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  • 1
    Language: English
    In: Bioanalysis, November 2013, Vol.5(21), pp.2713-31
    Description: Cannabis is the most widely used illicit drug in the world. The pharmacological properties of Δ(9)-tetrahydrocannabinol also make it a promising molecule in the treatment of different pathologies. Understanding the PKs and PDs of this drug requires the determination of the concentration of Δ(9)-tetrahydrocannabinol and metabolites in biological matrices. For this purpose many analytical methodologies using mass spectrometric detection have been developed. In recent years, LC-MS/MS has become the gold standard in analysis of tetrahydrocannabinol and its metabolites due to the high selectivity and sensitivity, but above all, due to the ability to determine free and conjugate analytes in one run.
    Keywords: Cannabinoids -- Analysis ; Chromatography, Liquid -- Methods ; Dronabinol -- Analysis ; Tandem Mass Spectrometry -- Methods
    ISSN: 17576180
    E-ISSN: 1757-6199
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(9), p.e0138130
    Description: Sphingolipids constitute bioactive molecules with functional implications in liver homeostasis. Particularly, ablation of very long chain ceramides in a knockout mouse model has been shown to cause a severe hepatopathy.We aimed to evaluate the serum sphingolipid profile of 244 patients with cirrhosis prospectively followed for a median period of 228±217 days via mass spectrometry.We thereby observed a significant decrease of long and very long chain ceramides, particularly of C24ceramide, in patients with increasing severity of cirrhosis (p〈0.001). Additionally, hydropic decompensation, defined by clinical presentation of ascites formation, was significantly correlated to low C24ceramide levels (p〈0.001) while a significant association to hepatic decompensation and poor overall survival was observed for low serum concentrations of C24ceramide (p〈0.001) as well. Multivariate analysis further identified low serum C24ceramide to be independently associated to overall survival (standard beta = -0.001, p = 0.022).In our current analysis serum levels of very long chain ceramides show a significant reciprocal correlation to disease severity and hepatic decompensation and are independently associated with overall survival in patients with cirrhosis. Serum sphingolipid metabolites and particularly C24ceramide may constitute novel molecular targets of disease severity, hepatic decompensation and overall prognosis in cirrhosis and should be further evaluated in basic research studies.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Diabetologia, 2014, Vol.57(5), pp.1067-1077
    Description: Byline: Dmitry Namgaladze (1), Sebastian Lips (1), Thomas J. Leiker (2), Robert C. Murphy (2), Kim Ekroos (3), Nerea Ferreiros (4), Gerd Geisslinger (4), Bernhard Brune (1) Keywords: [beta]-Oxidation; Endoplasmic reticulum stress; Fatty acids; Inflammation; Macrophages Abstract: Aims/hypothesis Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid [beta]-oxidation (FAO) affects macrophage responses to SFA. Methods We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. Results To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. Conclusions/interpretation Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO. Author Affiliation: (1) Faculty of Medicine, Institute of Biochemistry I/ZAFES, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany (2) Department of Pharmacology, University of Colorado Denver, Aurora, CO, USA (3) Zora Biosciences Oy, Espoo, Finland (4) pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany Article History: Registration Date: 13/01/2014 Received Date: 25/11/2013 Accepted Date: 02/01/2014 Online Date: 01/02/2014 Article note: Dmitry Namgaladze and Sebastian Lips contributed equally to this study. Electronic supplementary material The online version of this article (doi: 10.1007/s00125-014-3173-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
    Keywords: β-Oxidation ; Endoplasmic reticulum stress ; Fatty acids ; Inflammation ; Macrophages
    ISSN: 0012-186X
    E-ISSN: 1432-0428
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  • 4
    Language: English
    In: Gastroenterology, May 2014, Vol.146(5), pp.S-650-S-650
    Keywords: Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
    Source: ScienceDirect Journals (Elsevier)
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  • 5
    Language: English
    In: Analytica Chimica Acta, 15 November 2018, Vol.1031, pp.185-194
    Description: Lipid mediators play an important role as biological messengers involved in inflammatory processes. Deriving from different polyunsaturated fatty acids, endogenously built mediators featuring both pro- and anti-inflammatory properties as well as pro-resolving lipid mediators and their biological precursors have been investigated. A newly developed method using chiral chromatography-tandem mass spectrometry on human plasma has demonstrated its suitability for the simultaneous determination of prostaglandins, lipoxins, D-series derived resolvins as well as protectins, maresin 1, leukotriene B4 and several precursors of them in order to yield information about metabolic pathways. Due to the matrix complexity, a solid phase extraction method using an octadecyl-modified silica gel cartridge was carried out. The developed method allows the determination of 34 analytes in 25 min showing enough selectivity as well as precision and accuracy (≤15% relative standard deviation, ≤15% relative error) in the calibration range of 0.1–10 ng mL or 0.2–20 ng mL depending on the analytes. Stability of the analytes in plasma has been demonstrated for at least 3 h at room temperature, 72 h in the autosampler and 60 days in the freezer at −80 °C. This method has been validated and shown its suitability for the determination of all studied analytes in human plasma samples.
