TY - JOUR A1 - Shahid, Muhammad A1 - Manchi, G. A1 - Slunsky, Pavel A1 - Naseer, O. A1 - Fatima, A. A1 - Leo, B. A1 - Raila, Jens T1 - A systemic review of existing serological possibilities to diagnose canine osteoarthritis with a particular focus on extracellular matrix proteoglycans and protein JF - Polish journal of veterinary sciences : PJVS : the journal of Committee of Veterinary Sciences of Polish Academy of Sciences and University of Warmia and Mazury in Olsztyn N2 - Extra-cellular matrix (ECM) components are important and their stabilization is significant in maintaining normal healthy joint environment. In osteoarthritis (OA), ECM components are altered and indicate disease progression. The joint ECM is composed of proteoglycans (aggrecan, perlecan,inter α-trypsin inhibitor), glycoproteins (fibronectin, lubricin, COMP) and collagen types (most abundantly collagen type II) which represent structural and functional transformation during disease advancement. ECM investigation revealed significant biomarkers of OA that could be used as a diagnostic and therapeutic tool in different canine orthopedic diseases. This review deliberates our current findings of how the components of ECM change at the molecular level during disease progression in canine OA. KW - extra-cellular matrix KW - canine osteoarthritis KW - biomarker KW - synovial fluid KW - proteomix analysis Y1 - 2017 U6 - https://doi.org/10.1515/pjvs-2017-0024 SN - 1505-1773 SN - 2300-2557 VL - 20 IS - 1 SP - 189 EP - 201 PB - De Gruyter CY - Berlin ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Hasan, Ahmed A. A1 - Zeng, Shufei A1 - Hocher, Berthold T1 - Plasma ET-1 concentrations are elevated in pregnant women with hypertension - meta-analysis of clinical studies JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies. Methods: Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model. Results: Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria. Conclusion: Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure. KW - Et-1 KW - Pregnancy KW - Hypertension KW - Meta-analysis Y1 - 2017 U6 - https://doi.org/10.1159/000482004 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 4 SP - 654 EP - 663 PB - Karger CY - Basel ER - TY - JOUR A1 - Fayyaz, Susann A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Wigger, Dominik A1 - Schulz, Tim Julius A1 - Haubold, Kathrin A1 - Gulbins, Erich A1 - Völler, Heinz A1 - Kleuser, Burkhard T1 - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity. KW - Lysophosphatidic acid KW - Insulin signaling KW - Adipose tissue KW - Autotaxin KW - Hepatic insulin resistance KW - LPA(3) receptor subtype Y1 - 2017 U6 - https://doi.org/10.1159/000480470 SN - 1015-8987 SN - 1421-9778 VL - 43 SP - 445 EP - 456 PB - Karger CY - Basel ER - TY - JOUR A1 - Neuber, Corinna A1 - Schumacher, Fabian A1 - Gulbins, Erich A1 - Kleuser, Burkhard T1 - Mass Spectrometric Determination of Fatty Aldehydes Exemplified by Monitoring the Oxidative Degradation of (2E)-Hexadecenal in HepG2 Cell Lysates JF - Lipidomics N2 - Within the last few decades, liquid chromatography-mass spectrometry (LC-MS) has become a preferred method for manifold issues in analytical biosciences, given its high selectivity and sensitivity. However, the analysis of fatty aldehydes, which are important components of cell metabolism, remains challenging. Usually, chemical derivatization prior to MS detection is required to enhance ionization efficiency. In this regard, the coupling of fatty aldehydes to hydrazines like 2,4-dinitrophenylhydrazine (DNPH) is a common approach. Additionally, hydrazones readily react with fatty aldehydes to form stable derivatives, which can be easily separated using high-performance liquid chromatography (HPLC) and subsequently detected by MS. Here, we exemplarily present the quantification of the long-chain fatty aldehyde (2E)-hexadecenal, a break-down product of the bioactive lipid sphingosine 1-phosphate (S1P), after derivatization with 2-diphenylacetyl-1,3-indandione-1-hydrazone (DAIH) via isotope-dilution HPLC-electrospray ionization-quadrupole/time-of-flight (ESI-QTOF) MS. Moreover, we show that the addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) as a coupling agent allows for simultaneous determination of fatty aldehydes and fatty acids as DAIH derivatives. Taking advantage of this, we describe in detail how to monitor the degradation of (2E)-hexadecenal and the concurrent formation of its oxidation product (2E)-hexadecenoic acid in lysates of human hepatoblastoma (HepG2) cells within this chapter. KW - (2E)-hexadecenal KW - (2E)-hexadecenoic acid KW - Sphingosine 1-phosphate KW - Derivatization KW - DAIH KW - EDC KW - Isotope-dilution KW - HPLC-ESI-QTOF Y1 - 2017 SN - 978-1-4939-6946-3 SN - 978-1-4939-6944-9 U6 - https://doi.org/10.1007/978-1-4939-6946-3_10 SN - 0893-2336 SN - 1940-6045 VL - 125 SP - 147 EP - 158 PB - Humana Press CY - Totowa ER - TY - JOUR A1 - Schwiebs, Anja A1 - Thomas, Dominique Jeanette A1 - Kleuser, Burkhard A1 - Pfeilschifter, Josef A1 - Radeke, Heinfried H. T1 - Nuclear translocation of SGPP-1 and decrease of SGPL-1 activity contribute to sphingolipid rheostat regulation of inflammatory dendritic cells JF - Mediators of inflammation N2 - A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation. Y1 - 2017 U6 - https://doi.org/10.1155/2017/5187368 SN - 0962-9351 SN - 1466-1861 PB - Hindawi Publishing Corp. CY - London ER - TY - JOUR A1 - Hoehn, Richard S. A1 - Jernigan, Peter L. A1 - Japtok, Lukasz A1 - Chang, Alex L. A1 - Midura, Emily F. A1 - Caldwell, Charles C. A1 - Kleuser, Burkhard A1 - Lentsch, Alex B. A1 - Edwards, Michael J. A1 - Gulbins, Erich A1 - Pritts, Timothy A. T1 - Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation JF - Annals of surgery : a monthly review of surgical science and practice N2 - Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood. KW - acid sphingomyelinase KW - blood banking KW - ceramide KW - lung inflammation KW - microparticle Y1 - 2017 U6 - https://doi.org/10.1097/SLA.0000000000001648 SN - 0003-4932 SN - 1528-1140 VL - 265 IS - 1 SP - 218 EP - 226 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Yang, Xiaoping A1 - Darko, Kwame Oteng A1 - Huang, Yanjun A1 - He, Caimei A1 - Yang, Huansheng A1 - He, Shanping A1 - Li, Jianzhong A1 - Li, Jian A1 - Hocher, Berthold A1 - Yin, Yulong T1 - Resistant starch regulates gut microbiota BT - structure, biochemistry and cell signalling JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Starch is one of the most popular nutritional sources for both human and animals. Due to the variation of its nutritional traits and biochemical specificities, starch has been classified into rapidly digestible, slowly digestible and resistant starch. Resistant starch has its own unique chemical structure, and various forms of resistant starch are commercially available. It has been found being a multiple-functional regulator for treating metabolic dysfunction. Different functions of resistant starch such as modulation of the gut microbiota, gut peptides, circulating growth factors, circulating inflammatory mediators have been characterized by animal studies and clinical trials. In this mini-review, recent remarkable progress in resistant starch on gut microbiota, particularly the effect of structure, biochemistry and cell signaling on nutrition has been summarized, with highlights on its regulatory effect on gut microbiota. KW - Resistant starch KW - Gut microbiota KW - Nutrition Y1 - 2017 U6 - https://doi.org/10.1159/000477386 SN - 1015-8987 SN - 1421-9778 VL - 42 IS - 1 SP - 306 EP - 318 PB - Karger CY - Basel ER - TY - JOUR A1 - He, Jing A1 - Liu, Zhi-Wei A1 - Lu, Yong-Ping A1 - Li, Tao-Yuan A1 - Liang, Xu-Jing A1 - Arck, Petra A1 - Huang, Si-Min A1 - Hocher, Berthold A1 - Chen, You-Peng T1 - A systematic review and meta-analysis of influenza a virus infection during pregnancy associated with an increased risk for stillbirth and low birth weight JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: Impaired pregnancy outcomes, such as low birth weight are associated with increased disease risk in later life, however little is known about the impact of common infectious diseases during pregnancy on birth weight. The study had two aims: a) to investigate risk factors of influenza virus infection during pregnancy, and b) to analyze the impact of influenza virus infection on pregnancy outcome, especially birth weight. Methods: Prospective and retrospective observational studies found in PubMed, MEDLINE, Embase, Google Scholar, and WangFang database were included in this meta analysis. Data of included studies was extracted and analyzed by the RevMan software. Results: Pregnant women with anemia (P=0.004, RR=1.46, 95% CI: 1.13-1.88), obesity (P<0.00001, RR=1.35, 95% CI: 1.25-1.46) and asthma (P<0.00001, RR=1.99, 95% CI: 1.67-2.37) had higher rates of influenza virus infection. Regarding birth outcomes, influenza A virus infection did not affect the likelihood for cesarean section. Mothers with influenza had a higher rate of stillbirth (P=0.04, RR=2.36, 95% CI: 1.05-5.31), and their offspring had low 5-minute APGR Scores (P=0.009, RR=1.39, 95% CI: 1.08-1.79). Furthermore, the rate for birth weight < 2500g (P=0.04, RR=1.71, 95% CI: 1.03-2.84) was increased. Conclusion: Results of this study showed that anemia, asthma and obesity during pregnancy are risk factors influenza A virus infection during pregnancy. Moreover, gestational influenza A infection impairs pregnancy outcomes and increases the risk for low birth weight, a known risk factor for later life disease susceptibility. KW - Apgar score KW - Influenza virus KW - Offspring KW - Outcome KW - Pregnancy KW - Stillbirth KW - Birth weight Y1 - 2017 U6 - https://doi.org/10.1159/000477221 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 2 SP - 232 EP - 243 PB - Karger CY - Basel ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Heunisch, Fabian A1 - von Einem, Gina-Franziska A1 - Tsuprykov, Oleg A1 - Kellner, Karl-Heinz A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Hocher, Berthold T1 - Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application. Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE. Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at >= 3.5 mu mol/L. Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine >= 3.5 mu mol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography. KW - Contrast induced acute kidney injury KW - Coronary angiography KW - Major adverse kidney event KW - Kynurenine KW - Preinterventional biomarker Y1 - 2017 U6 - https://doi.org/10.1159/000477222 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 2 SP - 244 EP - 256 PB - Karger CY - Basel ER - TY - JOUR A1 - Xu, Mei A1 - Lu, Yong-Ping A1 - Hasan, Ahmed A. A1 - Hocher, Berthold T1 - Plasma ET-1 concentrations are elevated in patients with hypertension meta-analysis of clinical studies JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies. Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models. Results: Eleven studies fulfilling our in-and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95%Ci [0.47 similar to 2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg. Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage. KW - Hypertension KW - ET-1 KW - Meta-analysis Y1 - 2017 U6 - https://doi.org/10.1159/000477572 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 2 SP - 304 EP - 313 PB - Karger CY - Basel ER - TY - JOUR A1 - Gerecke, Christian A1 - Edlich, Alexander A1 - Giulbudagian, Michael A1 - Schumacher, Fabian A1 - Zhang, Nan A1 - Said, Andre A1 - Yealland, Guy A1 - Lohan, Silke B. A1 - Neumann, Falko A1 - Meinke, Martina C. A1 - Ma, Nan A1 - Calderon, Marcelo A1 - Hedtrich, Sarah A1 - Schaefer-Korting, Monika A1 - Kleuser, Burkhard T1 - Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes JF - Nanotoxicology N2 - Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery. KW - Drug delivery KW - nanoparticles KW - particle characterization KW - keratinocytes KW - nanotoxicology Y1 - 2017 U6 - https://doi.org/10.1080/17435390.2017.1292371 SN - 1743-5390 SN - 1743-5404 VL - 11 SP - 267 EP - 277 PB - Routledge, Taylor & Francis Group CY - Abingdon ER - TY - JOUR A1 - Sahle, Fitsum Feleke A1 - Gerecke, Christian A1 - Kleuser, Burkhard A1 - Bodmeier, Roland T1 - Formulation and comparative in vitro evaluation of various dexamethasone-loaded pH-sensitive polymeric nanoparticles intended for dermal applications JF - International Journal of Pharmaceutics N2 - pH-sensitive nanoparticles have a great potential for dermal and transfollicular drug delivery. In this study, pH-sensitive, dexamethasone-loaded Eudragit (R) L 100, Eudragit (R) L 100-55, Eudragit (R) 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 in vitro 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. KW - Cellulose acetate phthalate KW - Dexamethasone KW - Eudragit (R) KW - HPMCP KW - pH-sensitive nanoparticle KW - Skin nanocarrier Y1 - 2016 U6 - https://doi.org/10.1016/j.ijpharm.2016.11.029 SN - 0378-5173 SN - 1873-3476 VL - 516 IS - 1-2 SP - 21 EP - 31 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Heunisch, Fabian A1 - Chaykovska, Lyubov A1 - von Einem, Gina A1 - Alter, Markus A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Kellner, Karl-Heinz A1 - Hocher, Berthold T1 - ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography JF - Medicine N2 - Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide (NO)-synthase and a biomarker of endothelial dysfunction (ED). ED plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of our study was to evaluate serum ADMA concentration as a biomarker of an acute renal damage during the follow-up of 90 days after contrast medium (CM) application. Blood samples were obtained from 330 consecutive patients with diabetes mellitus or mild renal impairment immediately before, 24 and 48 hours after the CM application for coronary angiography. The patients were followed for 90 days. The composite endpoints were major adverse renal events (MARE) defined as occurrence of death, initiation of dialysis, or a doubling of serum creatinine concentration. Overall, ADMA concentration in plasma increased after CM application, although, there was no differences between ADMA levels in patients with and without CIN. ADMA concentration 24 hours after the CM application was predictive for dialysis with a specificity of 0.889 and sensitivity of 0.653 at values higher than 0.71 mu mol/L (area under the curve: 0.854, 95% confidential interval: 0.767-0.941, P<0.001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. 24 hours after the CM application, ADMA concentration in plasma was predictive for MARE with a specificity of 0.833 and sensitivity of 0.636 at a value of more than 0.70 mu mol/L (area under the curve: 0.750, 95% confidence interval: 0.602-0.897, P=0.004). Multivariate logistic regression analysis confirmed that ADMA and anemia were significant predictors of MARE. Further analysis revealed that increased ADMA concentration in plasma was highly significant predictor of MARE in patients with CIN. Moreover, patients with CIN and MARE had the highest plasma ADMA levels 24 hours after CM exposure in our study cohort. The impact of ADMA on MARE was independent of such known CIN risk factors as anemia, pre-existing renal failure, pre-existing heart failure, and diabetes. ADMA concentration in plasma is a promising novel biomarker of major contrast-induced nephropathy-associated events 90 days after contrast media exposure. KW - asymmetric dimethylarginine (ADMA) KW - biomarkers of renal failure KW - contrast-induced nephropathy Y1 - 2017 U6 - https://doi.org/10.1097/MD.0000000000006065 SN - 0025-7974 SN - 1536-5964 VL - 96 IS - 6 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Taylor, Vivien A1 - Goodale, Britton A1 - Raab, Andrea A1 - Schwerdtle, Tanja A1 - Reimer, Ken A1 - Conklin, Sean A1 - Karagas, Margaret R. A1 - Francesconi, Kevin A. T1 - Human exposure to organic arsenic species from seafood JF - The science of the total environment : an international journal for scientific research into the environment and its relationship with man N2 - Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be nontoxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge. KW - Organic arsenic KW - Seafood KW - Arsenosugar KW - Arsenolipid Y1 - 2017 U6 - https://doi.org/10.1016/j.scitotenv.2016.12.113 SN - 0048-9697 SN - 1879-1026 VL - 580 SP - 266 EP - 282 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Marschall, Talke Anu A1 - Kroepfl, Nina A1 - Jensen, Kenneth Bendix A1 - Bornhorst, Julia A1 - Meermann, B. A1 - Kühnelt, Doris A1 - Schwerdtle, Tanja T1 - Tracing cytotoxic effects of small organic Se species in human liver cells back to total cellular Se and Se metabolites JF - Metallomics N2 - Small selenium (Se) species play a major role in the metabolism, excretion and dietary supply of the essential trace element selenium. Human cells provide a valuable tool for investigating currently unresolved issues on the cellular mechanisms of Se toxicity and metabolism. In this study, we developed two isotope dilution inductively coupled plasma tandem-mass spectrometry based methods and applied them to human hepatoma cells (HepG2) in order to quantitatively elucidate total cellular Se concentrations and cellular Se species transformations in relation to the cytotoxic effects of four small organic Se species. Species-and incubation time-dependent results were obtained: the two major urinary excretion metabolites trimethylselenonium (TMSe) and methyl-2-acetamido-2-deoxy-1-seleno-beta- D-galactopyranoside (SeSugar 1) were taken up by the HepG2 cells in an unmodified manner and did not considerably contribute to the Se pool. In contrast, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet) were taken up in higher amounts, they were largely incorporated by the cells (most likely into proteins) and metabolized to other small Se species. Two new metabolites of MeSeCys, namely gamma-glutamyl-Se-methylselenocysteine and Se-methylselenoglutathione, were identified by means of HPLC-electrospray-ionization-Orbitrap-MS. They are certainly involved in the (de-) toxification modes of Se metabolism and require further investigation. Y1 - 2017 U6 - https://doi.org/10.1039/c6mt00300a SN - 1756-5901 SN - 1756-591X VL - 9 SP - 268 EP - 277 PB - Royal Society of Chemistry CY - Cambridge ER - TY - GEN A1 - Döge, Nadine A1 - Schumacher, Fabian A1 - Balzus, Benjamin A1 - Colombo, Miriam A1 - Hadam, Sabrina A1 - Rancan, Fiorenza A1 - Blume-Peytavi, Ulrike A1 - Kleuser, Burkhard A1 - Bodmeier, Roland A1 - Vogt, Annika T1 - Particle- based formulations and controlled skin barrier disruption have a signifi cant impact on the delivery and penetration kinetics of dexamethasone as assessed in an ex vivo microdialysis T2 - Journal der Deutschen Dermatologischen Gesellschaft N2 - Preclinical assessment of penetration not only in intact, but also in barrier‐disrupted skin is important to explore the surplus value of novel drug delivery systems, which can be specifically designed for diseased skin. Here, we characterized physical and chemical barrier disruption protocols for short‐term ex vivo skin cultures with regard to structural integrity, physiological and biological parameters. Further, we compared the penetration of dexamethasone (Dex) in different nanoparticle‐based formulations in stratum corneum, epidermis and dermis extracts of intact vs. barrier‐disrupted skin as well as by dermal microdialysis at 6, 12 and 24 hours after topical application. Dex was quantified by liquid‐chromatography ‐ tandem‐mass spectrometry (LC‐MS/MS). Simultaneously, we investigated the Dex efficacy by interleukin (IL) analysis. Tape‐stripping (TS) and 4 hours sodium lauryl sulfate 5 % (SLS) exposure were identified as highly effective barrier disruption methods assessed by reproducible transepidermal water loss (TEWL) changes and IL‐6/8 increase which was more pronounced in SLS‐treated skin. The barrier state has also a significant impact on the Dex penetration kinetics: for all formulations, TS highly increased dermal Dex concentration despite the fact that nanocrystals quickly and effectively penetrated both, intact and barrier‐disrupted skin reaching significantly higher dermal Dex concentration after 6 hours compared to Dex cream. The surplus value of encapsulation in ethyl cellulose nanocarriers could mostly be observed when applied on intact skin, in general showing a delayed Dex penetration. Estimation of cytokines was limited due to the trauma caused by probe insertion. In summary, ex vivo human skin is a highly interesting short‐term preclinical model for the analysis of penetration and efficacy of novel drug delivery systems. Y1 - 2017 SN - 1610-0379 SN - 1610-0387 VL - 15 SP - 182 EP - 182 PB - Wiley CY - Berlin ER - TY - JOUR A1 - Bönick, Josephine A1 - Huschek, Gerd A1 - Rawel, Harshadrai Manilal T1 - Determination of wheat, rye and spelt authenticity in bread by targeted peptide biomarkers JF - Journal of Food Composition and Analysis N2 - Adulteration of food and mislabeled products in global market is a major financial and reputational risk for food manufacturers and trade companies. Consequently, there is a necessity to develop analytical methods to meet these issues. An analytical strategy to check the authenticity of wheat, spelt and rye addition in bread products was developed based on database research, in silico digestion confirming peptide specificity and finally quantification by liquid chromatography-tandem mass spectrometry analysis. Peptide markers for wheat (SQQQISQQPQQLPQQQQIPQQPQQF; QQHQIPQQPQQFPQQQQF and QPHQPQQPYPQQ), spelt (ASIVVGIGGQ; SQQPGQIIPQQPQQPSPL) and rye (LPQSHKQHVGQGAL; AQVQGIIQPQQL and QQFPQQPQQSFPQQPQQPVPQQPL) were identified, verified by protein Basic Local Alignment Search Tool and database research and used for quantification in bread. The specific use of multi-reaction monitoring transitions of selected peptides permitted the identification of closely related species wheat and spelt. Other cereal species (emmer, einkorn, barley, maize, rye and oat) were also checked. The target peptides were quantified at different levels using own reference baked products (bread) after in-solution chymotryptic digestion. Sensitivity of the identification was 0.5-1% using flour-based (0-25%) matrix calibration and the analytical recovery in bread was 80-125%. The analytical strategy described here supplies an emerging, independent and flexible tool in controlling the labeling of bread. KW - Food analysis KW - Food composition KW - Food safety KW - Plant authentication KW - Wheat KW - Spelt KW - Rye KW - LC-MS-MS KW - Quantification of peptides KW - Food labeling Y1 - 2017 U6 - https://doi.org/10.1016/j.jfca.2017.01.019 SN - 0889-1575 SN - 1096-0481 VL - 58 SP - 82 EP - 91 PB - Elsevier CY - San Diego ER - TY - JOUR A1 - Balzus, Benjamin A1 - Sahle, Fitsum Feleke A1 - Hönzke, Stefan A1 - Gerecke, Christian A1 - Schumacher, Fabian A1 - Hedtrich, Sarah A1 - Kleuser, Burkhard A1 - Bodmeier, Roland T1 - Formulation and ex vivo evaluation of polymeric nanoparticles for controlled delivery of corticosteroids to the skin and the corneal epithelium JF - European journal of pharmaceutics and biopharmaceutics : EJPB ; official journal of the International Association for Pharmaceutical Technology N2 - Controlled delivery of corticosteroids using nanoparticles to the skin and corneal epithelium may reduce their side effects and maximize treatment effectiveness. Dexamethasone-loaded ethyl cellulose, Eudragit® RS and ethyl cellulose/Eudragit® RS nanoparticles were prepared by the solvent evaporation method. Dexamethasone release from the polymeric nanoparticles was investigated in vitro using Franz diffusion cells. Drug penetration was also assessed ex vivo using excised human skin. Nanoparticle toxicity was determined by MTT and H2DCFDA assays. Eudragit® RS nanoparticles were smaller and positively charged but had a lower dexamethasone loading capacity (0.3–0.7%) than ethyl cellulose nanoparticles (1.4–2.2%). By blending the two polymers (1:1), small (105 nm), positively charged (+37 mV) nanoparticles with sufficient dexamethasone loading (1.3%) were obtained. Dexamethasone release and penetration significantly decreased with decreasing drug to polymer ratio and increased when Eudragit® RS was blended with ethyl cellulose. Ex vivo, drug release and penetration from the nanoparticles was slower than a conventional cream. The nanoparticles bear no toxicity potentials except ethyl cellulose nanoparticles had ROS generation potential at high concentration. In conclusion, the nanoparticles showed great potential to control the release and penetration of corticosteroids on the skin and mucus membrane and maximize treatment effectiveness. KW - Dermal delivery KW - Dexamethasone KW - Ethyl cellulose KW - Eudragit (R) RS KW - Ocular delivery KW - Polymeric nanoparticle Y1 - 2017 U6 - https://doi.org/10.1016/j.ejpb.2017.02.001 SN - 0939-6411 SN - 1873-3441 VL - 115 SP - 122 EP - 130 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - McVey, Mark J. A1 - Kim, Michael A1 - Tabuchi, Arata A1 - Srbely, Victoria A1 - Japtok, Lukasz A1 - Arenz, Christoph A1 - Rotstein, Ori A1 - Kleuser, Burkhard A1 - Semple, John W. A1 - Kuebler, Wolfgang M. T1 - Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets JF - American journal of physiology : Lung cellular and molecular physiology N2 - Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products. KW - transfusion-related acute lung injury KW - ceramide KW - acid sphingomyelinase KW - platelets KW - storage Y1 - 2017 U6 - https://doi.org/10.1152/ajplung.00317.2016 SN - 1040-0605 SN - 1522-1504 VL - 312 IS - 5 SP - 625 EP - 637 PB - American Physiological Society CY - Bethesda ER - TY - JOUR A1 - Fruscalzo, Arrigo A1 - Frommer, Julia-Marie A1 - Londero, Ambrogio P. A1 - Henze, Andrea A1 - Schweigert, Florian J. A1 - Nofer, Jerzy-Roch A1 - Steinhard, Johannes A1 - Klockenbusch, Walter A1 - Schmitz, Ralf A1 - Raila, Jens T1 - First trimester TTR-RBP4-ROH complex and angiogenic factors in the prediction of small for gestational age infant’s outcome JF - Archives of gynecology and obstetrics N2 - To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95% CI 1.40-1.75) vs 1.62 (95% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95% CI 32.3-66.3) vs 62.9 pg/ml (95% CI 45.2-78.4) and 906 pg/ml (95% CI 727-1626) vs 1610 pg/ml (95% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses. KW - Low birth weight KW - Small for gestational age KW - Pregnancy KW - First trimester KW - Marker KW - RBP4 KW - TTR KW - Retinol KW - Vitamin A KW - sFlt-1 KW - PlGF Y1 - 2017 U6 - https://doi.org/10.1007/s00404-017-4338-4 SN - 0932-0067 SN - 1432-0711 VL - 295 SP - 1157 EP - 1165 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Folkesson, Maggie A1 - Vorkapic, Emina A1 - Gulbins, Erich A1 - Japtok, Lukasz A1 - Kleuser, Burkhard A1 - Welander, Martin A1 - Länne, Toste A1 - Wågsäter, Dick T1 - Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms JF - Journal of vascular surgery N2 - Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study. Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT. Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage. Y1 - 2016 U6 - https://doi.org/10.1016/j.jvs.2015.12.056 SN - 0741-5214 VL - 65 IS - 4 SP - 1171 EP - 1179 PB - Elsevier CY - New York ER - TY - JOUR A1 - Bernacchioni, Caterina A1 - Ghini, Veronica A1 - Cencetti, Francesca A1 - Japtok, Lukasz A1 - Donati, Chiara A1 - Bruni, Paola A1 - Turano, Paola T1 - NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells JF - Molecular oncology / Federation of European Biochemical Societies N2 - Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies. KW - NMR-based metabolomics KW - ovarian cancer KW - sphingosine kinase-1 KW - Warburg effect Y1 - 2017 U6 - https://doi.org/10.1002/1878-0261.12048 SN - 1878-0261 VL - 11 SP - 517 EP - 533 PB - Wiley CY - Hoboken ER - TY - GEN A1 - Halibasic, Emina A1 - Fuerst, Elisabeth A1 - Heiden, Denis A1 - Japtok, Lukasz A1 - Diesner, Susanne C. A1 - Hillebrand, P. A1 - Trauner, Michael A1 - Kleuser, Burkhard A1 - Kazemi-Shirazi, Lili A1 - Untersmayr, Eva T1 - Significantly reduced plasma levels of the bioactive sphingolipid S1P in lung transplanted cystic fibrosis patients are associated with gastrointestinal symptoms T2 - Allergy Y1 - 2017 SN - 0105-4538 SN - 1398-9995 VL - 72 IS - S103 SP - 195 EP - 195 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Kröpfl, Nina A1 - Marschall, Talke A. A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja A1 - Kuehnelt, Doris T1 - Quantitative determination of the sulfur-containing antioxidant ergothioneine by HPLC/ICP- QQQ-MS JF - Journal of Analytical Atomic Spectrometry N2 - Interest in the sulfur-containing antioxidant ergothioneine calls for reliable analytical methods for its quantification. In this work, a method based on reversed-phase high performance liquid chromatography (RP-HPLC) coupled with elemental mass spectrometry detection in mass shift mode (inductively coupled plasma triple quadrupole mass spectrometry, ICP-QQQ-MS) using oxygen as the reaction gas was developed for the element-selective determination of ergothioneine in complex biological matrices. Application of an instrumental setup using a 6-port-valve and the introduction of a methanol gradient allowed the time-efficient analysis of samples containing strongly retained sulfur species besides ergothioneine without compromising ICPMS detection. In aqueous solution, limits of detection and quantification (LOD and LOQ) of the optimized method for m/z 32 -> 48 (SO+) were 0.23 mu g S per L and 0.80 mu g S per L, respectively; measurements in a complex matrix (human hepatocyte carcinoma cells, HepG2) resulted in an LOD of 0.6 mu g S per L and an LOQ of 2.3 mu g S per L. Recoveries of ergothioneine from cell pellets spiked with the analyte before cell lysis (97 +/- 3%) matched those obtained for cell culture medium spiked before syringe filtration (96 +/- 9%) demonstrating that sample preparation did not impair the quantitative determination of ergothioneine. When HepG2 cells were exposed to ergothioneine via the culture medium, they showed low absorption; approximately 3% of the added ergothioneine was found in cell lysates, while most of it (>= 85%) remained in the cell culture medium. The method is capable of separating ergothioneine from other biologically relevant sulfur-containing species and is expected to be of broad future use. Furthermore, the potential use for the simultaneous separation of selenium species, thereby extending the scope of possible applications, was demonstrated by applying it to water extracts of oyster mushrooms. Y1 - 2017 U6 - https://doi.org/10.1039/c7ja00030h SN - 0267-9477 SN - 1364-5544 VL - 32 SP - 1571 EP - 1581 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Meyer, Sören A1 - Lopez-Serrano, Aniceto A1 - Mitze, Hanna A1 - Jakubowski, Norbert A1 - Schwerdtle, Tanja T1 - Single-cell analysis by ICP-MS/MS as a fast tool for cellular bioavailability studies of arsenite JF - Metallomics : integrated biometal science N2 - Single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) has become a powerful and fast tool to evaluate the elemental composition at a single-cell level. In this study, the cellular bioavailability of arsenite (incubation of 25 and 50 mu M for 0-48 h) has been successfully assessed by SC-ICP-MS/MS for the first time directly after re-suspending the cells in water. This procedure avoids the normally arising cell membrane permeabilization caused by cell fixation methods (e.g. methanol fixation). The reliability and feasibility of this SC-ICP-MS/MS approach with a limit of detection of 0.35 fg per cell was validated by conventional bulk ICP-MS/MS analysis after cell digestion and parallel measurement of sulfur and phosphorus. Y1 - 2017 U6 - https://doi.org/10.1039/c7mt00285h SN - 1756-5901 SN - 1756-591X VL - 10 IS - 1 SP - 73 EP - 76 PB - Royal Society of Chemistry CY - Cambridge ER - TY - GEN A1 - Pischon, Hannah A1 - Radbruch, Moritz A1 - Ostrowski, Anja A1 - Schumacher, Fabian A1 - Hoenzke, Stefan A1 - Kleuser, Burkhard A1 - Hedtrich, Sarah A1 - Fluhr, Joachim W. A1 - Gruber, Achim D. A1 - Mundhenk, Lars T1 - How Effective Is Tacrolimus in the Imiquimod BT - Induced Mouse Model of Psoriasis? T2 - The journal of investigative dermatology Y1 - 2017 U6 - https://doi.org/10.1016/j.jid.2017.09.019 SN - 0022-202X SN - 1523-1747 VL - 138 IS - 2 SP - 455 EP - 458 PB - Elsevier CY - New York ER - TY - JOUR A1 - Erbersdobler, Helmut F. A1 - Barth, Christian A. A1 - Jahreis, Gerhard T1 - Körnerleguminosen in der Humanernährung T1 - Grain Legumes in Human Nutrition Nutrient BT - Nährstoffgehalt und Proteinqualität von Hülsenfrüchten BT - Nutrient Content and Protein Quality of Pulses JF - Ernährungs-Umschau : Forschung & Praxis N2 - Fortsetzung aus Ernährungs Umschau Heft 9/2017 Fettsäurenverteilung Die Gehalte an den wichtigsten Fettsäuren (FS) sind in • Tabelle 4 und 5 aufgeführt, in g/100 g sowie in Prozent des Fettanteils (Etherextrakt bzw. g FS-Methylester pro 100 g der Summe der FS-Methylester). Erbsen und Ackerbohnen spielen als Fett- und FS-Quelle praktisch keine Rolle. Sojabohnen sind eine wesentliche Quelle für Linolsäure, die häufigste n-6-FS. An zweiter Stelle steht die Ölsäure. Aber auch der Gehalt an der n-3-FS α-Linolensäure (ALA) ist hoch, womit sich Sojaöl in die Reihe der Fette mit mittlerem ALA-Gehalt, wie Raps- und Walnussöl einreiht. Im Gegensatz zu Rapsöl entspricht jedoch das Linolsäure/α-Linolensäure- Verhältnis nicht dem empfohlenen Verhältnis von 5:1 in der Gesamt- Diät [13]. Zum Ausgleich für die Fette aus der übrigen Nahrung (Getreide, Lebensmittel tierischer Herkunft) sollten Pflanzenöle besser noch ein engeres Verhältnis als 5:1 aufweisen. Das trifft für Lupinen-Öl schon eher zu, wenngleich der absolute Beitrag an ALA hier eher gering ist. N2 - Continuation from Ernährungs Umschau issue 9/2017 Fatty acid distribution The levels of the most important fatty acids are listed in • Table 4 and 5 in g/100 g, and as a percentage of fat (ether extract or g of fatty acid methyl ester per 100 g of the sum of the fatty acid methylesters). Peas