scholarly journals Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raj Kumar Sah ◽  
Soumya Pati ◽  
Monika Saini ◽  
Shailja Singh
Keyword(s):  
Plasmodium Falciparum ◽  
Plasma Level ◽  
Growth And Development ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Parasite Load ◽  
Mice Model ◽  
Cellular Functions ◽  
Sphingosine 1 Phosphate

AbstractThe sphingolipid pool is key regulator of vital cellular functions in Plasmodium falciparum a causative agent for deadly malaria. Erythrocytes, the host for asexual stage of Plasmodium, are major reservoir for Sphingosine-1-phosphate (S1P). Erythrocyte possesses Sphingosine kinase (SphK) that catalyzed its biosynthesis from sphingosine (Sph). Since, Plasmodium lacks SphK homologous protein it can be envisaged that it co-opts sphingolipids from both intraerythrocytic as well as extracellular pools for its growth and development. Herein, by sphingosine-NBD probing, we report that infected erythrocytes imports Sph from extracellular pool, which is converted to S1P and thereby taken by P. falciparum. Next, by targeting of the SphK through specific inhibitor N,N-Dimethylsphingosine DMS, we show a reduction in erythrocyte endogenous S1P pool and SphK-phosphorylation that led to inhibition in growth and development of ring stage P. falciparum. Owing to the role of S1P in erythrocyte glycolysis we analyzed uptake of NBD-Glucose and production of lactate in DMS treated and untreated plasmodium. DMS treatment led to decreased glycolysis in Plasmodium. Interestingly the host free Plasmodium did not show any effect on glycolysis with DMS treatment indicating its host-mediated effect. Further to understand the in-vivo anti-plasmodial effects of exogenous and endogenous erythrocyte S1P level, Sphingosine-1-phosphate lyase (S1PL) inhibitor (THI), S1P and SphK-1 inhibitor (DMS), were used in Plasmodium berghei ANKA (PbA) mice model. DMS treatment led to reduction of endogenous S1P conferred significant decrease in parasite load, whereas the plasma level S1P modulated by (THI) and exogenous S1P have no effect on growth of Plasmodium. This suggested erythrocyte endogenous S1P pool is important for Plasmodium growth whereas the plasma level S1P has no effect. Altogether, this study provides insight on cellular processes regulated by S1P in P. falciparum and highlights the novel mechanistically distinct molecular target i.e. SphK-1.

scholarly journals Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

2004 ◽  
Vol 279 (50) ◽  
pp. 52487-52492 ◽  
Author(s):  
Maria L. Allende ◽  
Teiji Sasaki ◽  
Hiromichi Kawai ◽  
Ana Olivera ◽  
Yide Mi ◽  
...  
Keyword(s):  
Vascular Development ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Cellular Functions ◽  
Lymphocyte Trafficking ◽  
Signaling Molecule ◽  
Physiological Functions ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

scholarly journals Increased Expression of CCN2 in the Red Flashing Light-Induced Myopia in Guinea Pigs

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hong Wang ◽  
Kang Zhuang ◽  
Lei Gao ◽  
Linna Zhang ◽  
Hongling Yang
Keyword(s):  
Gene Expression ◽  
Animal Model ◽  
Axial Length ◽  
Growth And Development ◽  
Visual Environment ◽  
Biological Processes ◽  
Cellular Functions ◽  
Ocular Growth ◽  
Flashing Light

Visual environment plays an important role in the occurrence of myopia. We previously showed that the different flashing lights could result in distinct effects on the ocular growth and development of myopia. CCN2 has been reported to regulate various cellular functions and biological processes. However, whether CCN2 signaling was involved in the red flashing light-induced myopia still remains unknown. In the present study, we investigated the effects of the red flashing lights exposure on the refraction and axial length of the eyesin vivoand then evaluated their effects on the expression of CCN2 and TGF-βin sclera tissues. Our data showed that the eyes exposed to the red flashing light became more myopic with a significant increase of the axial length and decrease of the refraction. Both CCN2 and TGF-β, as well as p38 MAPK and PI3K, were highly expressed in the sclera tissues exposed to the red flashing light. Both CCN2 and TGF-βwere found to have the same gene expression profilein vivo. In conclusion, our findings found that CCN2 signaling pathway plays an important role in the red flashing light-induced myopiain vivo. Moreover, our study establishes a useful animal model for experimental myopia research.

Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations

Hypertension ◽  
2021 ◽  
Author(s):  
Jiujiang Liao ◽  
Yangxi Zheng ◽  
Mingyu Hu ◽  
Ping Xu ◽  
Li Lin ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Sphingosine Kinase ◽  
Actin Dynamics ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Sphingosine Kinase 1 ◽  
Sphingosine 1 Phosphate

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized trophoblast cells) cell invasion in a Hippo-signaling–dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA/ROCK induced actin polymerization. Mutation-based YAP-5SA demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

scholarly journals Overexpression of Sphingosine Kinase-1 and Sphingosine-1-Phosphate Receptor-3 in Severe Plasmodium falciparum Malaria with Pulmonary Edema

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Parnpen Viriyavejakul ◽  
Chuchard Punsawad
Keyword(s):  
Plasmodium Falciparum ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Sphingosine Kinase ◽  
Alveolar Epithelial Cells ◽  
Sphingosine Kinase 1 ◽  
Expression Levels ◽  
Alveolar Epithelial ◽  
Sphingosine 1 Phosphate

Pulmonary edema (PE) is a major cause of pulmonary manifestations of severe Plasmodium falciparum malaria and is usually associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The sphingosine kinase-1 (SphK-1)/sphingosine-1-phosphate receptor-3 (S1PR-3) pathway has recently been reported to affect the pathogenesis of lung injury, but the expression of these proteins in the lungs of severe P. falciparum malaria patients has not been investigated. The cellular expression of SphK-1 and S1PR-3 in lung tissues from autopsied patients with P. falciparum malaria was investigated using immunohistochemistry (IHC). Lung tissues from patients who died of severe P. falciparum malaria were classified into two groups based on histopathological findings: those with PE (18 patients) and those without PE (non-PE, 19 patients). Ten samples of normal lung tissues were used as the control group. The protein expression levels of SphK-1 and S1PR-3 were significantly upregulated in endothelial cells (ECs), alveolar epithelial cells, and alveolar macrophages (AMs) in the lungs of severe P. falciparum malaria patients with PE compared to those in the non-PE and control groups (all p<0.001). In addition, the SphK-1 and S1PR-3 expression levels were significantly positively correlated in pulmonary ECs (rs=0.922, p<0.001), alveolar epithelial cells (rs=0.995, p<0.001), and AMs (rs=0.969, p<0.001). In conclusion, both the SphK-1 and S1PR-3 proteins were overexpressed in the lung tissues of severe P. falciparum malaria patients with PE, suggesting that SphK-1 and S1PR-3 mediate the pathogenesis of PE in severe malaria. Targeting the regulation of SphK-1 and/or S1PR-3 may be an approach to treat pulmonary complications in severe P. falciparum patients.

scholarly journals δ-Catenin/NPRAP (neural plakophilin-related armadillo repeat protein) interacts with and activates sphingosine kinase 1

2004 ◽  
Vol 382 (2) ◽  
pp. 717-723 ◽  
Author(s):  
Toshitada FUJITA ◽  
Taro OKADA ◽  
Shun HAYASHI ◽  
Saleem JAHANGEER ◽  
Noriko MIWA ◽  
...  
Keyword(s):  
Cell Motility ◽  
Hippocampal Neurons ◽  
Mdck Cells ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Dependent Manner ◽  
Repeat Protein ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme ◽  
Armadillo Repeat

