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Search results for: SPHK1

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#32738398   2020/07/29 To Up

Generation of sphingosine-1-phosphate by sphingosine kinase 1 protects nonalcoholic fatty liver from ischemia/reperfusion injury through alleviating reactive oxygen species production in hepatocytes.

/Aims: Nonalcoholic fatty liver (NAFL) is emerging as a leading risk factor of hepatic ischemia/reperfusion (I/R) injury lacking of effective therapy. Lipid dyshomeostasis has been implicated in the hepatopathy of NAFL. Herein, we investigate the bioactive lipids that critically regulate I/R injury in NAFL.
Qingping Li, Jianping Qian, Yiyi Li, Pengxiang Huang, Hanbiao Liang, Hang Sun, Cuiting Liu, Jie Peng, Xinxin Lin, Xuefang Chen, Hongxian Peng, Zihuan Wang, Meiqi Liu, Yaru Shi, Hongmei Yan, Yiran Wei, Leyi Liao, Qinghua He, Xixin Huang, Fangyi Ruan, Cungui Mao, Jie Zhou, Kai Wang, Chuanjiang Li

1301 related Products with: Generation of sphingosine-1-phosphate by sphingosine kinase 1 protects nonalcoholic fatty liver from ischemia/reperfusion injury through alleviating reactive oxygen species production in hepatocytes.

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#32736077   2020/07/28 To Up

Development of SKI-349, a Dual-Targeted Inhibitor of Sphingosine Kinase and Microtubule Polymerization.

Our sphingosine kinase inhibitor (SKI) optimization studies originated with the optimization of the SKI-I chemotype by replacement of the substituted benzyl rings with substituted phenyl rings giving rise to the discovery of SKI-178. We have recently reported that SKI-178 is a dual-targeted inhibitor of both sphingosine kinase isoforms (SphK1/2) and a microtubule disrupting agent (MDA). In mechanism-of-action studies, we have shown that these two separate actions synergize to induce cancer cell death in acute myeloid leukemia (AML) cell and animal models. Owning to the effectiveness of SKI-178, we sought to further refine the chemotype while maintaining "on-target" SKI and MDA activities. Herein, we modified the "linker region" between the substituted phenyl rings of SKI-178 through a structure guided approach. These studies have yielded the discovery of an SKI-178 congener, SKI-349, with log-fold enhancements in both SphK inhibition and cytotoxic potency. Importantly, SKI-349 also demonstrates log-fold improvements in therapeutic efficacy in a retro-viral transduction model of MLL-AF9 AML as compared to previous studies with SKI-178. Together, our results strengthen the hypothesis that simultaneous targeting of the sphingosine kinases (SphK1/2) and the induction of mitotic spindle assembly checkpoint arrest, via microtubule disruption, might be an effective therapeutic strategy for hematological malignancies including AML.
Jeremy A Hengst, Shailaja Hegde, Robert F Paulson, Jong K Yun

2620 related Products with: Development of SKI-349, a Dual-Targeted Inhibitor of Sphingosine Kinase and Microtubule Polymerization.

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#32705189   2020/07/03 To Up

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma.

Osteosarcoma (OS) is one of the most common and aggressive malignancies in children and adolescents worldwide. Sphingosine kinase 1 (SphK1) has recently been reported to serve a role in OS progression. The present study aimed to investigate the role of SphK1 in the development of chemoresistance and glycolysis in OS cell lines. SphK1 expression levels in OS cell lines (U2OS, MG63 and SaoS2) were analyzed using western blotting and reverse transcription‑quantitative PCR (RT‑qPCR). A cell survival assay was conducted to determine doxorubicin‑resistance in OS cells, and glycolysis was also evaluated. SphK1 expression was increased in the U2OS and SaoS2 cell lines, and both cell lines were more resistant to doxorubicin when compared with the MG63 cell line. SphK1 knockdown or overexpression altered doxorubicin resistance and the viability of OS cell lines. In addition, hypoxia inducible factor‑1α (HIF‑1α) expression was positively associated with SphK1 expression, and partly mediated SphK1‑induced effects on doxorubicin resistance and glycolysis. The present study suggested that SphK1 participated in the development of doxorubicin resistance and contributed to glycolysis in OS cells by regulating HIF‑1α expression. However, further studies investigating the application of SphK1 associated therapies for patients with OS are required.
Xiaojun Ren, Chunhong Su

1222 related Products with: Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma.