and faba beans provide almost no fats. Soybeans are a good source of linoleic acid, the most common n-6 fatty acid followed by oleic acid. However, the level of the n-3 fatty acid α-linolenic acid (ALA) is also high, which puts soybean oil in the category of fats with medium ALA content, along with oils such as rapeseed oil and walnut oil. However, unlike rapeseed oil, the ratio of linoleic acid to α-linolenic acid is not the recommended ratio for the overall diet of 5:1 [13]. In order to balance out the fats from the rest of the diet (cereals, foods of animal origin), vegetable oils should ideally have a ratio even better than 5:1. Lupine oil has such a ratio, although its absolute ALA content is rather low. Y1 - 2017 UR - https://www.ernaehrungs-umschau.de/fileadmin/Ernaehrungs-Umschau/pdfs/pdf_2017/10_17/EU10_2017_WuF_Erbersdobler_englisch.pdf U6 - https://doi.org/10.4455.eu.2017.034 SN - 0174-0008 VL - 64 IS - 10 SP - 140 EP - 144 PB - Umschau-Zeitschriftenverl. CY - Frankfurt, Main ER - TY - GEN A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - DPP4 inhibition prevents AKI T2 - Oncotarget KW - acute kidney injury KW - DPP-4 inhibitors KW - ischemia reperfusion injury KW - gliptins KW - Dipeptidyl peptidase IV Y1 - 2017 U6 - https://doi.org/10.18632/oncotarget.20212 SN - 1949-2553 VL - 8 SP - 64655 EP - 64656 PB - Impact Journals LLC CY - Orchard Park ER - TY - JOUR A1 - Auyyuenyong, Ratchada A1 - Henze, Andrea A1 - Ungru, Julia A1 - Schweigert, Florian Johannes A1 - Raila, Jens A1 - Vervuert, Ingrid T1 - Determination of lipid profiles in serum of obese ponies before and after weight reduction by using multi-one-dimensional thin-layer chromatography JF - Research in veterinary science N2 - Obesity is a key component of equine metabolic syndrome, which is highly associated with laminitis. Feed restriction and/or exercise are known to alleviate the detrimental effects of insulin resistance in obese ponies. However, little is known about changes in the serum lipid patterns due to weight reduction and its association with disease outcomes. Therefore, the lipid patterns in the serum of 14 mature ponies before and after a 14-week body weight reduction program (BWRP) were investigated by multi-one-dimensional thin-layer chromatography (MOD-TLC). Additionally, sensitivity to insulin (SI), body condition scores (BCS) and cresty neck scores (CNS) were measured. A BWRP resulted in a significant loss of body weight (P < 0.001), which was associated with beneficial decreases in BCS and CNS (both, P < 0.001). Serum lipid compositions revealed significantly increased free fatty acid (FFA), sphingomyelin (SM; both P < 0.001), total cholesterol (C) and cholesterol ester (CE) (both P < 0.01) and triacylglycerol (TG; P < 0.05) densities. Improvement of SI after the BWRP was associated with increases in neutral lipids (C, CE and TG, all P < 0.01), FFA and the phospholipid SM (both, P < 0.001). The results show that a BWRP in obese ponies was effective and associated with changes in the concentrations of neutral lipids and the phospholipid SM, indicating that SM may play a role in insulin signaling pathways and thus in the pathogenesis of insulin resistance and the progression of metabolic syndrome in obese ponies. KW - Neutral lipids KW - Equine metabolic syndrome KW - Phospholipids KW - Horse KW - Thin layer chromatography Y1 - 2017 U6 - https://doi.org/10.1016/j.rvsc.2017.11.013 SN - 0034-5288 SN - 1532-2661 VL - 117 SP - 111 EP - 117 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Islam, Khan M. S. A1 - Khalil, Mahmoud Abd Elhamid A1 - Maenner, Klaus A1 - Raila, Jens A1 - Rawel, Harshadrai Manilal A1 - Zentek, Jürgen A1 - Schweigert, Florian J. T1 - Lutein Specific Relationships among Some Spectrophotometric and Colorimetric Parameters of Chicken Egg Yolk JF - The journal of poultry science N2 - Lutein is an essential dietary carotenoid with health benefits and is inter alia responsible for the colouration of egg yolk. The relationship between lutein accumulation and egg yolk colouration was therefore studied in more detail. After feeding a low-luteine diet for 21 days, 14 birds (Lohmann brown hens aged 20 weeks) were fed a diet containing marigold (80 mg lutein/kg feed) and 14 other birds were fed a diet containing oleoresin (45 mg lutein/kg feed) for 21 days; for both groups of birds, this feeding period was followed by withdrawal for 21 days. The Roche Yolk Colour Fan (RYCF) score (0 to 15, where higher values denote greater colour intensity; R-2=0.87; P<0.01) and redness (R-2=0.89; P<0.01) increased with increasing lutein content of egg yolk. Total carotenoid content had a poor relationship with lightness (R-2=0.13; P>0.05) and yellowness (R-2=0.12; P>0.05) of the yolk. It may be concluded that increased lutein is potentially responsible for an increased RYCF score and redness (a*), but decreased yellowness (b*) and lightness (L*), of egg yolk. KW - carotenoid KW - HPLC KW - iCheck KW - lutein KW - spectrophotometry KW - yolk Y1 - 2017 U6 - https://doi.org/10.2141/jpsa.0160065 SN - 1346-7395 VL - 54 SP - 271 EP - 277 PB - Japan Poultry Science Association CY - Tsukuba ER - TY - JOUR A1 - Berger, Beatrice A1 - Baldermann, Susanne A1 - Ruppel, Silke T1 - The plant growth-promoting bacterium Kosakonia radicincitans improves fruit yield and quality of Solanum lycopersicum JF - Journal of the Science of Food and Agriculture N2 - BACKGROUNDProduction and the quality of tomato fruits have a strong economic relevance. Microorganisms such as the plant growth-promoting bacterium (PGPB) Kosakonia radicincitans (DSM 16656) have been demonstrated to improve shoot and root growth of young tomato plants, but data on yield increase and fruit quality by K. radicincitans are lacking. RESULTSThis study investigated how K. radicincitans affects tomato fruits. After inoculation of tomato seeds with K. radicincitans or a sodium chloride buffer control solution, stalk length, first flowering and the amount of ripened fruits produced by inoculated and non-inoculated plants were monitored over a period of 21 weeks. Inoculation of tomato seeds with K. radicincitans accelerated flowering and ripening of tomato fruits. Sugars, acidity, amino acids, volatile organic compounds and carotenoids in the fruits were also analyzed. CONCLUSIONIt was found that the PGPBK. radicincitans affected the amino acid, sugar and volatile composition of ripened fruits, contributing to a more pleasant-tasting fruit without forfeiting selected quality indicators. (c) 2017 Society of Chemical Industry KW - plant growth-promoting bacteria KW - Kosakonia radicincitans KW - fruit metabolites KW - Solanum lycopersicum Y1 - 2017 U6 - https://doi.org/10.1002/jsfa.8357 SN - 0022-5142 SN - 1097-0010 VL - 97 SP - 4865 EP - 4871 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Kakkassery, Vinodh A1 - Skosyrski, S. A1 - Lüth, A. A1 - Kleuser, Burkhard A1 - van der Giet, Maria A1 - Tate, R. A1 - Reinhard, J. A1 - Faissner, Andreas A1 - Joachim, Stephanie Christine A1 - Kociok, N. T1 - Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells JF - Pathology & Oncology Research N2 - Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism. KW - Retinoblastoma KW - Sphingosine-1-phosphate KW - Chemotherapy resistance Y1 - 2017 U6 - https://doi.org/10.1007/s12253-017-0360-x SN - 1219-4956 SN - 1532-2807 VL - 25 IS - 1 SP - 391 EP - 399 PB - Springer CY - Dordrecht ER - TY - GEN A1 - Kleuser, Burkhard T1 - Medikamentennebenwirkungen auf Haut und Schleimhaut – allergische oder pharmakologisch erklärbare Reaktionen T2 - Allergologie T2 - Side Effects on Skin and Mucous Membrane - allergic or pharmacologically explainable Reactions Y1 - 2017 SN - 0344-5062 VL - 40 IS - 10 SP - 420 EP - 421 PB - Dustri-Verlag CY - Deisenhofen-München ER - TY - JOUR A1 - Groop, Per-Henrik A1 - Cooper, Mark E. A1 - Perkovic, Vlado A1 - Hocher, Berthold A1 - Kanasaki, Keizo A1 - Haneda, Masakazu A1 - Schernthaner, Guntram A1 - Sharma, Kumar A1 - Stanton, Robert C. A1 - Toto, Robert A1 - Cescutti, Jessica A1 - Gordat, Maud A1 - Meinicke, Thomas A1 - Koitka-Weber, Audrey A1 - Thiemann, Sandra A1 - von Eynatten, Maximilian T1 - Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction BT - the randomized MARLINA-T2D trial JF - Diabetes obesity & metabolism : a journal of pharmacology and therapeutics N2 - Aims: The MARLINA-T2D study (ClinicalTrials. gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/ mol), estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m(2) and urinary albumin-tocreatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% +/- 0.9% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics. KW - antidiabetic drug KW - clinical trial KW - diabetic nephropathy KW - DPP-IV inhibitor KW - glycaemic control KW - linagliptin Y1 - 2017 U6 - https://doi.org/10.1111/dom.13041 SN - 1462-8902 SN - 1463-1326 VL - 19 IS - 11 SP - 1610 EP - 1619 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Kachler, Katerina A1 - Bailer, Maximilian A1 - Heim, Lisanne A1 - Schumacher, Fabian A1 - Reichel, Martin A1 - Holzinger, Corinna D. A1 - Trump, Sonja A1 - Mittler, Susanne A1 - Monti, Juliana A1 - Trufa, Denis I. A1 - Rieker, Ralf J. A1 - Hartmann, Arndt A1 - Sirbu, Horia A1 - Kleuser, Burkhard A1 - Kornhuber, Johannes A1 - Finotto, Susetta T1 - Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma JF - Cancer research N2 - The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and-extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. (C) 2017 AACR. Y1 - 2017 U6 - https://doi.org/10.1158/0008-5472.CAN-16-3313 SN - 0008-5472 SN - 1538-7445 VL - 77 IS - 21 SP - 5963 EP - 5976 PB - American Association for Cancer Research CY - Philadelphia ER - TY - GEN A1 - Hocher, Berthold A1 - Tsuprykov, Oleg T1 - Renoprotective effects of GLP1R agonists and SGLT2 inhibitors T2 - Nature reviews nephroloy N2 - New data from the LEADER trial show that the glucagon-like peptide 1 receptor agonist liraglutide protects against diabetic nephropathy in patients with type 2 diabetes mellitus. The renoprotective efficacy of liraglutide is not, however, as great as that reported for the sodium-glucose cotransporter 2 inhibitor emplagiflozin in the EMPA-REG OUTCOME trial. Y1 - 2017 U6 - https://doi.org/10.1038/nrneph.2017.140 SN - 1759-5061 SN - 1759-507X VL - 13 SP - 728 EP - 729 PB - Nature Publ. Group CY - New York ER - TY - CHAP A1 - Tsuprykov, Oleg A1 - Buse, Claudia A1 - Skoblo, Roman A1 - Hocher, Berthold T1 - Free 25 (OH) vitamin D, but not total 25 (OH) vitamin D, is strongly correlated with gestational age and calcium in normal human pregnancy T2 - Journal of bone and mineral research Y1 - 2017 SN - 0884-0431 SN - 1523-4681 VL - 32 SP - S323 EP - S323 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Flemmig, Martin A1 - Domsalla, Andre A1 - Rawel, Harshadrai Manilal A1 - Melzig, Matthias F. T1 - Isolation and Characterization of Mauritanicain, a Serine Protease from the Latex of Euphorbia mauritanica L. JF - Planta medica : journal of medicinal plant and natural product research N2 - A protease called Mauritanicain was isolated from the latex of Euphorbia mauritanica L. (Euphorbiaceae) by combining ion exchange chromatography, ultrafiltration, and gel filtration chromatography. It has a high proteolytic activity against casein. The activity was only inhibited by specific serine protease inhibitors, classifying it to the serine protease family. An optimal