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  • 1
    Language: English
    In: The Journal of biological chemistry, 01 January 2016, Vol.291(1), pp.58-71
    Description: Acting during phase II metabolism, sulfotransferases (SULTs) serve detoxification by transforming a broad spectrum of compounds from pharmaceutical, nutritional, or environmental sources into more easily excretable metabolites. However, SULT activity has also been shown to promote formation of reactive metabolites that may have genotoxic effects. SULT subtype 1E1 (SULT1E1) was identified as a key player in estrogen homeostasis, which is involved in many physiological processes and the pathogenesis of breast and endometrial cancer. The development of an in silico prediction model for SULT1E1 ligands would therefore support the development of metabolically inert drugs and help to assess health risks related to hormonal imbalances. Here, we report on a novel approach to develop a model that enables prediction of substrates and inhibitors of SULT1E1. Molecular dynamics simulations were performed to investigate enzyme flexibility and sample protein conformations. Pharmacophores were developed that served as a cornerstone of the model, and machine learning techniques were applied for prediction refinement. The prediction model was used to screen the DrugBank (a database of experimental and approved drugs): 28% of the predicted hits were reported in literature as ligands of SULT1E1. From the remaining hits, a selection of nine molecules was subjected to biochemical assay validation and experimental results were in accordance with the in silico prediction of SULT1E1 inhibitors and substrates, thus affirming our prediction hypotheses.
    Keywords: Drug Design ; Drug Metabolism ; Liver Metabolism ; Molecular Dynamics ; Molecular Modeling ; Sulfotransferase ; Molecular Dynamics Simulation ; Sulfotransferases -- Chemistry
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: Analytica Chimica Acta, April 13, 2012, Vol.722, p.70(10)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.aca.2012.01.063 Byline: Anja Luth, Corinna Neuber, Burkhard Kleuser Keywords: (2E)-Hexadecenal; Sphingosine-1-phosphate lyase; Derivatisation; Tandem mass spectrometry; Fluorescence Abstract: Display Omitted Author Affiliation: University of Potsdam, Institute of Nutritional Science, Dept. Nutritional Toxicology, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal (Bergholz-Rehbrucke), Germany Article History: Received 5 August 2011; Revised 24 January 2012; Accepted 25 January 2012
    Keywords: Phosphates -- Measurement ; Phosphates -- Methods ; Fluorescence -- Measurement ; Fluorescence -- Methods ; Sphingosine -- Measurement ; Sphingosine -- Methods ; Mass Spectrometry -- Measurement ; Mass Spectrometry -- Methods ; Liquid Chromatography -- Measurement ; Liquid Chromatography -- Methods ; Spectroscopy -- Measurement ; Spectroscopy -- Methods
    ISSN: 0003-2670
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry, 15 February 2013, Vol.21(4), pp.874-882
    Description: In this study we describe the design and synthesis of a series of modified B-13 and LCL-464 analogues with different substituents as inhibitors of recombinant acid and neutral ceramidases. We show that the inhibition potential of B-13 could be enhanced both in in vitro and in intact cells by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed some potent compounds for the inhibition of both aCDase and nCDase with the elevation of ceramide level. Induction of apoptosis mediated by the inhibition of ceramidases has been shown to enhance the efficacy of conventional chemotherapy in several cancer models. Among the inhibitors of ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal acid ceramidase in living cells, LCL-464 a modified derivative of B-13 containing a basic ω-amino group at the fatty acid was reported to have higher potency towards lysosomal acid ceramidase in living cells. In a search for more potent inhibitors of ceramidases, we have designed a series of compounds with structural modifications of B-13 and LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known ceramidase inhibitors B-13 and LCL-464 generates more potent ceramidase inhibitors that are active in intact cells and not only elevates the cellular ceramide levels, but also enhances cell death.