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#32697651   2020/07/22 To Up

Neonatal Therapy with PF543, a Sphingosine Kinase 1 Inhibitor, Ameliorates Hyperoxia-Induced Airway Remodeling in a Murine Model of Bronchopulmonary Dysplasia.

Hyperoxia (HO)-induced lung injury contributes to bronchopulmonary dysplasia (BPD) in preterm newborns. Intractable wheezing seen in BPD survivors is associated with airway remodeling (AWRM). Sphingosine kinase 1 (SPHK1)/ Sphingosine-1-phosphate (S1P) signaling promotes HO-mediated neonatal BPD; however, its role in the sequela of AWRM is not known. We noted an increased concentration of S1P in tracheal aspirates of neonatal infants with severe BPD, and earlier, demonstrated that Sphk1 mice showed protection against HO-induced BPD. Role of SPHK1/S1P in promoting AWRM following exposure of neonates to HO was investigated in a murine model. Therapy using PF543, the specific SPHK1 inhibitor, during neonatal HO reduced alveolar simplification followed by reduced AWRM in adult mice. This was associated with reduced airway hyperreactivity (AHR) to intravenous methacholine. Neonatal HO exposure was associated with increased expression of SPHK1 in lung tissue of adult mice, which was reduced with PF543 therapy in the neonatal stage. This was accompanied by amelioration of HO-induced reduction of E-cadherin in airway epithelium. This may be suggestive of arrested partial epithelial mesenchymal transition (EMT) induced by HO. In vitro studies using human primary airway epithelial cells (HAEpCs) showed that SPHK1 inhibition or deletion restored HO-induced reduction in E-cadherin and reduced formation of mitochondrial reactive oxygen species (mtROS). Blocking mtROS with MitoTempo attenuated HO-induced partial EMT of HAEpCs. These results collectively support a therapeutic role for PF543 in preventing HO-induced BPD in neonates and the long-term sequela of AWRM, thus conferring a long-term protection resulting in improved lung development and function.
Alison W Ha, Tara Sudhadevi, David L Ebenezer, Panfeng Fu, Evgeny V Berdyshev, Steven J Ackerman, Viswanathan Natarajan, Anantha Harijith

2028 related Products with: Neonatal Therapy with PF543, a Sphingosine Kinase 1 Inhibitor, Ameliorates Hyperoxia-Induced Airway Remodeling in a Murine Model of Bronchopulmonary Dysplasia.

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#32696422   2020/07/22 To Up

Generation of mice with hepatocyte-specific conditional deletion of sphingosine kinase 1.

SphK1 gene has different roles in various types of cells in liver diseases, but most studies are based on global knockout mice, which hampers the study on the cellular and molecular mechanisms of SphK1. In order to further study the role of SphK1 in liver, SphK1 conditional knockout mice were constructed. A liver-specific SphK1 gene knockout mouse model was constructed by the Cre/Loxp recombinant enzyme system. PCR technologies and western blotting were used to identified the elimination of SphK1 gene in hepatocytes. SphK1 mice were used as a control group to verify the effectiveness of SphK1 liver-specific knockout mice from the profile, pathology, and serology of mice. The ablation of SphK1 in hepatic parenchymal cells was demonstrated by fluorescent in situ hybridization and the contents of S1P and Sph were measured by ELISA kit. The genotypes of liver in SphK1 conditional knockout mice were different from that of other organs. The mRNA and protein levels of SphK1 in liver tissue of SphK1 conditional knockout mice were almost depleted by compared with SphK1 mice. Physiology and pathology showed no significant difference between SphK1 liver conditional knockout mice and SphK1 mice. Additionally, SphK1 was eliminated in hepatocytes, leading to the reduce of S1P content in hepatocytes and liver tissues and the increase of Sph content in hepatocytes. The model of SphK1 gene liver conditional knockout mice was successfully constructed, providing a tool for the study of the roles of SphK1 in hepatocyte and liver diseases.
Jinfeng Yu, Jiale Dong, Kangdi Chen, Yaping Ding, Zhicheng Yang, Tian Lan

2569 related Products with: Generation of mice with hepatocyte-specific conditional deletion of sphingosine kinase 1.

