TY - JOUR A1 - Mühlenbruch, Kristin A1 - Zhuo, Xiaohui A1 - Bardenheier, Barbara A1 - Shao, Hui A1 - Laxy, Michael A1 - Icks, Andrea A1 - Zhang, Ping A1 - Gregg, Edward W. A1 - Schulze, Matthias Bernd T1 - Selecting the optimal risk threshold of diabetes risk scores to identify high-risk individuals for diabetes prevention BT - a cost-effectiveness analysis JF - Acta Diabetologica N2 - Aims: Although risk scores to predict type 2 diabetes exist, cost-effectiveness of risk thresholds to target prevention interventions are unknown. We applied cost-effectiveness analysis to identify optimal thresholds of predicted risk to target a low-cost community-based intervention in the USA. Methods: We used a validated Markov-based type 2 diabetes simulation model to evaluate the lifetime cost-effectiveness of alternative thresholds of diabetes risk. Population characteristics for the model were obtained from NHANES 2001-2004 and incidence rates and performance of two noninvasive diabetes risk scores (German diabetes risk score, GDRS, and ARIC 2009 score) were determined in the ARIC and Cardiovascular Health Study (CHS). Incremental cost-effectiveness ratios (ICERs) were calculated for increasing risk score thresholds. Two scenarios were assumed: 1-stage (risk score only) and 2-stage (risk score plus fasting plasma glucose (FPG) test (threshold 100 mg/dl) in the high-risk group). Results: In ARIC and CHS combined, the area under the receiver operating characteristic curve for the GDRS and the ARIC 2009 score were 0.691 (0.677-0.704) and 0.720 (0.707-0.732), respectively. The optimal threshold of predicted diabetes risk (ICER < $50,000/QALY gained in case of intervention in those above the threshold) was 7% for the GDRS and 9% for the ARIC 2009 score. In the 2-stage scenario, ICERs for all cutoffs >= 5% were below $50,000/QALY gained. Conclusions: Intervening in those with >= 7% diabetes risk based on the GDRS or >= 9% on the ARIC 2009 score would be cost-effective. A risk score threshold >= 5% together with elevated FPG would also allow targeting interventions cost-effectively. KW - diabetes mellitus KW - type 2 KW - cost-effectiveness analysis KW - lifestyle risk reduction KW - clinical prediction rule Y1 - 2019 U6 - https://doi.org/10.1007/s00592-019-01451-1 SN - 0001-5563 SN - 0940-5429 SN - 1432-5233 VL - 57 IS - 4 SP - 447 EP - 454 PB - Springer CY - Mailand ER - TY - JOUR A1 - Harms, Laura M. A1 - Scalbert, Augustin A1 - Zamora-Ros, Raul A1 - Rinaldi, Sabina A1 - Jenab, Mazda A1 - Murphy, Neil A1 - Achaintre, David A1 - Tjønneland, Anne A1 - Olsen, Anja A1 - Overvad, Kim A1 - Aleksandrova, Krasimira T1 - Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations BT - a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort JF - British Journal of Nutrition N2 - Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 % CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 % CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 % CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 % CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 % CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 % CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies. KW - polyphenols KW - plasma measurements KW - C-reactive protein KW - inflammation KW - chronic diseases Y1 - 2019 U6 - https://doi.org/10.1017/S0007114519002538 SN - 0007-1145 SN - 1475-2662 VL - 123 IS - 2 SP - 198 EP - 208 PB - Cambridge University Press CY - Cambridge ER - TY - JOUR A1 - Solger, Franziska A1 - Kunz, Tobias C. A1 - Fink, Julian A1 - Paprotka, Kerstin A1 - Pfister, Pauline A1 - Hagen, Franziska A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Seibel, Jürgen A1 - Rudel, Thomas T1 - A role of sphingosine in the intracellular survival of Neisseria gonorrhoeae JF - Frontiers in Cellular and Infection Microbiology N2 - Obligate human pathogenic Neisseria gonorrhoeae are the second most frequent bacterial cause of sexually transmitted diseases. These bacteria invade different mucosal tissues and occasionally disseminate into the bloodstream. Invasion into epithelial cells requires the activation of host cell receptors by the formation of ceramide-rich platforms. Here, we investigated the role of sphingosine in the invasion and intracellular survival of gonococci. Sphingosine exhibited an anti-gonococcal activity in vitro. We used specific sphingosine analogs and click chemistry to visualize sphingosine in infected cells. Sphingosine localized to the membrane of intracellular gonococci. Inhibitor studies and the application of a sphingosine derivative indicated that increased sphingosine levels reduced the intracellular survival of gonococci. We demonstrate here, that sphingosine can target intracellular bacteria