    Keywords: Sphingolipids ; Ceramide ; Ceramidase Inhibitors ; Structure–Activity-Relationship ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 4
    Language: English
    In: Analytical chemistry, 16 September 2014, Vol.86(18), pp.9065-73
    Description: Sphingosine 1-phosphate (S1P), a bioactive lipid involved in various physiological processes, can be irreversibly degraded by the membrane-bound S1P lyase (S1PL) yielding (2E)-hexadecenal and phosphoethanolamine. It is discussed that (2E)-hexadecenal is further oxidized to (2E)-hexadecenoic acid by the long-chain fatty aldehyde dehydrogenase ALDH3A2 (also known as FALDH) prior to activation via coupling to coenzyme A (CoA). Inhibition or defects in these enzymes, S1PL or FALDH, result in severe immunological disorders or the Sjögren-Larsson syndrome, respectively. Hence, it is of enormous importance to simultaneously determine the S1P breakdown product (2E)-hexadecenal and its fatty acid metabolites in biological samples. However, no method is available so far. Here, we present a sensitive and selective isotope-dilution high performance liquid chromatography-electrospray ionization-quadrupole/time-of-flight mass spectrometry method for simultaneous quantification of (2E)-hexadecenal and its fatty acid metabolites following derivatization with 2-diphenylacetyl-1,3-indandione-1-hydrazone and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide. Optimized conditions for sample derivatization, chromatographic separation, and MS/MS detection are presented as well as an extensive method validation. Finally, our method was successfully applied to biological samples. We found that (2E)-hexadecenal is almost quantitatively oxidized to (2E)-hexadecenoic acid, that is further activated as verified by cotreatment of HepG2 cell lysates with (2E)-hexadecenal and the acyl-CoA synthetase inhibitor triacsin C. Moreover, incubations of cell lysates with deuterated (2E)-hexadecenal revealed that no hexadecanoic acid is formed from the aldehyde. Thus, our method provides new insights into the sphingolipid metabolism and will be useful to investigate diseases known for abnormalities in long-chain fatty acid metabolism, e.g., the Sjögren-Larsson syndrome, in more detail.
    Keywords: Spectrometry, Mass, Electrospray Ionization ; Aldehydes -- Analysis ; Lysophospholipids -- Metabolism ; Palmitic Acids -- Analysis ; Sphingosine -- Analogs & Derivatives
    ISSN: 00032700
    E-ISSN: 1520-6882
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  • 5
    Language: English
    In: International Journal of Molecular Sciences, 01 October 2018, Vol.19(10), p.3126
    Keywords: N/a ; Biology
    ISSN: International Journal of Molecular Sciences
    E-ISSN: 1422-0067
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  • 6
    Language: English
    In: Diabetologia, 2014, Vol.57(2), pp.373-382
    Description: Byline: Susann Fayyaz (1), Janin Henkel (2), Lukasz Japtok (1), Stephanie Kramer (3), Georg Damm (4), Daniel Seehofer (4), Gerhard P. Puschel (2), Burkhard Kleuser (1) Keywords: FTY720; Insulin signalling; Palmitate; S1P receptors; Sphingolipids; Sphingosine 1-phosphate Abstract: Aims/hypothesis Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. Methods The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Results Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P.sub.2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P.sub.2, was not able to inhibit insulin signalling. Conclusions/interpretation These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P.sub.2 receptor to impair insulin signalling. In particular, S1P.sub.2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance. Author Affiliation: (1) Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558, Nuthetal, Potsdam, Germany (2) Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Nutritional Biochemistry, University of Potsdam, Potsdam, Germany (3) Max Rubner Laboratory, German Institute of Human Nutrition, Nuthetal, Germany (4) Department of General-, Visceral- and Transplantation Surgery, Charite University of Medicine Berlin, Berlin, Germany Article History: Registration Date: 18/11/2013 Received Date: 10/10/2013 Accepted Date: 06/11/2013 Online Date: 29/11/2013 Article note: Susann Fayyaz and Janin Henkel contributed equally to this work. Electronic supplementary material The online version of this article (doi: 10.1007/s00125-013-3123-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
    Keywords: FTY720 ; Insulin signalling ; Palmitate ; S1P receptors ; Sphingolipids ; Sphingosine 1-phosphate
    ISSN: 0012-186X
    E-ISSN: 1432-0428
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  • 7
    Language: English
    In: International Journal of Pharmaceutics, 10 January 2017, Vol.516(1-2), pp.21-31
    Description: pH-sensitive nanoparticles have a great potential for dermal and transfollicular drug delivery. In this study, pH-sensitive, dexamethasone-loaded Eudragit L 100, Eudragit L 100-55, Eudragit S 100, HPMCP-50, HPMCP-55 and cellulose acetate phthalate nanoparticles were prepared by nanoprecipitation and characterized. The pH-dependent swelling, erosion, dissolution and drug release kinetics were investigated using dynamic light scattering and Franz diffusion cells, respectively. Their toxicity potential was assessed by the ROS and MTT assays. 100–700 nm nanoparticles with high drug loading and entrapment efficiency were obtained. The nanoparticles bear no toxicity potential. Cellulose phthalates nanoparticles were more sensitive to pH than acrylates nanoparticles. They dissolved in 10 mM pH 7.5 buffer and released 〉 80% of the drug within 7 h. The acrylate nanoparticles dissolved in 40 mM pH 7.5 buffer and released 65–70% of the drug within 7 h. The nanoparticles remained intact in 10 and 40 mM pH 6.0 buffers (HPMCP nanoparticles dissolved in 40 mM pH 6.0 buffer) and released slowly. The nanoparticles properties could be modulated by blending the different polymers. In conclusion, various pH-sensitive nanoparticles that could release differently on the skin surface and dissolve and release in the hair follicles were obtained.
