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"Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs: Methoxy-FTY720, Fluoro-FTY720, and β-Glucuronide-FTY720".

Effective therapeutic agents are lacking for the prevention and reversal of vascular leak, a frequent pathophysiologic result of inflammatory processes such as acute respiratory distress syndrome (ARDS) and sepsis. We previously demonstrated the potent barrier-enhancing effects of related compounds sphingosine 1-phosphate (S1P), the pharmaceutical agent FTY720, and its analog (S)-FTY720 phosphonate (Tys) in models of inflammatory lung injury. In this study, we characterize additional novel FTY720 analogs for their potential to reduce vascular leak as well as utilize them as tools to better und…

Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR) inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella) larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased surviva…

Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension.

Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A … acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 …

FTY720 normalizes hyperglycemia by stimulating β-cell in vivo regeneration in db/db mice through regulation of cyclin D3 and p57(KIP2).

Loss of insulin-producing β-cell mass is a hallmark of type 2 diabetes in humans and diabetic db/db mice. Pancreatic β-cells can modulate their mass in response to a variety of physiological and pathophysiological cues. There are currently few effective therapeutic approaches targeting β-cell regeneration although some anti-diabetic drugs may positively affect β-cell mass. Here we show that oral administration of FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, to db/db mice normalizes fasting blood glucose by increasing β-cell mass and blood insulin levels without affecting insulin…

Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart.

BACKGROUND: Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transdu … ed cardiac hypertrophy in Pak1(cko) mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1(cko) mice, suggesting that the antihypertrophic effect of …

Stereo-selective inhibition of transient receptor potential TRPC5 cation channels by neuroactive steroids.

BACKGROUND AND PURPOSE: Transient receptor potential canonical 5 (TRPC5) channels are widely expressed, including in the CNS, where they pot … ogesterone was the most potent of the steroids, especially against TRPC5 channel activity evoked by sphingosine-1-phosphate. In outside-out patch recordings, bath-applied progesterone and dihydrotestosterone had strong and reversible effects, suggesting relatively direct mechanisms of action. Progesterone inhibited native TRPC5-containing channel activity, ev …

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice.

AIMS/HYPOTHESIS: NOD.Igmicro ( null ) mice lacking mature B cells are highly resistant to diabetes and display poor CD4 T cell responses to … creatic lymph nodes in NOD mice was enhanced tenfold. NOD B cells showed no chemotactic response to sphingosine-1-phosphate, which normally acts to retain B cells in the peritoneum. Peritoneal B cells of NOD mice also presented insulin autoantigen to CD4 T cells, inducing T cell proliferation. CONCLUSIONS/INTERPRETATION: NOD peritoneal B cells are hyperactiv …

Physiological basis for contractile dysfunction in heart failure.

The purpose of this review is to enlighten the mechanisms of skeletal muscle dysfunction in heart failure. The muscle hypothesis suggests th … necrosis factor and in vitro experiments have shown that it can be induced by its second messenger sphingosine. Apoptosis correlates with the severity of the heart failure syndrome. It involves activation of caspases 3 and 9 and mitochondrial cytochrome c release. Sarcomeric protein oxidation and its consequent contractile impairment can form another cause o …

Gelsolin is depleted in post-shock mesenteric lymph.

BACKGROUND: Gelsolin is a plasma protein that functions to depolymerize actin filaments preventing capillary plug formation following tissue injury. It also functions to mediate the inflammatory response by binding proinflammatory lipids such as lysophosphatidic acid, sphingosine-1-phosphate and phosphoinositides. Clinically, reduced gelsolin concentrations have been associated with increased mortality in critically ill, trauma, and burn patients. We have previously shown that following hemorrhagic shock with splanchnic hypoperfusion, mesenteric lymph contains lipid components that cause neutr…

Silymarin protects against liver damage in BALB/c mice exposed to fumonisin B1 despite increasing accumulation of free sphingoid bases.

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides found on corn and corn-based foods. It causes equine leukoencepha … rating cells. Silymarin dramatically potentiated FB(1)-induced accumulation of free sphinganine and sphingosine in both liver and kidney. Silymarin itself slightly increased expression of hepatic TNF-alpha; however, it prevented the FB(1)-induced increases in TNF-alpha, TNF receptor 1, TNF receptor-associated apoptosis-inducing ligand, lymphotoxin beta, and i …

Sphingolipid profile in the CNS of the twitcher (globoid cell leukodystrophy) mouse: a lipidomics approach.

Globoid cell leukodystrophy (Krabbe disease) is caused by mutations in galactosylceramidase, a lysosomal enzyme that acts to digest galactosylceramide, a glycolipid concentrated in myelin, and psychosine (galactosylsphingosine). Globoid cell leukodystrophy has been identified in many species including humans and twitcher mice. Several studies on human tissue have examined the lipid profile in this disease by gas, liquid or thin layer chromatography. Electrospray ionization tandem mass spectrometry combined with reverse phase HPLC has become a powerful alternative strategy, used here to compare…

Degradation of blood group A glycolipid A-6-2 by normal and mutant human skin fibroblasts.

