUSION: This Xenopus transgenic line …