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Pharmacokinetics of H002, a novel S1PR_1 modulator, and its metabolites in rat blood using liquid chromatography–tandem mass spectrometry

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Acta Pharmaceutica Sinica B 2016年第6期6卷 576-583页

作者： Jiaqi Mi Manman Zhao Shu Yang Shuang Yang Jing Jin Xiaojian Wang Qiong Xiao Jinping Hu Yan Li Department of Drug Metabolism Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD StudyKey Laboratory of Active Substances Discovery and Drug Ability Evaluation State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College

A rapid and sensitive liquid chromatography–tandem mass spectrometry(LC–MS/MS) method was developed and validated for the simultaneous determination of H002 and its phosphorylated metabolite, H002-P and hydroxylated metabolite H002-M, in rat blood. H001, an analogue of H002, was used as the internal standard.Blood samples were prepared by simple protein precipitation. The analytes and internal standard were separated on a Zorbax SB-C18 column with a gradient mobile phase consisting of methanol and water containing 0.1% formic acid at a flow rate of 0.2 mL /min with an operating temperature of 20 1C. The detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization in multiple-reaction monitoring mode.Linear detection responses were obtained from 0.2–100 ng/mL for H002 and H002-M, while 0.5–100 ng/mL for H002-P. The intra- and inter-day precision(RSD%) was within 11.76%, with the accuracy(RE%) ranging from –9.84% to 9.12%. The analytes were shown to be stable during sample storage, preparation and analytic procedures.The method was applied to determine the pharmacokinetics of H002 in rats, and a preliminary study showed that the pharmacokinetics of H002 correlated with its biological effect on peripheral blood lymphocytes.

关键词： S1P receptor S1PR1 modulator sphingosine-1-phosphate S1P analogue Metabolite LC–MS/MS Pharmacokinetics Periphery blood lymphocyte

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High density lipoproteins and atherosclerosis: emerging aspects

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Journal of Geriatric Cardiology 2012年第4期9卷 401-407页

作者： Federica Sala Alberico Luigi Catapano Giuseppe Danilo Norata Department of Pharmacological Sciences University of Milan Via Balzaretti 9 Milan 20133 Italy IRCCSMult imedica ViaMilanese 300 Sesto San Giovanni Milan Italy Centro SISAper lo Studio dell’Aterosclerosi Ospedale Bassini Via Gorki50 Cinisello Bal samo Italy The Blizard Institute Barts and the LondonSchool of Medicine & Dentistry Queen Mary University Turner Street London E1 2AD UK

High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis,includingmonocyte-macrophages, B and T lymphocytes.Furthermore, during inflammation, the composition of this class of lipoproteins varies to a large extent, thus promoting the formation of dysfunctional HDL. The aim of this review is to discuss the emerging role of HDL in modulating the activity of immune cells and immune-inflammatory mediators during atherogenesis.

关键词： Apolipoprotein High density lipoproteins Immune response sphingosine-1-phosphate

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Sphingolipid metabolism and drug resistance in ovarian cancer

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Cancer Drug Resistance 2018年第3期1卷 181-197页

作者： Kelly M.Kreitzburg Robert C.A.Mvan Waardenburg Karina J.Yoon Department of Pharmacology and Toxicology University of Alabama at BirminghamBirminghamAL 35294USA

Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer,virtually all patients succumb to drug resistant disease at relapse.Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance.Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents.Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum-and taxane-based agents.The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer.The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.

关键词： Ovarian cancer drug-resistance ceramide sphingosine-1-phosphate sphingolipid metabolism

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Bile acids as global regulators of hepatic nutrient metabolism

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Liver Research 2017年第1期1卷 10-16页

作者： Phillip B.Hylemon Kazuaki Takabe Mikhail Dozmorov Masayuki Nagahashi Huiping Zhou Department of Microbiology and Immunology Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondVAUSA McGuire VA Medical Center RichmondVAUSA Department of Surgery Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondVAUSA Department of Biostatistics Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondVAUSA Department of Surgery Niigata UniversityJapan

Bile acids(BA)are synthesized from cholesterol in the liver.They are essential for promotion of the absorption of lipids,cholesterol,and lipid-soluble vitamins from the intestines.BAs are hormones that regulate nutrient metabolism by activating nuclear receptors(farnesoid X receptor(FXR),pregnane X receptor,vitamin D)and G protein-coupled receptors(e.g.,TGR5,sphingosine-1-phosphate receptor 2(S1PR2))in the liver and intestines.In the liver,S1PR2 activation by conjugated BAs activates the extracellular signal-regulated kinase 1/2 and AKT signaling pathways,and nuclear sphingosine kinase 2.The latter produces sphingosine-1-phosphate(S1P),an inhibitor of histone deacetylases 1/2,which allows for the differential up-regulation of expression of genes involved in the metabolism of sterols and lipids.We discuss here the emerging concepts of the interactions of BAs,FXR,insulin,S1P signaling and nutrient metabolism.