and may therefore exert a direct bactericidal effect inside cells. KW - Neisseria gonorrhoeae KW - sphingosine KW - sphingolipids KW - sphingosine kinases KW - invasion KW - survival KW - click chemistry Y1 - 2020 U6 - https://doi.org/10.3389/fcimb.2020.00215 SN - 2235-2988 VL - 10 PB - Frontiers Media CY - Lausanne ER - TY - GEN A1 - Kotthoff, Lisa A1 - Lisec, Jan A1 - Schwerdtle, Tanja A1 - Koch, Matthias T1 - Prediction of transformation products of monensin by electrochemistry compared to microsomal assay and hydrolysis T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - The knowledge of transformation pathways and identification of transformation products (TPs) of veterinary drugs is important for animal health, food, and environmental matters. The active agent Monensin (MON) belongs to the ionophore antibiotics and is widely used as a veterinary drug against coccidiosis in broiler farming. However, no electrochemically (EC) generated TPs of MON have been described so far. In this study, the online coupling of EC and mass spectrometry (MS) was used for the generation of oxidative TPs. EC-conditions were optimized with respect to working electrode material, solvent, modifier, and potential polarity. Subsequent LC/HRMS (liquid+ chromatography/high resolution mass spectrometry) and MS/MS experiments were performed to identify the structures of derived TPs by a suspected target analysis. The obtained EC-results were compared to TPs observed in metabolism tests with microsomes and hydrolysis experiments of MON. Five previously undescribed TPs of MON were identified in our EC/MS based study and one TP, which was already known from literature and found by a microsomal assay, could be confirmed. Two and three further TPs were found as products in microsomal tests and following hydrolysis, respectively. We found decarboxylation, O-demethylation and acid-catalyzed ring-opening reactions to be the major mechanisms of MON transformation T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1340 KW - transformation products KW - monensin KW - veterinary drugs KW - electrochemistry KW - hydrolysis KW - LC/HRMS Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-473262 SN - 1866-8372 IS - 1340 ER - TY - GEN A1 - Rancan, Fiorenza A1 - Volkmann, Hildburg A1 - Giulbudagian, Michael A1 - Schumacher, Fabian A1 - Stanko, Jessica Isolde A1 - Kleuser, Burkhard A1 - Blume-Peytavi, Ulrike A1 - Calderón, Marcelo A1 - Vogt, Annika T1 - Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1339 KW - tacrolimus formulation KW - nanogels KW - skin penetration KW - drug delivery KW - human excised skin KW - Jurkat cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-473270 SN - 1866-8372 IS - 1339 ER - TY - JOUR A1 - Baesler, Jessica A1 - Kopp, Johannes Florian A1 - Pohl, Gabriele A1 - Aschner, Michael A1 - Haase, Hajo A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Zn homeostasis in genetic models of Parkinson’s disease in Caenorhabditis elegans JF - Journal of Trace Elements in Medicine and Biology N2 - While the underlying mechanisms of Parkinson’s disease (PD) are still insufficiently studied, a complex interaction between genetic and environmental factors is emphasized. Nevertheless, the role of the essential trace element zinc (Zn) in this regard remains controversial. In this study we altered Zn balance within PD models of the versatile model organism Caenorhabditis elegans (C. elegans) in order to examine whether a genetic predisposition in selected genes with relevance for PD affects Zn homeostasis. Protein-bound and labile Zn species act in various areas, such as enzymatic catalysis, protein stabilization pathways and cell signaling. Therefore, total Zn and labile Zn were quantitatively determined in living nematodes as individual biomarkers of Zn uptake and bioavailability with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) or a multi-well method using the fluorescent probe ZinPyr-1. Young and middle-aged deletion mutants of catp-6 and pdr-1, which are orthologues of mammalian ATP13A2 (PARK9) and parkin (PARK2), showed altered Zn homeostasis following Zn exposure compared to wildtype worms. Furthermore, age-specific differences in Zn uptake were observed in wildtype worms for total as well as labile Zn species. These data emphasize the importance of differentiation between Zn species as meaningful biomarkers of Zn uptake as well as the need for further studies investigating the role of dysregulated Zn homeostasis in the etiology of PD. KW - Caenorhabditis elegans KW - Zinc KW - Zinc homeostasis KW - Parkinson disease KW - Labile zinc Y1 - 2019 U6 - https://doi.org/10.1016/j.jtemb.2019.05.005 VL - 55 SP - 44 EP - 49 PB - Elsevier CY - München ER - TY - JOUR A1 - Koelman, Liselot A. A1 - Pivovarova-Ramich, Olga A1 - Pfeiffer, Andreas F. H. A1 - Grune, Tilman A1 - Aleksandrova, Krasimira T1 - Cytokines for evaluation of chronic inflammatory status in ageing research BT - reliability and phenotypic characterisation JF - Immunity & Ageing N2 - Background: There is a growing interest in the role of inflammageing for chronic disease development. Cytokines are potent soluble immune mediators that can be used as target biomarkers of inflammageing; however, their measurement in human samples has been challenging. This study aimed to assess the reliability of a pro- and anti-inflammatory cytokine panel in a sample of healthy people measured with a novel electrochemiluminescent multiplex immunoassay platform (Meso Scale Discovery, MSD), and to characterize their associations with metabolic and inflammatory phenotypes. KW - Reliability KW - Cytokines KW - Multiplex platforms KW - Inflammaging KW - Biomarkers KW - Ageing KW - BMI Y1 - 2019 U6 - https://doi.org/10.1186/s12979-019-0151-1 SN - 1742-4933 VL - 16 PB - BMC CY - London ER - TY - JOUR A1 - Volkert, Dorothee A1 - Kiesswetter, Eva A1 - Cederholm, Tommy A1 - Donini, Lorenzo M. A1 - Egiseer, Doris A1 - Norman, Kristina A1 - Schneider, Stephane M. A1 - Stroebele-Benschop, Nanette A1 - Torbahn, Gabriel A1 - Wirth, Rainer A1 - Visser, Marjolein T1 - Development of a Model on Determinants of Malnutrition in Aged Persons BT - A MaNuEL Project JF - Gerontology and Geriatric Medicine N2 - In older persons, the origin of malnutrition is often multifactorial with a multitude of factors involved. Presently, a common understanding about potential causes and their mode of action is lacking, and a consensus on the theoretical framework on the etiology of malnutrition does not exist. Within the European Knowledge Hub "Malnutrition in the Elderly (MaNuEL)," a model of "Determinants of Malnutrition in Aged Persons" (DoMAP) was developed in a multistage consensus process with live meetings and written feedback (modified Delphi process) by a multiprofessional group of 33 experts in geriatric nutrition. DoMAP consists of three triangle-shaped levels with malnutrition in the center, surrounded by the three principal conditions through which malnutrition develops in the innermost level: low intake, high requirements, and impaired nutrient bioavailability. The middle level consists of factors directly causing one of these conditions, and the outermost level contains factors indirectly causing one of the three conditions through the direct factors. The DoMAP model may contribute to a common understanding about the multitude of factors involved in the etiology of malnutrition, and about potential causative mechanisms. It may serve as basis for future research and may also be helpful in clinical routine to identify persons at increased risk of malnutrition. KW - older persons KW - malnutrition KW - determinants KW - etiology KW - model Y1 - 2019 U6 - https://doi.org/10.1177/2333721419858438 SN - 2333-7214 VL - 5 PB - Sage Publ. CY - Thousand Oaks ER - TY - JOUR A1 - Gerecke, Christian A1 - Schumacher, Fabian A1 - Berndzen, Alide A1 - Homann, Thomas A1 - Kleuser, Burkhard T1 - Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells JF - Epigenetics : the official journal of the DNA Methylation Society N2 - Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of alpha-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116 IDH1(R132H/+) (harbouring a mutated IDH1 allele) and the parental cells HCT116 IDH1(+/+) (wild type IDH1). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumour suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment of IDH1/2 mutated cancers. KW - Vitamin C KW - epigenetics KW - IDH1 KW - TET KW - cancer cells Y1 - 2019 U6 - https://doi.org/10.1080/15592294.2019.1666652 SN - 1559-2294 SN - 1559-2308 VL - 15 IS - 3 SP - 307 EP - 322 PB - Taylor & Francis Group CY - Philadelphia ER - TY - GEN A1 - Ponce, Carol Barahona A1 - Scherer, Dominique A1 - Boekstegers, Felix A1 - Garate-Calderon, Valentina A1 - Jenab, Mazda A1 - Aleksandrova, Krasimira A1 - Katzke, Verena A1 - Weiderpass, Elisabete A1 - Bonet, Catalina A1 - Moradi, Tahereh A1 - Fischer, Krista A1 - Bossers, Willem A1 - Brenner, Hermann A1 - Schöttker, Ben A1 - Holleczek, Bernd A1 - Hveem, Kristian A1 - Eklund, Niina A1 - Voelker, Uwe A1 - Waldenberger, Melanie A1 - Bermejo, Justo Lorenzo T1 - Arsenic and gallbladder cancer risk BT - Mendelian randomization analysis of European prospective data T2 - International journal of cancer KW - arsenic KW - gallbladder cancer KW - Mendelian randomization Y1 - 2019 U6 - https://doi.org/10.1002/ijc.32837 SN - 0020-7136 SN - 1097-0215 VL - 146 IS - 9 SP - 2648 EP - 2650 PB - Wiley CY - Hoboken ER -