100 ug 5 G50 ug100 400 Assays50 ug2 Pieces/Box4 Arrays/Slide1 mg2 Pieces/Box4001 ml

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#32695095   2020/06/26 To Up

Macrophage Sphingosine 1-Phosphate Receptor 2 Blockade Attenuates Liver Inflammation and Fibrogenesis Triggered by NLRP3 Inflammasome.

NLR family pyrin domain containing 3 (NLRP3) inflammasome accompanies chronic liver injury and is a critical mediator of inflammation-driven liver fibrosis. Sphingosine 1-phosphate (S1P)/S1P Receptor (S1PR) signaling participates in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophage (BMM) activation. However, the relationship between S1P/S1PR signaling and NLRP3 inflammasome in BMMs remains unclear. Here, we found significantly elevated gene expression of NLRP3 inflammasome components (NLRP3, pro-interleukin-1β, and pro-interleukin-18) and the activation of NLRP3 inflammasome significantly elevated during murine chronic liver injury induced by a bile duct ligation operation, a methionine-choline-deficient and high-fat diet, or carbon tetrachloride intraperitoneal injection. Moreover, the increased expression of sphingosine kinase 1 (SphK1), the rate-limiting synthetic enzyme of S1P, was positively correlated with NLRP3 inflammasome components in both patients and mouse model livers. Flow cytometry analysis and immunofluorescence staining showed BMMs contributed to the significant proportion of NLRP3 cells in murine inflammatory livers, but not Kupffer cells, dendritic cells, endothelial cells, T cells, and hepatocytes. Focusing on macrophages, S1P promoted NLRP3 inflammasome priming and activation in a dose-dependent manner. Blockade of S1PR by JTE-013 (antagonist of S1PR) or S1PR-siRNA inhibited S1P-induced NLRP3 inflammasome priming and inflammatory cytokine (interleukin-1β and interleukin-18) secretion, whereas blockade of S1PR or S1PR had no such effect. , a β1,3-d-glucan-encapsulated siRNA particle (GeRP) delivery system is capable of silencing genes in macrophages specifically. Treatment with S1PR siRNA-GeRPs markedly reduced NLRP3 inflammasome priming and activation and attenuated liver inflammation and fibrosis. Together, the conclusions indicated that targeting macrophage S1PR retarded liver inflammation and fibrogenesis via downregulating NLRP3 inflammasome, which may represent an effective therapeutic strategy for chronic liver injury.
Lei Hou, Le Yang, Na Chang, Xinhao Zhao, Xuan Zhou, Chengbin Dong, Fuquan Liu, Lin Yang, Liying Li

1240 related Products with: Macrophage Sphingosine 1-Phosphate Receptor 2 Blockade Attenuates Liver Inflammation and Fibrogenesis Triggered by NLRP3 Inflammasome.

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#32694981   2020/06/30 To Up

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model.

Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases using primary astrocytes isolated from mice and using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.
Rong Chen, Xing Cao, Wenxiu Luo, Haodi Yang, Xinya Luo, Juming Yu, Jiaming Luo

2437 related Products with: Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model.

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#32690594   2020/07/20 To Up

Depletion of adipocyte sphingosine kinase 1 causes cell hypertrophy, impaired lipolysis, and NAFLD.