关键词： sphingosine-1-phosphate sphingosine kinase 2 sphingosine-1-phosphate receptor 2 Fatty liver Epigenetics

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Sphingolipids in cardiovascular and cerebrovascular systems:Pathological implications and potential therapeutic targets

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World Journal of Cardiology 2013年第4期5卷 75-86页

作者： Masahito Kawabori Rachid Kacimi Joel S Karliner Midori A Yenari Department of Neurology San Francisco and San Francisco Veterans Affairs Medical CenterUniversity of CaliforniaSan FranciscoCA 94121United States Department of Cardiology VA Medical CenterUniversity of California San FranciscoSan FranciscoCA 94121United States

The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.

关键词： Sphingolipids sphingosine-1-phosphate sphingosine kinase Ceramide kinase

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To stay or to leave: Stem cells and progenitor cells navigating the S1P gradient

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World Journal of Biological Chemistry 2011年第1期2卷 1-13页

作者： Andrew Hsu Jen-Fu Lee Daniel E Cramer Menq-Jer Lee Department of Pathology Wayne State University School of Medicine Detroit MI 48202 United States Department of Surgery University of Illinois at Chicago Chicago IL 60612 United States

Most hematopoietic stem progenitor cells (HSPCs) reside in bone marrow (BM), but a small amount of HSPCs have been found to circulate between BM and tissues through blood and lymph. Several lines of evidence suggest that sphingosine-1-phosphate (S1P) gradient triggers HSPC egression to blood circulation after mobilization from BM stem cell niches. Stem cells also visit certain tissues. After a temporary 36 h short stay in local tissues, HSPCs go to lymph in response to S1P gradient between lymph and tissue and eventually enter the blood circulation. S1P also has a role in the guidance of the primitive HSPCs homing to BM in vivo, as S1P analogue FTY720 treatment can improve HSPC BM homing and engraftment. In stress conditions, various stem cells or progenitor cells can be attracted to local injured tissues and participate in local tissue cell differentiation and tissue rebuilding through modulation the expression level of S1P1, S1P2 or S1P3 receptors. Hence, S1P is important for stem cells circulation in blood system to accomplish its role in body surveillance and injury recovery.

关键词： Hematopoietic stem progenitor cells Tissue specific stem/progenitor cells Mesenchymal stem cell Stem cell homing Stem cell egress sphingosine-1-phosphate sphingosine-1-phosphate gradient sphingosine-1-phosphate receptors

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p38 mitogen-activated protein kinase regulates type-Ⅰ vs type-Ⅱ phenotyping of human vascular endothelial cells

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World Journal of Translational Medicine 2015年第3期4卷 101-112页

作者： Masako Nakahara Miwako Nishio Koichi Saeki Akira Yuo Kumiko Saeki Department of Disease Control Research Institute National Center for Global Health and Medicine Section of Cell Engineering Department of Basic Research DNAVEC Center ID Pharma Co. Ltd. PRESTO Japan Science and Technology Agency

AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteomic kinase assays were performed to identify the crucial kinase involved in the phenotype regulation of human VECs using typeⅠ VECs, which promotes the proliferation of human vascular smooth muscle cells(VSMCs), and typeⅡ VECs, which suppress the proliferation of human VSMCs. The assays were performed using multiple pairs of typeⅠ and typeⅡ VECs to obtain the least number of candidates. The involvement of the candidate kinases was verified by evaluating the effects of their specific inhibitors on the phenotype regulation of human VECs as well as the expression levels of regulator of RGS5, which is the causative gene for the "typeⅡ to typeⅠ" phenotype conversion of human VECs. RESULTS: p38α mitogen-activated protein kinase(p38α MAPK) was the only kinase that showed distinctive activities between typeⅠ and typeⅡ VECs: p38α MAPK activities were low and high in type-Ⅰand typeⅡ VECs, respectively. We found that an enforced expression of RGS5 indeed lowered p38α MAPK activitiesin typeⅡ VECs. Furthermore, treatments with a p38α MAPK inhibitor nullified the anti-proliferative potential in typeⅡ VECs. Interestingly, MAPK inhibitor treatments enhanced the induction of RGS5 gene. Thus, there is a vicious cycle between "RGS5 induction" and "p38α MAPK inhibition", which can explain the unidirectional process in the stress-induced "typeⅡ to typeⅠ" conversions of human VECs. To understand the upstream signaling of RGS5, which is known as an inhibitory molecule against the G protein-coupled receptor(GPCR)-mediated signaling, we examined the effects of RGS5 overexpression on the signaling events from sphingosine-1-phosphate(S1P) to N-cadherin, because S1 P receptors belong to the GPCR family gene and N-cadherin, one of their downstream effectors, is reportedly involved in the regulation of VEC-VSMC interactions. We foun

关键词： vascular endothelial cells vascular smooth muscle cells proteomic kinase assay p38αmitogenactivated protein kinase regulator of G-protein signaling 5 sphingosine-1-phosphate N-cadherin

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Role of sphingosine kinase localization in sphingolipid signaling

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World Journal of Biological Chemistry 2010年第12期1卷 362-368页

作者： Binks W Wattenberg Clinical and Translational Research Building Room 419 505 South Hancock St. Louisville KY 40202 United States

The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to theplasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.

关键词： Sphingolipid Lipid signaling Ceramide sphingosine-1-phosphate sphingosine

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