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Clinical Significance of Plasma Sphingosine-1-Phosphate Decline in Progression of Spinal and Bulbar Muscular Atrophy.

BACKGROUND AND PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked neuromuscular disorder characterized by slowly progressive motor decline. However, there is no specific fluid marker that reflects the severity or progression of the disease. Therefore, identifying measurable markers that reflect disease progression remains a major unmet need in SBMA management. METHODS: Plasma samples from 21 Korean patients with SBMA were collected at baseline and after 3 years. Untargeted and targeted metabolomics profiling was performed, and plasma sphingosine-1-phosphate (S1P) was the fi…

Оценка зависящего от шпинстера гомолога 2 (Spns2) переноса фингозина-1-фосфата в качестве терапевтической цели.

СФИННОСИН-1-Фосфат (S1P) рецепторный модулятор (СРМ), подавляющий функционирование иммунной системы путем пресечения незаконного оборота лимфоцитов. Другой стратегией модуляции иммунной системы является блокирование переноса S1P. В этом исследовании проверяется гипотеза о том, что блокаторы S1P-перевозок (STBs) при посредничестве гомолога 2 (Spns2) приближают эффективность SRM без их неблагоприятного воздействия. ЭКСПЛУАТАЦИОННЫЙ ПОДХОД: Мы обнаружили и оптимизировали СТБ, с тем чтобы можно было исследовать биологию S1P и определить, является ли транспорт S1P законной целью. СТБ SLF80821178 бы

Совпадение в аннотации оригинала
BACKGROUND AND PURPOSE: Sphingosine-1-phosphate (S1P) receptor modulator (SRM) drugs suppress immune system function by disrupting lymphocyte trafficking, but SRMs are broadly immunosuppressive with on-target liabilities. Another strategy to modulate the immune system is to block S1P transport. This study tests the hypothesis that blockers of S1P transport (…

Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection leads to hyper-inflammation and amplified immune response in severe cases that may progress to cytokine storm and multi-organ injuries like acute respiratory distress syndrome and acute lung injury. In addition to pro-inflammatory cytokines, different mediators are involved in SARS-CoV-2 pathogenesis and infection, such as sphingosine-1-phosphate (S1P). S1P is a bioactive lipid found at a high level in plasma, and it is synthesized from sphingomyelin by the action of sphingosine kinase. It is involved in inflammation, …

Effect of sphingosine and phytosphingosine ceramide ratio on lipid arrangement and barrier function in skin lipid models.

The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main subclasses in the SC lipid matrix are ceramides (CER), cholesterol, and free fatty acids. In inflammatory skin diseases, such as atopic dermatitis and psoriasis, the SC lipid composition is modulated compared to the composition in healthy SC. One of the main alterations is the molar ratio between the concentration of CER N-(tetracosanoyl)-sphingosine (CER NS) and CER N-(tetracosanoyl)-phytosphingosine (CER NP), which correlated with an impaired skin barri…

Hypogelsolinemia and Decrease in Blood Plasma Sphingosine-1-Phosphate in Patients Diagnosed with Severe Acute Pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a frequent hospitalization cause of patients suffering from gastrointestinal disorders. Gelsolin has an ability to bind bioactive lipids including different sphingolipids engaged in inflammatory response. Importantly, hypogelsolinemia was observed in patients with different states of acute and chronic inflammation. AIMS: The aim of the present study was to assess the interplay of blood plasma gelsolin and blood plasma sphingosine-1-phosphate (S1P) concentration in patients diagnosed with acute pancreatitis. MATERIALS AND METHODS: To assess the concentra…

Anti-hyperalgesic effects of two sphingosine derivatives in different acute and chronic models of hyperalgesia in mice.