degradation of the substrate casein takes place at a temperature of 55-65 degrees C and a pH of 5.5-6.5, and is unstable at pH < 5 and pH > 9. The protease is stable at temperatures from 20-70 degrees C, whereby the activity decreases drastically to less than 20% at 75 degrees C. SDS-PAGE and matrix-assisted laser desorption time-of-flight analysis yielded a molecular weight of 73 kDa; possibly, it is natively present as a non-covalently linked dimer of a higher molecular mass > 132 kDa. Without heat denaturation, a breakdown in fractions of 73 kDa and 52 kDa was observed in SDS-PAGE. Only in some properties it shows a similarity to other characterized proteases in the plant family Euphorbiaceae, such that Mauritanicain can be presented as a new isolated protease. KW - Euphorbia mauritanica KW - Euphorbiaceae KW - Mauritanicain KW - serine protease KW - plant protease KW - latex Y1 - 2017 U6 - https://doi.org/10.1055/s-0042-117645 SN - 0032-0943 SN - 1439-0221 VL - 83 SP - 551 EP - 556 PB - Thieme CY - Stuttgart ER - TY - JOUR A1 - Aschner, Michael A. A1 - Palinski, Catherine A1 - Sperling, Michael A1 - Karst, U. A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Imaging metals in Caenorhabditis elegans JF - Metallomics : integrated biometal science N2 - Systemic trafficking and storage of essential metal ions play fundamental roles in living organisms by serving as essential cofactors in various cellular processes. Thereby metal quantification and localization are critical steps in understanding metal homeostasis, and how their dyshomeostasis might contribute to disease etiology and the ensuing pathologies. Furthermore, the amount and distribution of metals in organisms can provide insight into their underlying mechanisms of toxicity and toxicokinetics. While in vivo studies on metal imaging in mammalian experimental animals are complex, time- and resource-consuming, the nematode Caenorhabditis elegans (C. elegans) provides a suitable comparative and complementary model system. Expressing homologous genes to those inherent to mammals, including those that regulate metal homeostasis and transport, C. elegans has become a powerful tool to study metal homeostasis and toxicity. A number of recent technical advances have been made in the development and application of analytical methods to visualize metal ions in C. elegans. Here, we briefly summarize key findings and challenges of the three main techniques and their application to the nematode, namely sensing fluorophores, microbeam synchrotron radiation X-ray fluorescence as well as laser ablation ( LA) coupled to inductively coupled plasma-mass spectrometry (ICP-MS). Y1 - 2017 U6 - https://doi.org/10.1039/c6mt00265j SN - 1756-5901 SN - 1756-591X VL - 9 SP - 357 EP - 364 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Wallmeyer, Leonie A1 - Dietert, Kristina A1 - Sochorova, Michaela A1 - Gruber, Achim D. A1 - Kleuser, Burkhard A1 - Vavrova, Katerina A1 - Hedtrich, Sarah T1 - TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents JF - Scientific reports N2 - Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4(+) T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD. Y1 - 2017 U6 - https://doi.org/10.1038/s41598-017-00670-2 SN - 2045-2322 VL - 7 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Samarin, Azadeh Mohagheghi A1 - Falke, Luise Gabriele A1 - Putra, Sulistyo Emantoko Dwi A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Antonenko, Viktoriia A1 - Curato, Caterina A1 - Rippmann, Joerg A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury JF - British journal of pharmacology : journal of The British Pharmacological Society N2 - BACKGROUND AND PURPOSE Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. EXPERIMENTAL APPROACH IRI was induced in uninephrectomizedmale rats by renal artery clamping for 30 min. The shamgroup was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p. o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg.kg(-1).day(-1)), vildagliptin (8mg.kg(-1).day(-1)) and sitagliptin (30 mg.kg(-1).day(-1)). An additional group received sitagliptin until study end (before IRI: 30 mg.kg(-1).day(-1); after IRI: 15mg.kg(-1).day(-1)). KEY RESULTS Plasma-active glucagon-like peptide type 1 (GLP(-1)) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP(-1) plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. CONCLUSIONS AND IMPLICATIONS In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage. Y1 - 2017 U6 - https://doi.org/10.1111/bph.13822 SN - 0007-1188 SN - 1476-5381 VL - 174 SP - 2273 EP - 2286 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Frede, Katja A1 - Ebert, Franziska A1 - Kipp, Anna Patricia A1 - Schwerdtle, Tanja A1 - Baldermann, Susanne T1 - Lutein Activates the Transcription Factor Nrf2 in Human Retinal Pigment Epithelial Cells JF - Journal of agricultural and food chemistry : a publication of the American Chemical Society N2 - The degeneration of the retinal pigment epithelium caused by oxidative damage is a stage of development in age related macular degeneration (AMD). The carotenoid lutein is a major macular pigment that may reduce the incidence and progression of AMD, but the underlying mechanism is currently not fully understood. Carotenoids are known to be direct antioxidants. However, carotenoids can also activate cellular pathways resulting in indirect antioxidant effects. Here, we investigate the influence of lutein on the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes in human retinal pigment epithelial cells (ARPE-19 cells) using lutein-loaded Tween40 micelles. The micelles were identified as a suitable delivery system since they were nontoxic in APRE-19 cells up to 0.04% Tween40 and led to a cellular lutein accumulation of 62 mu M +/- 14 mu M after 24 h. Lutein significantly enhanced Nrf2 translocation to the nucleus 1.5 +/- 0.4-fold compared to that of unloaded micelles after 4 h. Furthermore, lutein treatment for 24 h significantly increased the transcripts of NAD(P)H:quinone oxidoreductase 1 (NQO1) by 1.7 +/- 0.1-fold, glutamate-cysteine ligase regulatory subunit (GCLm) by 1.4 +/- 0.1-fold, and heme oxygenase-1 (HO-1) by 1.8 +/- 0.3-fold. Moreover, we observed a significant enhancement of NQO1 activity by 1.2 +/- 0.1-fold. Collectively, this study indicates that lutein not only serves as a direct antioxidant but also activates Nrf 2 in ARPE-19 cells. KW - lutein KW - Nif2 KW - ARPE-19 cells KW - AMD KW - Tween40 micelles Y1 - 2017 U6 - https://doi.org/10.1021/acs.jafc.7b01929 SN - 0021-8561 SN - 1520-5118 VL - 65 SP - 5944 EP - 5952 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Raila, Jens A1 - Schweigert, Florian J. A1 - Stanitznig, A. A1 - Lambacher, B. A1 - Franz, S. A1 - Baldermann, Susanne A1 - Wittek, T. T1 - No detectable carotenoid concentrations in serum of llamas and alpacas JF - Journal of animal physiology and animal nutrition N2 - Carotenoids are lipid-soluble pigments and important for a variety of physiological functions. They are major dietary vitamin A precursors and act as lipophilic antioxidants in a variety of tissues and are associated with important health benefits in humans and animals. All animals must acquire carotenoids from their diet, but to our knowledge, there are no studies investigating the intestinal carotenoid absorption and their blood concentrations in New World camelids. The present study aimed to assess the serum concentrations of selected carotenoids in llamas (n=13) and alpacas (n=27). Serum carotenoids as well as retinol (vitamin A) and -tocopherol (vitamin E) were determined by high-performance liquid chromatography coupled with mass spectrometry and these were unable to detect any carotenoids (- and -carotene, - and -cryptoxanthin, lutein, zeaxanthin, lycopene) in the samples. The concentrations of retinol in alpacas (2.89 +/- 1.13mol/l; mean +/- SD) were higher (p=0.024) than those found in llamas (2.05 +/- 0.87mol/l); however, the concentrations of -tocopherol were not significantly (p=0.166) different (llamas: 3.98 +/- 1.83mol/l; alpacas: 4.95 +/- 2.14mol/l). The results show that both llamas and alpacas are not able to absorb intact carotenoids, but efficiently convert provitamin A carotenoids to retinol. KW - New World camelids KW - carotenoids KW - vitamins Y1 - 2017 U6 - https://doi.org/10.1111/jpn.12638 SN - 0931-2439 SN - 1439-0396 VL - 101 SP - 629 EP - 634 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Wiesner-Reinhold, Melanie A1 - Schreiner, Monika A1 - Baldermann, Susanne A1 - Schwarz, Dietmar A1 - Hanschen, Franziska S. A1 - Kipp, Anna Patricia A1 - Rowan, Daryl D. A1 - Bentley-Hewitt, Kerry L. A1 - McKenzie, Marian J. T1 - Mechanisms of Selenium Enrichment and Measurement in Brassicaceous Vegetables, and Their Application to Human Health JF - Frontiers in plant science N2 - Selenium (Se) is an essential micronutrient for human health. Se deficiency affects hundreds of millions of people worldwide, particularly in developing countries, and there is increasing awareness that suboptimal supply of Se can also negatively affect human health. Selenium enters the diet primarily through the ingestion of plant and animal products. Although, plants are not dependent on Se they take it up from the soil through the sulphur (S) uptake and assimilation pathways. Therefore, geographic differences in the availability of soil Se and agricultural practices have a profound influence on the Se content of many foods, and there are increasing efforts to biofortify crop plants with Se. Plants from the Brassicales are of particular interest as they accumulate and synthesize Se into forms with additional health benefits, such as methylselenocysteine (MeSeCys). The Brassicaceae are also well-known to produce the glucosinolates; S-containing compounds with demonstrated human health value. Furthermore, the recent discovery of the selenoglucosinolates in the Brassicaceae raises questions regarding their potential bioefficacy. In this review we focus on Se uptake and metabolism in the Brassicaceae in the context of human health, particularly cancer prevention and immunity. We investigate the close relationship between Se and S metabolism in this plant family, with particular emphasis on the selenoglucosinolates, and consider the methodologies available for identifying and quantifying further novel Se-containing compounds in plants. Finally, we summarize the research of multiple groups investigating biofortification of the Brassicaceae and discuss which approaches might be most successful for supplying Se deficient populations in the future. KW - Brassica vegetables KW - selenium KW - biofortification KW - glucosinolates KW - human health KW - immune system KW - cancer KW - analytical methods Y1 - 2017 U6 - https://doi.org/10.3389/fpls.2017.01365 SN - 1664-462X VL - 8 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Goetz, Klaus-Peter A1 - Chmielewski, Frank M. A1 - Goedeke, Kristin A1 - Wolf, Kristine A1 - Jander, Elisabeth A1 - Sievers, Steven A1 - Homann, Thomas A1 - Huschek, Gerd A1 - Rawel, Harshadrai Manilal T1 - Assessment of amino acids during winter rest and ontogenetic development in sweet cherry buds (Prunus avium. L.) JF - Scientia horticulturae : an international journal sponsored by the International Society for Horticultural Science N2 - This study examined changes in sweet cherry buds of ‘Summit’ cultivar in four seasons (2011/12–2014/15) with respect to the nitrogen (N) content