    Keywords: Cellulose Acetate Phthalate ; Dexamethasone ; Eudragit® ; Hpmcp ; Ph-Sensitive Nanoparticle ; Skin Nanocarrier ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0378-5173
    E-ISSN: 1873-3476
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  • 8
    Language: English
    In: Analytica Chimica Acta, 13 April 2012, Vol.722, pp.70-79
    Description: ► Very sensitive tandem-MS method for (2 )-hexadecenal. ► Easily practicable HPLC/fluorescence detection method for (2 )-hexadecenal. ► HPLC/fluorescence: for the first time in the present sphingolipid research. ► Derivatization with DAIH to generate a comfortable analyzable azine. ► Determination of (2 )-hexadecenal level in biological samples for the first time ever. Sphingosine-1-phosphate lyase (SPL) is the only known enzyme that irreversibly cleaves sphingosine-1-phosphate (S1P) into phosphoethanolamine and (2 )-hexadecenal during the final step of sphingolipid catabolism. Because S1P is involved in a wide range of physiological and diseased processes, determining the activity of the degrading enzyme is of great interest. Therefore, we developed two procedures based on liquid chromatography (LC) for analysing (2 )-hexadecenal, which is one of the two S1P degradation products. After separation, two different quantification methods were performed, tandem mass spectrometry (MS) and fluorescence detection. However, (2 )-hexadecenal as a long-chain aldehyde is not ionisable by electrospray ionisation (ESI) for MS quantification and has an insufficient number of corresponding double bonds for fluorescence detection. Therefore, we investigated 2-diphenylacetyl-1,3-indandione-1-hydrazone (DAIH) as a derivatisation reagent. DAIH transforms the aldehyde into an ionisable and fluorescent analogue for quantitative analysis. Our conditions were optimised to obtain the outstanding limit of detection (LOD) of 1 fmol per sample (30 μL) for LC–MS/MS and 0.75 pmol per sample (200 μL) for LC determination with fluorescence detection. We developed an extraction procedure to separate and concentrate (2 )-hexadecenal from biological samples for these measurements. To confirm our new methods, we analysed the (2 )-hexadecenal level of different cell lines and human plasma for the first time ever. Furthermore, we treated HT-29 cells with different concentrations of 4-deoxypyridoxine (DOP), which competitively inhibits pyridoxal-5-phosphate (P5P), an essential cofactor for SPL activity, and observed a significant decrease in (2 )-hexadecenal relative to the untreated cells.
    Keywords: (2e)-Hexadecenal ; Sphingosine-1-Phosphate Lyase ; Derivatisation ; Tandem Mass Spectrometry ; Fluorescence ; Chemistry
    ISSN: 0003-2670
    E-ISSN: 1873-4324
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  • 9
    Language: English
    In: International Journal of Molecular Sciences, 01 March 2018, Vol.19(3), p.722
    Description: Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.
    Keywords: Sphingolipids ; Sphingosine Kinase ; Fibrosis ; Non-Alcoholic Fatty Liver Disease ; Insulin Resistance ; Liver Fibrosis ; Biology
    E-ISSN: 1422-0067
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  • 10
    Language: English
    In: 2012, Vol.7(11), p.e49427
    Description: Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P 2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P 2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Dermatology ; Biochemistry
    E-ISSN: 1932-6203
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