BACKGROUND: The study evaluated the effects of two sphingosine derivatives N-(2-tert-butoxycarbamylhexadecyl)glutaramide (AA) and N-(1-benzyloxyhexadec-2-yl)glutaramide (OA) in different models of hypersensitivity in mice. METHODS: Male Swiss mice were orally pre-treated with AA or OA (0.3-3mg/kg). After 1h, they received λ-carrageenan (300μg/paw), lipopolysaccharide (LPS; 100ng/paw), bradykinin (BK; 500ng/paw) or prostaglandin E2 (PGE2; 0.1nmol/paw) or epinephrine (100ng/paw), and the mechanical withdrawal thresholds were evaluated using von Frey filament (0.6g) at different time points. The…

Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo.

Sphingosine-1-phospate is a potent bioactive lipid metabolite that regulates cancer progression. Because sphingosine kinase 1 and sphingosine kinase 2 (SPHK 1/2) are both essential for sphingosine-1-phospate production, they could be a therapeutic target in various cancers. Peretinoin, an acyclic retinoid, inhibits post-therapeutic recurrence of hepatocellular carcinoma via unclear mechanisms. In this study, we assessed effects of peretinoin on SPHK expression and liver cancer development in vitro and in vivo. We examined effects of peretinoin on expression, enzymatic and promoter activity of …

Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.

The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 …

Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators.

Sphingosine kinase 1 (SK1) is over-expressed in many cancers where it provides a selective growth and survival advantage to these cells. SK1 is thus a target for anti-cancer agents that can promote apoptosis of cancer cells. In previous work, we synthesized a novel allosteric SK1 inhibitor, (S)-FTY720 vinylphosphonate. We now report a more expeditious route to this inhibitor which features B-alkyl Suzuki coupling as a key step and show that replacement of the amino group in (S)-FTY720 vinylphosphonate with an azido group converts the vinylphosphonate from an allosteric inhibitor to an activato…

The Sjögren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway.

Sphingosine 1-phosphate (S1P) functions not only as a bioactive lipid molecule, but also as an important intermediate of the sole sphingolipid-to-glycerolipid metabolic pathway. However, the precise reactions and the enzymes involved in this pathway remain unresolved. We report here that yeast HFD1 and the Sjögren-Larsson syndrome (SLS)-causative mammalian gene ALDH3A2 are responsible for conversion of the S1P degradation product hexadecenal to hexadecenoic acid. The absence of ALDH3A2 in CHO-K1 mutant cells caused abnormal metabolism of S1P/hexadecenal to ether-linked glycerolipids. Moreover,…

Modulation of human arterial tone during pregnancy: the effect of the bioactive metabolite sphingosine-1-phosphate.

Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that has been implicated in cardiovascular disease. The objective of the present study was to determine the vasoactive effects and underlying mechanisms of S1P on adult human maternal arteries. The isometric tensions of the omental and myometrial arteries isolated from normal pregnant women at term were assessed in response to incremental doses of S1P in the presence or absence of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The putative involvement of Rho-associated kinases (ROCKs) in intact art…

Treatment effects on sphingosine-1-phosphate and its receptors in major depressive disorder: implications for biomarkers.

BACKGROUND: The diagnosis of major depressive disorder (MDD) currently relies on subjective clinical assessments, highlighting a critical need for objective biological markers. The sphingosine-1-phosphate (S1P) signaling pathway, a pivotal regulator of neuro-immune interactions, has emerged as a potential contributor to MDD pathophysiology, yet its role remains incompletely understood. This study aimed to investigate plasma levels of S1P and its key receptors, S1PR1 and S1PR3, as potential diagnostic and predictive biomarkers for MDD, with a specific focus on sex differences and treatment effe…

The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology.

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1-S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer's disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal sur…

The Involvement of Ceramide, Sphingosine-1-Phosphate and Ganglioside GM1 in Regulating Some Nervous System Functions.