and the profile of eight free amino acids (asparagine (Asn), aspartic acid (Asp), isoleucine (Ile), glutamine (Gln), glutamic acid (Glu), arginine (Arg), alanine (Ala), histidine (His)). The presented results are to our knowledge the first under natural conditions in fruit tree orchards with a high temporal resolution from the dormant stage until cluster development. The N content in the buds from October, during endo- and ecodormancy until the beginning of ontogenetic development was a relatively stable parameter in each of the four seasons. The N accumulation into the buds began after ‘swollen bud’ and significant differences were visible at ‘green tip’ with an N content of 3.24, 3.12, 3.08, 2.40 which increased markedly to the mean of ‘tight’ and ‘open cluster’ by 3.77%, 3.78%, 3.44% and 3.10% in 2012–2015, respectively. In the buds, levels of asparagine were higher (up to 44 mg g−1 DW−1) than aspartic acid (up to 2 mg g−1 DW−1) and aspartic acid higher than isoleucine (up to 0.83 mg g−1 DW−1). Levels of glutamine were higher (up to 25 mg g−1 DW−1) than glutamic acid (up to 20 mg g−1 DW−1). The course of the arginine content was higher in 2011/12 compared to 2012/13, 2013/14 and 2014/15 which showed only slight differences. The alanine content in the buds was denoted in the four seasons only by relatively minor changes. The histidine content was higher in 2011/12 and 2012/13 compared to 2013/14 and 2014/15 which showed a comparable pattern. For 6 amino acids (Asn, Asp, Ile, Glu, Arg, Ala), the highest content was observed in 2012/13, the warmest period between swollen bud and open cluster. However in 2014/15, the season with the lowest mean temperature of 8.8 °C, only the content of Gln was the lowest. It was not possible to explain any seasonal differences in the amino acid content by environmental factors (air temperature) on the basis of few seasons. From none of the measured free amino acids could a clear determination of the date of endodormancy release (t1) or the beginning of the ontogenetic development (t1*) be derived. Therefore, these amino acids are no suitable markers to improve phenological models for the beginning of cherry blossom. KW - Amino acids KW - Flower buds KW - Prunus avium L. KW - Dormancy KW - Ontogenetic development Y1 - 2017 U6 - https://doi.org/10.1016/j.scienta.2017.05.001 SN - 0304-4238 SN - 1879-1018 VL - 222 SP - 102 EP - 110 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Witt, Barbara A1 - Meyer, Sören A1 - Ebert, Franziska A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Toxicity of two classes of arsenolipids and their water-soluble metabolites in human differentiated neurons JF - Archives of toxicology : official journal of EUROTOX N2 - Arsenolipids are lipid-soluble organoarsenic compounds, mainly occurring in marine organisms, with arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) representing two major subgroups. Recently, toxicity studies of several arsenolipids showed a high cytotoxic potential of those arsenolipids in human liver and bladder cells. Furthermore, feeding studies with Drosophila melanogaster indicated an accumulation of arsenolipids in the fruit fly’s brain. In this study, the neurotoxic potential of three AsHCs, two AsFAs and three metabolites (dimethylarsinic acid, thio/oxo-dimethylarsenopropanoic acid) was investigated in comparison to the toxic reference arsenite (iAsIII) in fully differentiated human brain cells (LUHMES cells). Thereby, in the case of AsHCs both the cell number and cell viability were reduced in a low micromolar concentration range comparable to iAsIII, while AsFAs and the applied metabolites were less toxic. Mechanistic studies revealed that AsHCs reduced the mitochondrial membrane potential, whereas neither iAsIII nor AsFAs had an impact. Furthermore, neurotoxic mechanisms were investigated by examining the neuronal network. Here, AsHCs massively disturbed the neuronal network and induced apoptotic effects, while iAsIII and AsFAs showed comparatively lesser effects. Taking into account the substantial in vitro neurotoxic potential of the AsHCs and the fact that they could transfer across the physiological barriers of the brain, a neurotoxic potential in vivo for the AsHCs cannot be excluded and needs to be urgently characterized. KW - Arsenolipids KW - Neurons KW - Cytotoxicity KW - Neurotoxicity KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids Y1 - 2017 U6 - https://doi.org/10.1007/s00204-017-1933-x SN - 0340-5761 SN - 1432-0738 VL - 91 SP - 3121 EP - 3134 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Ngwene, Benard A1 - Neugart, Susanne A1 - Baldermann, Susanne A1 - Ravi, Beena A1 - Schreiner, Monika T1 - Intercropping Induces Changes in Specific Secondary Metabolite Concentration in Ethiopian Kale (Brassica carinata) and African Nightshade (Solanum scabrum) under Controlled Conditions JF - Frontiers in plant science N2 - Intercropping is widespread in small-holder farming systems in tropical regions and is also practiced in the cultivation of indigenous vegetables, to alleviate the multiple burdens of malnutrition. Due to interspecific competition and/or complementation between intercrops, intercropping may lead to changes in plants accumulation of minerals and secondary metabolites and hence, alter nutritional quality for consumers. Intercropping aims to intensify land productivity, while ensuring that nutritional quality is not compromised. This study aimed to investigate changes in minerals and secondary plant metabolites in intercropped Brassica carinata and Solanum scabrum, two important African indigenous vegetables, and evaluated the suitability of this combination for dryer areas. B. carinata and S. scabrum were grown for 6 weeks under controlled conditions in a greenhouse trial. Large rootboxes (8000 cm(3) volume) were specifically designed for this experiment. Each rootbox was planted with two plants, either of the same plant species (mono) or one of each plant species (mixed). A quartz sand/soil substrate was used and fertilized adequately for optimal plant growth. During the last 4 weeks of the experiment, the plants were either supplied with optimal (65% WHC) or low (30% WHC) irrigation, to test the effect of a late-season drought. Intercropping increased total glucosinolate content in B. carinata, while maintaining biomass production and the contents of other health related minerals in both B. carinata and S. scabrum. Moreover, low irrigation led to an increase in carotene accumulation in both mono and intercropped S. scabrum, but not in B. carinata, while the majority of kaempferol glycosides and hydroxycinnamic acid derivatives of both species were decreased by intercropping and drought treatment. This study indicates that some health-related phytochemicals can be modified by intercropping or late-season drought, but field validation of these results is necessary before definite recommendation can be made to stakeholders. KW - intercropping KW - indigenous leafy vegetables KW - nutrition security KW - secondary plant metabolites KW - Brassica carinata KW - Solanum scabrum Y1 - 2017 U6 - https://doi.org/10.3389/fpls.2017.01700 SN - 1664-462X VL - 8 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Strehlau, Jenny A1 - Weber, Till A1 - Luerenbaum, Constantin A1 - Bornhorst, Julia A1 - Galla, Hans-Joachim A1 - Schwerdtle, Tanja A1 - Winter, Martin A1 - Nowak, Sascha T1 - Towards quantification of toxicity of lithium ion battery electrolytes - development and validation of a liquid-liquid extraction GC-MS method for the determination of organic carbonates in cell culture materials JF - Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica N2 - A novel method based on liquid-liquid extraction with subsequent gas chromatography separation and mass spectrometric detection (GC-MS) for the quantification of organic carbonates in cell culture materials is presented. Method parameters including the choice of extraction solvent, of extraction method and of extraction time were optimised and the method was validated. The setup allowed for determination within a linear range of more than two orders of magnitude. The limits of detection (LODs) were between 0.0002 and 0.002 mmol/L and the repeatability precisions were in the range of 1.5-12.9%. It could be shown that no matrix effects were present and recovery rates between 98 and 104% were achieved. The methodology was applied to cell culture models incubated with commercial lithium ion battery (LIB) electrolytes to gain more insight into the potential toxic effects of these compounds. The stability of the organic carbonates in cell culture medium after incubation was studied. In a porcine model of the blood-cerebrospinal fluid (CSF) barrier, it could be shown that a transfer of organic carbonates into the brain facing compartment took place. KW - Liquid-liquid extraction KW - GC-MS KW - Lithiumion battery (LIB) KW - Organic carbonates KW - Cell culture materials Y1 - 2017 U6 - https://doi.org/10.1007/s00216-017-0549-6 SN - 1618-2642 SN - 1618-2650 VL - 409 SP - 6123 EP - 6131 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Neugart, Susanne A1 - Baldermann, Susanne A1 - Ngwene, Benard A1 - Wesonga, John A1 - Schreiner, Monika T1 - Indigenous leafy vegetables of Eastern Africa - A source of extraordinary secondary plant metabolites JF - Food research international N2 - Indigenous African leafy vegetables vary enormously in their secondary plant metabolites whereat genus and the species have a great impact. In African nightshade (Solanum scabrum), spiderplant (Cleome gynandra), amaranth (Amaranthus cruentus), cowpea (Vigna unguiculata), Ethiopian kale (Brassica carinata) and common kale (Brassica oleracea) the specific secondary metabolite profile was elucidated and gained detailed data about carotenoids, chlorophylls, glucosinolates and phenolic compounds all having an appropriate contribution to health beneficial properties of indigenous African leafy vegetables. Exemplarily, various quercetin glycosides such as quercetin-3-rutinoside occur in high concentrations in African nightshade, spiderplant, and amaranth between similar to 1400-3300 mu g/g DW. Additionally the extraordinary hydroxydnnamic acid derivatives such as glucaric isomers and isocitric acid isomers are found especially in amaranth (up to similar to 1250 mu g/g DW) and spiderplant (up to 120 mu g/g DW). Carotenoids concentrations are high in amaranth (up to 101.7 mu g/g DW) and spiderplants (up to 64.7 mu g/g DW) showing high concentrations of beta-carotene, the pro-vitamin A. In contrast to the ubiquitous occurring phenolics and carotenoids, glucosinolates are only present in the Brassicales species Ethiopian kale, common kale and spiderplant characterized by diverse glucosinolate profiles. Generally, the consumption of a variety of these indigenous African leafy vegetables can be recommended to contribute to different benefits such as antioxidant activity, increase pro-vitamin A and anticancerogenic compounds in a healthy diet. (C) 2017 Elsevier Ltd. All rights reserved. KW - Indigenous African leafy vegetables KW - Flavonoid glycosides KW - Hydroxycinnamic acids KW - Carotenoids KW - Glucosinolates Y1 - 2017 U6 - https://doi.org/10.1016/j.foodres.2017.02.014 SN - 0963-9969 SN - 1873-7145 VL - 100 SP - 411 EP - 422 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Erbersdobler, Helmut F. A1 - Barth, Christian A. A1 - Jahreis, Gerhard T1 - Körnerleguminosen in der Humanernährung T1 - Grain Legumes in the Human Nutrition BT - Nährstoffgehalt und Proteinqualität von Hülsenfrüchten BT - Nutrient Content and Protein Quality of Pulses JF - Ernährungs-Umschau : Forschung & Praxis Y1 - 2017 U6 - https://doi.org/10.4455/eu.2017.038 SN - 0174-0008 VL - 64 IS - 9 SP - 134 EP - 139 PB - Umschau-Zeitschriftenverl. CY - Frankfurt, Main ER - TY - JOUR A1 - Witzel, Katja A1 - Strehmel, Nadine A1 - Baldermann, Susanne A1 - Neugart, Susanne A1 - Becker, Yvonne A1 - Becker, Matthias A1 - Berger, Beatrice A1 - Scheel, Dierk A1 - Grosch, Rita A1 - Schreiner, Monika A1 - Ruppel, Silke T1 - Arabidopsis thaliana root and root exudate metabolism is altered by the growth-promoting bacterium Kosakonia radicincitans DSM 16656(T) JF - Plant and soil N2 - Plant growth-promoting bacteria (PGPB) affect host physiological processes in various ways. This study aims at elucidating the dependence of bacterial-induced growth promotion on the plant genotype and characterizing plant metabolic adaptations to PGPB. Eighteen Arabidopsis thaliana accessions were inoculated with the PGPB strain Kosakonia radicincitans DSM 16656(T). Colonisation pattern was assessed by enhanced green fluorescent protein (eGFP)-tagged K. radicincitans in three A. thaliana accessions differing in their growth response. Metabolic impact of bacterial colonisation was determined for the best responding accession by profiling distinct classes of plant secondary metabolites and root exudates. Inoculation of 18 A. thaliana accessions resulted in a wide range of growth responses, from repression to enhancement. Testing the bacterial colonisation of three accessions did not reveal a differential pattern. Profiling of plant secondary metabolites showed a differential accumulation of glucosinolates, phenylpropanoids and carotenoids in roots. Analysis of root exudates demonstrated that primary and secondary metabolites were predominantly differentially depleted by bacterial inoculation. The plant genotype controls the bacterial growth promoting traits. Levels of lutein and beta-carotene were elevated in inoculated roots. Supplementing a bacterial suspension with beta-carotene increased bacterial growth, while this was not the case when lutein was applied, indicating that beta-carotene could be a positive regulator of plant growth promotion. KW - Arabidopsis KW - Carotenoids KW - Glucosinolates KW - Plant growth promoting bacteria KW - Phenylpropanoids KW - Root exudates Y1 - 2017 U6 - https://doi.org/10.1007/s11104-017-3371-1 SN - 0032-079X SN - 1573-5036 VL - 419 SP - 557 EP - 573 PB - Springer CY - Dordrecht ER - TY - JOUR A1 - Li, Mingjun A1 - Gao, Lingyan A1 - Schlaich, Christoph A1 - Zhang, Jianguang A1 - Donskyi, Ievgen S. A1 - Yu, Guozhi A1 - Li, Wenzhong A1 - Tu, Zhaoxu A1 - Rolff, Jens A1 - Schwerdtle, Tanja A1 - Haag, Rainer A1 - Ma, Nan T1 - Construction of Functional Coatings with Durable and Broad-Spectrum Antibacterial Potential Based on Mussel-Inspired Dendritic Polyglycerol and in Situ-Formed Copper Nanoparticles JF - ACS applied materials & interfaces N2 - A novel surface coating with durable broad-spectrum antibacterial ability was prepared based on mussel inspired dendritic polyglycerol (MI-dPG) embedded with copper nanoparticles (Cu NPs). The functional surface coating is fabricated via a facile dip-coating process followed by in situ reduction of copper ions with a MI-dPG coating to introduce Cu NPs into the coating matrix. This coating has been demonstrated to possess efficient long-term antibacterial properties against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and kanamycin-resistant E. coli through an "attract-kill-release" strategy. The synergistic antibacterial activity of the coating was shown by the combination of two functions of the contact killing, reactive oxygen species production and Cu ions released from the coating. Furthermore, this coating inhibited biofilm formation and showed good compatibility to eukaryotic cells. Thus, this newly developed Cu NP-incorporated MI-dPG surface coating may find potential application in the design of antimicrobial coating, such as implantable devices. KW - Cu NP-incorporated MI-dPG coating KW - universal coating KW - in situ chemical reduction KW - antibacterial effect KW - drug-resistant bacteria Y1 - 2017 U6 - https://doi.org/10.1021/acsami.7b10541 SN - 1944-8244 VL - 9 SP - 35411 EP - 35418 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Khozroughi, Amin Ghadiri A1 - Jander, Elisabeth A1 - Schirrmann, Michael A1 - Rawel, Harshadrai Manilal A1 - Kroh, Lothar W. A1 - Schlueter, Oliver T1 - The role of myoglobin degradation in the formation of zinc protoporphyrin IX in the longissimus lumborum of pork JF - LWT - food science and technology : an official journal of the Swiss Society of Food Science and Technology (SGLWT/SOSSTA) and the International Union of Food Science and Technology (IUFoST) N2 - Investigations on the post mortal formation of fluorescent zinc protoporphyrin (ZnPP) IX in pork meat are currently in focus of meat science research. The role of myoglobin degradation in this context appears to be one of the most diversely discussed issues. To address this question meat-extracts of longissimus lumborum (LL) muscle (0.8 mg/mL) were incubated at 30 degrees C for up to 72 h and investigated by HPSEC-UV-fluorescence, SDS-PAGE and MALDI-TOF-MS. Between 0 and 72 h of incubation the fluorescence intensity (lambda(ex)./(em). = 420/590 nm) of the meat-extracts rose significantly (p < 0.001) from 10.9 +/- 0.8 to 34.8 +/- 0.3 (rel. units) while the staining intensity of the SDS-PAGE of myoglobin non-significantly (p > 0.4) changed from 6.2 +/- 0.5 x 105 to 5.0 +/- 0.3 x 105 (rel. units). The results indicate that ZnPP is formed by a Fe(II)-Zn(II)-substitution in myoglobin heme where an accompanying myoglobin degradation is not necessarily obligatory. (C) 2017 Elsevier Ltd. All rights reserved. KW - Meat KW - Fluorescence KW - Proteolysis KW - Post mortem chemistry Y1 - 2017 U6 - https://doi.org/10.1016/j.lwt.2017.06.047 SN - 0023-6438 SN - 1096-1127 VL - 85 SP - 22 EP - 27 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Putra, Sulistyo E. Dwi A1 - Reichetzeder, Christoph A1 - Meixner, Martin A1 - Liere, Karsten A1 - Slowinski, Torsten A1 - Hocher, Berthold T1 - DNA methylation of the glucocorticoid receptor gene promoter in the placenta is associated with blood pressure regulation in human pregnancy JF - Journal of hypertension N2 - Background: Blood pressure (BP) regulation during pregnancy is influenced by hormones of placental origin. It was shown that the glucocorticoid system is altered in hypertensive pregnancy disorders such as preeclampsia. Epigenetic mechanism might influence the activity of genes involved in placental hormone/hormone receptor synthesis/action during pregnancy. Method: In the current study, we analyzed the association of 50-C-phosphate-G-30 (CpG) site methylation of different glucocorticoid receptor gene (NR3C1) promoter regions with BP during pregnancy. The study was performed as a nested case-control study (n = 80) out of 1045 mother/ child pairs from the Berlin Birth Cohort. Placental DNA was extracted and bisulfite converted. Nested PCR products from six NR3C1 proximal promoter regions [glucocorticoid receptor gene promotor region B (GR-1B), C (GR-1C), D (GR-1D), E (GR-1E), F (GR-1F), and H (GR-1H)] were analyzed by next generation sequencing. Results: NR3C1 promoter regions GR-1D and GR-1E had a much higher degree of DNA methylation as compared to GR-1B, GR-1F or GR-1H when analyzing the entire study population. Comparison of placental NR3C1 CpG site methylation among hypotensive, normotensive and hypertensive mothers revealed several differently methylated CpG sites in the GR-1F promoter region only. Both hypertension and hypotension were associated with increased DNA methylation of GR-1F CpG sites. These associations were independent of confounding factors, such as family history of hypertension, smoking status before pregnancy and prepregnancy BMI. Assessment of placental glucocorticoid receptor expression by western blot showed that observed DNA methylation differences were not associated with altered levels of placental glucocorticoid receptor expression. However, correlation matrices of all NR3C1 proximal promoter regions demonstrated different correlation patterns of intraregional and interregional DNA methylation in the three BP groups, putatively indicating altered transcriptional control of glucocorticoid receptor isoforms. Conclusion: Our study provides evidence of an independent association between placental NR3C1 proximal promoter methylation and maternal BP. Furthermore, we observed different patterns of NR3C1 promoter methylation in normotensive, hypertensive and hypotensive pregnancy. KW - DNA methylation KW - epigenetics KW - glucocorticoid receptor KW - hypertension KW - hypotension KW - NR3C1 gene KW - placenta KW - pregnancy Y1 - 2017 U6 - https://doi.org/10.1097/HJH.0000000000001450 SN - 0263-6352 SN - 1473-5598 VL - 35 SP - 2276 EP - 2286 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Witt, Barbara A1 - Ebert, Franziska A1 - Meyer, Sören A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Assessing neurodevelopmental effects of arsenolipids in pre-differentiated human neurons JF - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology N2 - Scope: In the general population exposure to arsenic occurs mainly via diet. Highest arsenic concentrations are found in seafood, where arsenic is present predominantly in its organic forms including arsenolipids. Since recent studies have provided evidence that arsenolipids could reach the brain of an organism and exert toxicity in fully differentiated human neurons, this work aims to assess the neurodevelopmental toxicity of arsenolipids. Methods and results: Neurodevelopmental effects of three arsenic-containing hydrocarbons (AsHC), two arsenic-containing fatty acids (AsFA), arsenite and dimethylarsinic acid (DMA(V)) were characterized in pre-differentiated human neurons. AsHCs and arsenite caused substantial cytotoxicity in a similar, low concentration range, whereas AsFAs and DMA(V) were less toxic. AsHCs were highly accessible for cells and exerted pronounced neurodevelopmental effects, with neurite outgrowth and the mitochondrial membrane potential being sensitive endpoints; arsenite did not substantially decrease those two endpoints. In fully differentiated neurons, arsenite and AsHCs caused neurite toxicity. Conclusion: These results indicate for a neurodevelopmental potential of AsHCs. Taken into account the possibility that AsHCs might easily reach the developing brain when exposed during early life, neurotoxicity and neurodevelopmental toxicity cannot be excluded. Further studies are needed in order to progress the urgently needed risk assessment. KW - Arsenic-containing fatty acids KW - Arsenic-containing hydrocarbons KW - Arsenite KW - Arsenolipids KW - Neurodevelopmental toxicity Y1 - 2017 U6 - https://doi.org/10.1002/mnfr.201700199 SN - 1613-4125 SN - 1613-4133 VL - 61 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Chmielewski, Frank M. A1 - Götz, Klaus-Peter A1 - Homann, Thomas A1 - Rawel, Harshadrai Manilal T1 - Identification of Endodormancy Release for Cherries (Prunus Avium L.) by Abscisic Acid and Sugars JF - Journal of Horticulture N2 - In order