Sphingosine kinase (SPHK) is a key enzyme catalysing the formation of sphingosine 1-phosphate (SPP), a lipid messenger that is implicated in the regulation of a wide variety of important cellular events acting through intracellular, as well as extracellular, mechanisms. However, the molecular mechanism of intracellular actions of SPP remains unclear. Here, we have identified δ-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) as a potential binding partner for SPHK1 by yeast two-hybrid screening. From co-immunoprecipitation analyses, the C-terminal portion of δ-catenin/NPRAP containing the seventh to tenth armadillo repeats was found to be required for interaction with SPHK1. Endogenous δ-catenin/NPRAP was co-localized with endogenous SPHK1 and transfected δ-catenin/NPRAP was co-localized with transfected SPHK1 in dissociated rat hippocampal neurons. MDCK (Madin–Darby canine kidney) cells stably expressing δ-catenin/NPRAP contained elevated levels of intracellular SPP. In a purified system δ-catenin/NPRAP stimulated SPHK1 in a dose-dependent manner. Furthermore, δ-catenin/NPRAP-induced increased cell motility in MDCK cells was completely inhibited by dimethylsphingosine, a specific inhibitor of SPHK1. These results strongly suggest that at least some of δ-catenin/NPRAP functions, including increased cell motility, are mediated by an SPHK–SPP signalling pathway.

scholarly journals Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma

Blood ◽  
2014 ◽  
Vol 124 (12) ◽  
pp. 1915-1925 ◽  
Author(s):  
Jagadish Kummetha Venkata ◽  
Ningfei An ◽  
Robert Stuart ◽  
Luciano J. Costa ◽  
Houjian Cai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Sphingosine Kinase 2 ◽  
Key Points

Key Points SK2 is overexpressed in myeloma cells and contributes to myeloma cell survival and proliferation. SK2-specific inhibitor promotes proteasome degradation of Mcl-1 and c-Myc and inhibits myeloma growth in vitro and in vivo.

scholarly journals NADPH Oxidase-Mediated Activation of Neutral Sphingomyelinase Is Responsible for Diesel Particulate Extract-Induced Keratinocyte Apoptosis

2020 ◽  
Vol 21 (3) ◽  
pp. 1001 ◽  
Author(s):  
Hyun-Seok Lee ◽  
Hye Yoon Park ◽  
Sung Pil Kwon ◽  
Bogyeong Kim ◽  
Yerin Lee ◽  
...  
Keyword(s):  
Cell Fate ◽  
Air Pollutants ◽  
Specific Inhibitor ◽  
Ros Generation ◽  
Cellular Functions ◽  
Diesel Particulate ◽  
Neutral Sphingomyelinase ◽  
Sphingosine 1 Phosphate ◽  
Pre Treatment ◽  
Diesel Particulate Extract

Human epidermis is positioned at the interface with the external environment, protecting our bodies against external challenges, including air pollutants. Emerging evidence suggests that diesel particulate extract (DPE), a major component of air pollution, leads to impairment of diverse cellular functions in keratinocytes (KC). In this study, we investigated the cellular mechanism underlying DPE-induced KC apoptosis. We first addressed cell death occurring in KC exposed to DPE, paralleled by increased activation of NADPH oxidases (NOXs) and subsequent ROS generation. Blockade of NOX activation with a specific inhibitor attenuated the expected DPE-induced KC apoptosis. In contrast, pre-treatment with a specific inhibitor of reactive oxygen species (ROS) generation did not reverse DPE/NOX-mediated increase in KC apoptosis. We next noted that NOX-mediated KC apoptosis is mainly attributable to neutral sphingomyelinase (SMase)-mediated stimulation of ceramides, which is a well-known pro-apoptotic lipid. Moreover, we found that inhibition of NOX activation significantly attenuated DPE-mediated increase in the ratio of ceramide to its key metabolite sphingosine-1-phosphate (S1P), an important determinant of cell fate. Together, these results suggest that activation of neutral SMase serves as a key downstream signal for the DPE/NOX activation-mediated alteration in ceramide and S1P productions, and subsequent KC apoptosis.

Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1

2012 ◽  
Vol 444 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Mark E. Schnute ◽  
Matthew D. McReynolds ◽  
Tom Kasten ◽  
Matthew Yates ◽  
Gina Jerome ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Inflammatory Diseases ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Head And Neck Carcinoma ◽  
High Rate ◽  
Neck Carcinoma ◽  
Sphingosine 1 Phosphate ◽  
Proportional Increase ◽  
And Migration

SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a Ki of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling.

scholarly journals SphK2/S1P Promotes Metastasis of Triple-Negative Breast Cancer Through the PAK1/LIMK1/Cofilin1 Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiwei Shi ◽  
Ding Ma ◽  
Yin Cao ◽  
Lili Hu ◽  
Shuwen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Tnbc Cell ◽  
Sphingosine 1 Phosphate

BackgroundTriple-negative breast cancer (TNBC) features a poor prognosis, which is partially attributed to its high metastatic rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, and HER-2, respectively) in cancer. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalyst sphingosine-1-phosphate (S1P) in TNBC metastasis and the effect of the SphK2-specific inhibitor ABC294640 on TNBC metastasis.MethodsThe function of SphK2 and S1P in TNBC cell metastasis was evaluated using transwell migration and wound-healing assays. The molecular mechanism of SphK2/S1P mediating TNBC metastasis was investigated using Western blot, histological examination, and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in an in vivo TNBC lung metastatic model.ResultsSphingosine kinase 2 promoted TNBC cell migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo. p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1), and Cofilin1 were the downstream signaling molecules of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P-induced TNBC cell migration.ConclusionSphingosine kinase 2/sphingosine-1-phosphate promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 inhibits TNBC metastasis in vivo and could be developed as a novel agent for the clinical treatment of TNBC.

scholarly journals Basal and angiopoietin-1–mediated endothelial permeability is regulated by sphingosine kinase-1

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3489-3497 ◽  
Author(s):  
Xiaochun Li ◽  
Milena Stankovic ◽  
Claudine S. Bonder ◽  
Christopher N. Hahn ◽  
Michelle Parsons ◽  
...  
Keyword(s):  
Endothelial Permeability ◽  
Sphingosine Kinase ◽  
Dominant Negative ◽  
Sphingosine Kinase 1 ◽  
Sphingosine 1 Phosphate ◽  
Functional States ◽  
Interfering Rna ◽  
Angiopoietin 1

Abstract Endothelial cells (ECs) regulate the barrier function of blood vessels. Here we show that basal and angiopoietin-1 (Ang-1)–regulated control of EC permeability is mediated by 2 different functional states of sphingosine kinase-1 (SK-1). Mice depleted of SK-1 have increased vascular leakiness, whereas mice transgenic for SK-1 in ECs show attenuation of leakiness. Furthermore, Ang-1 rapidly and transiently stimulates SK-1 activity and phosphorylation, and induces an increase in intracellular sphingosine-1-phosphate (S1P) concentration. Overexpression of SK-1 resulted in inhibition of permeability similar to that seen for Ang-1, whereas knockdown of SK-1 by small interfering RNA blocked Ang-1-mediated inhibition of permeability. Transfection with SKS225A, a nonphosphorylatable mutant of SK-1, inhibited basal leakiness, and both SKS225A and a dominant-negative SK-1 mutant removed the capacity of Ang-1 to inhibit permeability. These effects were independent of extracellular S1P as knockdown or inhibition of S1P1, S1P2, or S1P3, did not affect the Ang-1 response. Thus, SK-1 levels in ECs powerfully regulate basal permeability in vitro and in vivo. In addition, the Ang-1–induced inhibition of leakiness is mediated through activation of SK-1, defining a new signaling pathway in the Ang-1 regulation of permeability.

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