Sphingolipids have become established participants in the pathogenesis of obesity and  associated maladies. Sphingosine kinase 1 (SPHK1), which generates sphingosine-1-phosphate, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 knockout mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and non-alcoholic fatty liver disease, suggesting SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction is recognized as a central instigator of obesity-induced metabolic disease, we hypothesized that  adipocyte SPHK1   may contribute to HFD-induced  pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1) and placed them on a high fat diet. In contrast to our initial hypothesis, SK1 mice gained more weight on HFD and showed exacerbated impairment in glucose clearance. Proinflammatory cytokines and adipose tissue neutrophils were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of proinflammatory cytokines and collagen 1a1 were exacerbated in SK1fatKO mice on high fat diet, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ crosstalk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.
Andrea K Anderson, Johana M Lambert, Davod Montefusco, Bao Ngan Tran, Patrick Roddy, William L Holland, L Ashley Cowart

2170 related Products with: Depletion of adipocyte sphingosine kinase 1 causes cell hypertrophy, impaired lipolysis, and NAFLD.

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#32637407   2020/06/19 To Up

Decoding the Role of Sphingosine-1-Phosphate in Asthma and Other Respiratory System Diseases Using Next Generation Knowledge Discovery Platforms Coupled With Luminex Multiple Analyte Profiling Technology.

Sphingosine-1-phosphate (S1P) is a pleiotropic sphingolipid derived by the phosphorylation of sphingosine either by sphingosine kinase 1 (SPHK1) or SPHK2. Importantly, S1P acts through five different types of G-protein coupled S1P receptors (S1PRs) in immune cells to elicit inflammation and other immunological processes by enhancing the production of various cytokines, chemokines, and growth factors. The airway inflammation in asthma and other respiratory diseases is augmented by the activation of immune cells and the induction of T-helper cell type 2 (Th2)-associated cytokines and chemokines. Therefore, studying the S1P mediated signaling in airway inflammation is crucial to formulate effective treatment and management strategies for asthma and other respiratory diseases. The central aim of this study is to characterize the molecular targets induced through the S1P/S1PR axis and dissect the therapeutic importance of this key axis in asthma, airway inflammation, and other related respiratory diseases. To achieve this, we have adopted both high throughput next-generation knowledge discovery platforms such as SwissTargetPrediction, WebGestalt, Open Targets Platform, and Ingenuity Pathway Analysis (Qiagen, United States) to delineate the molecular targets of S1P and further validated the upstream regulators of S1P signaling using cutting edge multiple analyte profiling (xMAP) technology (Luminex Corporation, United States) to define the importance of S1P signaling in asthma and other respiratory diseases in humans.
Sami Bahlas, Laila A Damiati, Ayman S Al-Hazmi, Peter Natesan Pushparaj

1283 related Products with: Decoding the Role of Sphingosine-1-Phosphate in Asthma and Other Respiratory System Diseases Using Next Generation Knowledge Discovery Platforms Coupled With Luminex Multiple Analyte Profiling Technology.

100 mg10 mg500 tests96 tests3 inhibitors

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#32634578   2020/07/04 To Up

Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.

Emerging evidence indicates that Huntington's disease (HD) may be described as multi-organ pathology. In this context, we and others have contributed to demonstrate that the disease is characterized by an impairment of the homeostasis of gastro-intestinal (GI) tract. Sphingolipids represent a class of molecules involved in the regulation and maintenance of different tissues and organs including GI system. In this study, we investigated whether the alteration of Sphingosine-1-phosphate (S1P) metabolism, previously described in human HD brains and animal models, is also detectable peripherally in R6/2 HD mice. Our findings indicate, for the first time, that sphingolipid metabolism is perturbed early in the disease in the intestinal tract of HD mice and, its modulation by K6PC-5, a selective activator of S1P synthesis, preserved intestinal integrity and homeostasis. These results further support the evidence that modulation of sphingolipid pathways may represent a potential therapeutic option in HD and suggest that it has also the potential to counteract the peripheral disturbances which may usually complicate the management of the disease and affect patient's quality of life.
A Di Pardo, G Pepe, L Capocci, F Marracino, E Amico, L Del Vecchio, S Giova, S K Jeong, B M Park, B D Park, V Maglione

2887 related Products with: Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.

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