    Keywords: Specialized Pro-Resolving Lipid Mediators ; Chiral Chromatography ; LC-MS/MS ; Sensitivity ; Resolution ; Chemistry
    ISSN: 0003-2670
    E-ISSN: 1873-4324
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(7), p.e103532
    Description: Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P〈0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365-0.905, P = 0.017).Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Pharmaceutical Research, 2015, Vol.32(12), pp.3986-3998
    Description: Byline: Susanne Beyer (1), Aline Moosmann (2), Astrid S. Kahnt (3), Thomas Ulshofer (4), Michael J. Parnham (4), Nerea Ferreiros (5), Sylvia Wagner (2), Matthias G. Wacker (1) Keywords: biorelevant release; Eudragit[R] RS 100; nanoparticles; peroral drug delivery; Ussing chamber Abstract: Purpose The contribution of permeability and drug release to drug targeting were investigated in the course of development of a nanosized formulation of the anti-inflammatory compound TMP-001, for the local treatment in the gastrointestinal tract. Methods TMP-001 was encapsulated by nanoprecipitation into Eudragit[R] RS 100. The permeability of these carriers was investigated in an Ussing chamber model and the release rate was determined under biorelevant conditions. Formulation toxicity and particle-cell-interaction were investigated by flow cytometry, fluorescence and electron microscopy. Furthermore, spray drying was performed. Results Effective internalization of Eudragit[R]-nanoparticles into cancer cells was demonstrated. A burst release of the nanoparticles implied poor interaction of TMP-001 with Eudragit[R]. A sustained release (70.5% release after 30 min compared to 98.0% for the API) was accomplished after spray drying yielded an increased particle size. Recovery rate of TMP-001 after spray drying was 94.2[+ or -]5.9%. Conclusion The release of API from polymeric nanoparticles contributes profoundly to the in vivo-performance of drug delivery devices in the gastrointestinal tract. The impact of drug-polymer interaction and particle size was analyzed. Sustained release of TMP-001 could only be achieved by increasing particle size. Therefore, biorelevant release testing has been demonstrated to be a valid tool for nanoformulation design. Author Affiliation: (1) Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt (Main), Germany (2) Department of Bioprocess Technologies & Nanotechnology, Fraunhofer Institute for Biomedical Engineering, Ensheimer Stra[sz]e 48, 66386, St. Ingbert, Germany (3) Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt (Main), Germany (4) Fraunhofer Institute of Molecular Biology and Applied Ecology, Project Group for Translational Medicine and Pharmacology, Theodor-Stern-Kai 7, 60596, Frankfurt (Main), Germany (5) Institute of Clinical Pharmacology, Goethe University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany Article History: Registration Date: 15/07/2015 Received Date: 30/04/2015 Accepted Date: 15/07/2015 Online Date: 28/07/2015
    Keywords: biorelevant release ; Eudragit® RS 100 ; nanoparticles ; peroral drug delivery ; Ussing chamber
    ISSN: 0724-8741
    E-ISSN: 1573-904X
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  • 8
    Language: English
    In: Analytical and Bioanalytical Chemistry, 2015, Vol.407(13), pp.3693-3704