Sphingolipids are a large group of molecules, crucial components of all mammalian cells, that are particularly abundant in the central and peripheral nervous system and associated with important human brain functions. Sphingolipids are necessary for membrane organization and driving functions. Ceramide, sphingosine-1-phosphate and GM1, show bioactive properties. Ceramide and sphingosine-1-phosphate play a crucial role in the regulation of physio-pathological conditions. Small changes in their levels, in the ratio sphingosine-1-phosphate/ceramide as well as in chain length profiles of sphingoli…

Computational screening and in vitro evaluation of sphingosine-1-phosphate analogues as therapeutics for Non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is a prevalent hematological malignancy that includes a variety of B-cell and T-cell proliferations. The S1P (sphingosine-1-phosphate) pathway, involved in cell survival, proliferation, and migration, plays a critical role in NHL pathogenesis. Targeting S1PR1, the receptor for S1P, may provide a therapeutic strategy for NHL. The primary objective of this study was to identify and evaluate the efficacy of S1P analogues against the S1PR1 receptor through computational methods and experimental validation. The crystal structure of S1PR1 was obtained from the Protein Da…

Study on the CHJ01 antitumor activity and mechanism via targeting sphingosine kinase 1 in A549 cells.

The SphK1 inhibitor development is of great importance for the treatment of non-small cell lung cancer (NSCLC). In this study, CHJ01 which has been previously shown anti-tumor effects was introduced to investigate the detailed antitumor mechanism both in vitro and in vivo. CHJ01 inhibited the A549 ​cell proliferation, migration, and invasion significantly and showed cytotoxicity to A549. CHJ01 induced G0/G1 cell cycle arrest by increasing ceramide levels and altered the expression of TRAF2, Bcl-2, Bax and RELA. CHJ01 inhibited the TRAF2/NF-κB signaling pathway and promoted apoptosis by downreg

Сфингосин-1-Фосфатные модуляторы для лечения ультразвукового колита: обзор наррации, сосредоточенный на безопасности.

Ульцеративный колит представляет собой хроническое иммуносодержащее воспалительное заболевание толстой кишки, которое вызывает значительную заболеваемость и повышает риск рака цвета. Был разработан ряд целевых методов лечения умеренно-сильного язвительного колита, что значительно улучшило его лечение. Озанимод и этирасимод, пероральные небольшие молекулярные препараты, являются последним дополнением. Они относятся к классу модуляторов сфингосин-1-фосфатного рецептора (S1PR) и являются первыми членами этого класса, получившими официальное утверждение на наличие язвительного колита. Они действую

Совпадение в аннотации оригинала
Ulcerative colitis is a chronic immune-mediated inflammatory disease of the colon that causes considerable morbidity and increases the risk … imod and etrasimod, oral small-molecule drugs, are the latest addition. They belong to the class of sphingosine-1-phosphate receptor (S1PR) modulators and are the first members of this class to be granted approval for ulcerative colitis. They act by blocking lymphocyte trafficking from lymph nodes to inflamed tissues without impairing other immune system func …

A role for plasma membrane Ca2+ ATPases in regulation of cellular Ca2+ homeostasis by sphingosine kinase-1.

Sphingosine-1-phosphate (S1P) is a ubiquitous lipid mediator, acting via specific G-protein-coupled receptors (GPCR) and intracellularly. Previous work has shown that deletion of S1P lyase caused a chronic elevation of cytosolic [Ca2+]i and enhanced Ca2+ storage in mouse embryonic fibroblasts. Here, we studied the role of sphingosine kinase (SphK)-1 in Ca2+ signaling, using two independently generated EA.hy926 cell lines with stable knockdown of SphK1 (SphK1-KD1/2). Resting [Ca2+]i and thapsigargin-induced [Ca2+]i increases were reduced in both SphK1-KD1 and -KD2 cells. Agonist-induced [Ca2+]i…

Sphingosine 1-phosphate receptor 2 in keratinocytes plays a key role in reducing inflammation in psoriasis.

BACKGROUND: Psoriasis is an inflammatory skin condition where immune cells play a significant role. The importance of the cross-talk between … imiquimod (IMQ)-induced psoriasis-like inflammation in S1pr2fl/fl K14-Cre mice that could not sense sphingosine-1-phosphate (S1P) in the epidermis through the S1PR2 receptor. RESULTS: Our analysis suggests that S1PR2 in keratinocytes plays a major role in psoriasis-like inflammation compared to other S1PRs. It acts as a down-regulator, inhibiting the recruit …