The degradation of blood group glycolipid A-6-2 (GalNAc(alpha1-->3)[Fuc alpha1-->2]Gal(beta1-->4)GlcNAc(beta1-->3)Gal(beta1-->4)Glc(beta1--> … ls, the expected array of less polar products and some lipids resulting from re-using the liberated sphingosine, mainly sphingomyelin and phosphatidylcholine, were formed. In alpha-N-acetylgalactosaminidase-deficient cells, the glycolipid was virtually not degraded; product formation was less than 2% of the normal control rate, suggesting that blood group A-a …

CaMKII mediates stimulation of chloride conductance by calcium in T84 cells.

We used the secretory colonic cell line T84 to study the regulatory pathways controlling the Ca-stimulated Cl conductance [GCl(Ca)]. Under whole cell patch clamp, basal (unstimulated) current levels averaged 73 +/- 9 pA/20 pF (n = 93) and increased to 600 +/- 100 pA/20 pF (n = 53; at +100 mV) on exposure to 1-2 microM ionomycin. Bath application of the calmodulin (CaM) antagonists trifluoperazine, calmidazolium, or sphingosine (50 microM) reversibly inhibited GCl(Ca), whereas the protein kinase C antagonists H7 and phloretin (50 microM) were without effect. This suggests that increases in intr…

A ceramide analogue inhibits T cell proliferative response through inhibition of glycosphingolipid synthesis and enhancement of N,N-dimethylsphingosine synthesis.

The ceramide analogue 1-phenyl-2-(decanoylamino)-3-morpholino-1-propanol (PDMP) (particularly the D-threo isomer, D-PDMP) caused inhibition … s ceramide accumulated. Importantly, metabolically labeled radioactive bands, corresponding to free sphingosine and N-monomethylsphingosine, were found to be present in very small quantities (5-12%) relative to the band corresponding to N,N-dimethylsphingosine (DMS), which showed significant accumulation in D-PDMP-treated lymphocytes. The quantity of IL2 rece …

The therapeutic benefits of epigallocatechin gallate in rats with experimentally induced ulcerative colitis are achieved by influencing inflammation and apoptosis.

BACKGROUND: The potential therapeutic effects of epigallocatechin gallate (EGCG), a compound found in green tea with antioxidant and anti-in … factor kappa-light-chain-enhancer of activated B cells (NFκB), tumor necrosis factor alpha (TNF-α), sphingosine kinase 1 (SphK1), macrophage inflammatory protein 1-alpha (MIP-1α), B-cell lymphoma 2 (BCL2), and BCL2 associated X (BAX), as well as the activities of caspase-3/8/9. Additionally, colon sections were stained with Masson trichrome to investigate tis …

Microbial Metabolites in Allergic Diseases: Beyond Short-Chain Fatty Acids.

PURPOSE OF REVIEW: The gut microbiota contributes to host homeostasis through the production of bioactive metabolites that regulate immune f … ate the inflammatory response by regulating the levels of bioactive lipids, including ceramides and sphingosine-1-phosphate. Lastly, alterations in the bacterial metabolism of polyamines, including spermidine, and OCFA-containing metabolites, including lysophosphatidylcholines (LCP), have also been reported in allergic diseases. The microbiota metabolism modu …

[Update on drug therapy for ulcerative colitis].

Ulcerative colitis (UC) is classified as a chronic inflammatory bowel disease (IBD) and can present in various degrees of severity. In addit … us kinase (JAK) inhibitors, an interleukin (IL)-12/-23p40 antibody, various IL-23p19 antibodies and sphingosine-1-phosphate receptor (S1PR) modulators have broadened the therapeutic landscape and found their way into the clinical treatment of UC patients. In this article we will discuss case-based decision paths for the selection of fitting anti-inflammatory …

Воздействие лечения на стероидом у женщин с множественным склерозом.

Множественный склероз (MS) — хроническое воспалительное нейродегенеративное заболевание центральной нервной системы. Происхождение MS связано с стероидными изменениями во время менструального цикла и беременности. Поскольку данных о воздействии лечения противомоскитных препаратов на стероидом недостаточно, мы провели оценку стерейдомичных изменений (79 стероидов) у 61 женщины-психолога репродуктивного возраста 39 лет (29, 47 лет) после лечения с помощью антимиосных препаратов на платформе GC-MS/MS и иммуномассы (кортизол и эстрадиол). Эти изменения были оценены с использованием уровней стероид

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. The manifestation of MS is relate … phase. Anti-CD20 monoclonal antibodies (mAb), such as ofatumumab and ocrelizumab; inhibitors of the sphingosine-1-phosphate receptor (S1PRI); and IFNβ-1a decreased circulating 17-hydroxy-pregnanes and shifted the CYP17A1 functioning from the hydroxylase- toward the lyase step. Decreased conjugated/unconjugated steroid ratios were found after treatment with an …

Deciphering S1P downregulation and sphingolipid homeostasis disruption in fungal keratitis via multi-omics and MALDI-MSI analysis.

PURPOSE: The absence of effective treatment strategies in Fungal Keratitis (FK) emphasizes the critical need to understand the pathogenic me … used to reveal the driver genes in FK. We further investigated the effect of FTY-720, a mimetic of sphingosine 1-phosphate (S1P), on the progression of FK. RESULTS: MALDI-MSI analysis of FK patients revealed a downregulation of sphingolipids, with sphingolipid metabolism identified as the most prominently enriched pathway. These alterations were validated i …

Lysophospholipid receptors in neurodegeneration and neuroprotection.

The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of majo … ically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors i …