    Description: Nucleosides and nucleoside triphosphates are the building blocks of nucleic acids and important bioactive metabolites, existing in all living cells. In the present study, two liquid chromatography tandem mass spectrometry methods were developed to quantify both groups of compounds from the same sample with a shared extraction procedure. After a simple protein precipitation with methanol, the nucleosides were separated with reversed phase chromatography on an Atlantis T3 column while for the separation of the nucleoside triphosphates, an anion exchange column (BioBasic AX) was used. No addition of ion pair reagent was required. A 5500 QTrap was used as analyzer, operating as triple quadrupole. The analytical method for the nucleoside triphosphates has been validated according to the guidelines of the US Food and Drug Administration. The lower limit of quantification values were determined as 10 pg on column (0.5 ng/mL in the injection solution) for deoxyadenosine triphosphate and deoxyguanosine triphosphate, 20 pg (1 ng/mL) for deoxycytidine triphosphate and thymidine triphosphate, 100 pg (5 ng/mL) for cytidine triphosphate and guanosine triphosphate, and 500 pg (25 ng/mL) for adenosine triphosphate und uridine triphosphate respectively. This methodology has been applied to the quantitation of nucleosides and nucleoside triphosphates in primary human CD4 T lymphocytes and macrophages. As expected, the concentrations for ribonucleosides and ribonucleoside triphophates were considerably higher than those obtained for the deoxy derivatives. Upon T cell receptor activation, the levels of all analytes, with the notable exceptions of deoxyadenosine triphosphate and deoxyguanosine triphosphate, were found to be elevated in CD4 T cells.
    Keywords: Nucleosides ; NTP ; LC-MS/MS ; Macrophages ; T lymphocytes
    ISSN: 1618-2642
    E-ISSN: 1618-2650
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 October 2018, Vol.115(43), pp.E10022-E10031
    Description: SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.
    Keywords: Samhd1 ; Allosteric Regulation ; Dntpase ; Nucleotide Analog Drugs ; Substrate Selection ; Allosteric Site -- Drug Effects ; Catalytic Domain -- Drug Effects ; Drug Interactions -- Physiology ; Leukemia, Myeloid, Acute -- Metabolism ; SAM Domain and HD Domain-Containing Protein 1 -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    Language: English
    In: The Journal of biological chemistry, 22 June 2018, Vol.293(25), pp.9685-9695
    Description: Prostaglandin (PG) E is an important lipid mediator that is involved in several pathophysiological processes contributing to fever, inflammation, and pain. Previous studies have shown that early and continuous application of nonsteroidal anti-inflammatory drugs significantly reduces pain behavior in the spared nerve injury (SNI) model for trauma-induced neuropathic pain. However, the role of PGE and its receptors in the development and maintenance of neuropathic pain is incompletely understood but may help inform strategies for pain management. Here, we sought to define the nociceptive roles of the individual PGE receptors (EP1-4) in the SNI model using EP knockout mice. We found that PGE levels at the site of injury were increased and that the expression of the terminal synthase for PGE, cytosolic PGE synthase was up-regulated in resident positive macrophages located within the damaged nerve. Only genetic deletion of the EP3 receptor affected nociceptive behavior and reduced the development of late-stage mechanical allodynia as well as recruitment of immune cells to the injured nerve. Importantly, EP3 activation induced the release of CC-chemokine ligand 2 (CCL2), and antagonists against the CCL2 receptor reduced mechanical allodynia in WT but not in EP3 knockout mice. We conclude that selective inhibition of EP3 might present a potential approach for reducing chronic neuropathic pain.
    Keywords: Ccl2 ; G Protein-Coupled Receptor (Gpcr) ; Prostaglandin E2 ; Chemokine ; Mast Cells ; Neuroinflammation ; Neuropathic Pain ; Pain ; Peripheral Neuron ; Prostaglandin ; Chemokine Ccl2 -- Toxicity ; Hyperalgesia -- Prevention & Control ; Neuralgia -- Prevention & Control ; Receptors, Prostaglandin E, Ep3 Subtype -- Physiology ; Sciatic Nerve -- Physiopathology
    E-ISSN: 1083-351X
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