to develop reliable and physiologically sound models for the plant development in spring, the date of endodormancy release is always a crucial and mostly unknown model parameter. Until present, classical approaches - such as climate chamber experiments - are used to derive this unknown parameter. In these experiments, progressive plant development or significant changes in bud’s fresh weight or water content are measurable markers for dormancy release. This study presents an alternative approach, which is based on four well-known metabolites. For 5 seasons (2011/12-2015/16), the content of abscisic acid (ABA) and sugars such as fructose, sucrose and glucose in sweet cherry flower buds (cultivar ‘Summit’) were weekly analysed between beginning of October and April. These data allow comparing the annual course of these metabolites with the date of endodormancy release, derived from a classical climate chamber experiment, published in a previous study. Results showed that ABA and sucrose are two important metabolites which can help to identify the date of endodormancy release of sweet cherries. On average, ABA content reached a plateau of 5.65 μg g-1 DW-1 during endodormancy, which was maintained for 3-6 weeks. The significant reduction of the ABA content after this period to 4.41 μg g-1 DW-1 on average during ecodormancy was nearly in agreement with the date of endodormancy release of ‘Summit’ on 28 November (332 DOY). The annual cycle of sucrose, which has a cryoprotective effect during winter, is well comprehensible and showed a close relationship to the annual course of minimum air temperature after leaf fall(r=-0.90). The nearly constant level of sucrose during ecodormancy (21.0 mg g-1 DW-1, 5 yr. mean) did not only allow deriving the date of endodormancy release but can also be helpful to define the beginning of ontogenetic development. KW - Endodormancy KW - Abscisic acid KW - Sucrose KW - Prunus avium L. KW - Flower buds KW - Phenological modelling Y1 - 2017 U6 - https://doi.org/10.4172/2376-0354.1000210 SN - 2376-0354 VL - 4 IS - 3 ER - TY - THES A1 - Eckel, Nathalie T1 - Metabolically healthy obesity and metabolically unhealthy normal weight - identification and associated risks Y1 - 2017 ER - TY - THES A1 - Leupelt, Anke Verena T1 - Hormonelle Körpergewichtsregulation nach Gewichtsreduktion im Rahmen der multimodalen randomisierten Interventionsstudie MAINTAIN T1 - Hormonal Regulation of Weight Maintenance: Results of a randomized controlled trial analyzing the effects of a lifestyle intervention on weight maintenance in adults N2 - Adipositas wird mit einer Vielzahl schwerwiegender Folgeerkrankungen in Verbindung gebracht. Eine Gewichtsreduktion führt zu einer Verbesserung der metabolischen Folgen der Adipositas. Es ist bekannt, dass die Mehrzahl der adipösen Personen in den Monaten nach der Gewichtsreduktion einen Großteil des abgenommenen Gewichts wieder zunimmt. Nichtsdestotrotz existiert eine hohe Variabilität hinsichtlich des Langzeiterfolges einer Gewichtsreduktion. Der erfolgreiche Erhalt des reduzierten Körpergewichts einiger Personen führt zu der Frage nach den Faktoren, die einen Gewichtserhalt beeinflussen, mit dem Ziel einen Ansatzpunkt für mögliche Therapiestrategien zu identifizieren. In der vorliegenden Arbeit wurde im Rahmen einer kontrollierten, randomisierten Studie mit 143 übergewichtigen Probanden untersucht, ob nach einer dreimonatigen Gewichtsreduktion eine zwölfmonatige gewichtsstabilisierende Lebensstilintervention einen Einfluss auf die Veränderungen der neuroendokrinen Regelkreisläufe und damit auf den langfristigen Gewichtserhalt über einen Zeitraum von achtzehn Monaten hat. Hierbei wurde im Vergleich der beiden Behandlungsgruppen primär festgestellt, dass die multimodale Lebensstilintervention zu einer Gewichtstabilisierung über die Dauer dieser zwölfmonatigen Behandlungsphase führte. In der Kontrollgruppe kam es zu einer moderaten Gewichtszunahme . Dadurch war nach Beendigung der Interventionsphase der BMI der Teilnehmer in der Kontrollgruppe höher als der in der Interventionsgruppe (34,1±6,0 kg*m-2 vs. 32,4±5,7 kg*m-2; p<0,01). Während der Nachbeobachtungszeit war die Interventionsgruppe durch eine signifikant stärkere Gewichtswiederzunahme im Vergleich zur Kontrollgruppe gekennzeichnet, so dass der BMI zwischen beiden Behandlungsgruppen bereits sechs Monate nach der Intervention keinen Unterschied mehr aufwies. Bezüglich der hormonellen Veränderung durch die Gewichtsreduktion wurde, wie erwartet, eine Auslenkung des endokrinen Systems beobachtet. Jedoch konnte kein Unterschied der untersuchten Hormone im Vergleich der beiden Behandlungsgruppen ausfindig gemacht werden. Im Verlauf der Gewichtsabnahme und der anschließenden Studienphasen zeigten sich tendenziell drei verschiedene Verlaufsmuster in den hormonellen Veränderungen. Nach einer zusätzlichen Adjustierung auf den jeweiligen BMI des Untersuchungszeitpunktes konnte für die TSH-Spiegel (p<0,05), die Schilddrüsenhormone (p<0,001) und für die IGF 1-Spiegel (p<0,001) eine über die Studienzeit anhaltende Veränderung festgestellt werden. Abschließend wurde behandlungsgruppenunabhängig untersucht, ob die Hormonspiegel nach Gewichtsreduktion oder ob die relative hormonelle Veränderung während der Gewichtsreduktion prädiktiv für den Erfolg der Gewichterhaltungsphase ist. Hier fand sich für die Mehrzahl der hormonellen Parameter kein Effekt auf die Langzeitentwicklung der Gewichtszunahme. Jedoch konnte gezeigt werden, dass eine geringere Abnahme der 24h Urin-Metanephrin-Ausscheidung während der Gewichtsabnahmephase mit einem besseren Erfolg bezüglich des Gewichtserhalts über die achtzehnmonatige Studienzeit assoziiert war (standardisiertes Beta= -0,365; r2=0,133 p<0,01). Die anderen hormonellen Achsen zeigten keinen nachweislichen Effekt. N2 - Although it is known that obesity is associated with a variety of serious conditions, there is no consensus regarding the optimal therapy for severely obese people. Unfortunately the majority of conventional weight loss therapies often fail long term and diet-induced weight loss is accompanied by several physiological changes and neuroendocrine responses that encourage weight regain. The present research addresses the question whether the hormonal counter-regulation can be modified by a behavioral weight maintenance intervention (diet, excercise, behavioral treatment) and whether such an intervention strategy could support long-term body weight maintenance. Moreover, this thesis focused on the potential predictive role of several hormonal circuits on long-term weight control. In the present study the influence of a twelve-month, weight-stabilizing lifestyle intervention on long-term weight maintenance across 18 months was assessed in a randomized controlled trial. 156 subjects participated in the weight reduction program. 143 subjects reduced their body weight by at least 8% of baseline (inclusion criterion) and were randomized to the maintenance trial. 112 female and 31 male participants were examined. Weight regain after 18 months (T18), defined as changes of BMI between randomization (T0) and T18, was the primary outcome of the trial. The evaluation of endocrine parameters involved in energy homeostasis was a pre-defined secondary outcome. Mean BMI was reduced by 4.67±1.47 kg*m-2 (12.6±3.7 %) during the initial weight loss period. The multimodal lifestyle intervention improved the weight maintenance after weight loss compared to control . However, this effect did not persist in the 6-month follow up and no BMI difference was observed at T18. Furthermore, the initial weight loss induced partially persisting hormonal changes of IGF-1, fT3, fT4, Leptin and Insulin. Changes of sympathetic nervous activity, TSH, GLP-1 and GIP were almost reversed within 18 months. The variability of weight regain at T18 was considerable, but comparable in both groups. Numerous hormonal alterations were found after weight loss. However, exclusively metanephrine excretion independently predicted regainBMI (standardized beta= -0.365, r2=0.134; p<0.01), while all other hormonal circuits analysed here had no predictive power. The 12-month lifestyle intervention did not modify any of these endocrine circuits. In conclusion, a 12-months multimodal lifestyle intervention regarding weight loss maintenance demonstrated a substantial benefit only as long as the subsequent maintenance intervention was performed. However, the hormonal response was not additionally affected by this intervention. KW - Adipositas KW - Körpergewichtsregulation KW - Hormone KW - Gewichtserhalt KW - randomisierte Studie KW - obesity KW - weight regulation KW - hormones KW - weight maintenance KW - randomized controlled trial Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-413181 ER - TY - THES A1 - Jank, Anne-Marie T1 - Effects of senescence on microenvironment-progenitor cell interaction Y1 - 2017 ER - TY - THES A1 - Kasch, Juliane T1 - Impact of maternal high-fat consumption on offspring exercise performance, skeletal muscle energy metabolism, and obesity susceptibility T1 - Einfluss der maternalen Ernährung auf den Energiestoffwechsel des Skelettmuskels, die Ausdauerleistung und die Adipositasentwicklung der Nachkommen N2 - Background: Obesity is thought to be the consequence of an unhealthy nutrition and a lack of physical activity. Although the resulting metabolic alterations such as impaired glucose homeostasis and insulin sensitivity can usually be improved by physical activity, some obese patients fail to enhance skeletal muscle metabolic health with exercise training. Since this might be largely heritable, maternal nutrition during pregnancy and lactation is hypothesized to impair offspring skeletal muscle physiology. Objectives: This PhD thesis aims to investigate the consequences of maternal high-fat diet (mHFD) consumption on offspring skeletal muscle physiology and exercise performance. We could show that maternal high-fat diet during gestation and lactation decreases the offspring’s training efficiency and endurance performance by influencing the epigenetic profile of their skeletal muscle and altering the adaptation to an acute exercise bout, which in long-term, increases offspring obesity susceptibility. Experimental setup: To investigate this issue in detail, we conducted several studies with a similar maternal feeding regime. Dams (C57BL/6J) were either fed a low-fat diet (LFD; 10 energy% from fat) or high-fat diet (HFD; 40 energy% from fat) during pregnancy and lactation. After weaning, male offspring of both maternal groups were switched to a LFD, on which they remained until sacrifice in week 6, 15 or 25. In one study, LFD feeding was followed by HFD provision from week 15 until week 25 to elucidate the effects on offspring obesity susceptibility. In week 7, all mice were randomly allocated to a sedentary group (without running wheel) or an exercised group (with running wheel for voluntary exercise training). Additionally, treadmill endurance tests were conducted to investigate training performance and efficiency. In order to uncover regulatory mechanisms, each study was combined with a specific analytical setup, such as whole genome microarray analysis, gene and protein expression analysis, DNA methylation analyses, and enzyme activity assays. Results: mHFD offspring displayed a reduced training efficiency and endurance capacity. This was not due to an altered skeletal muscle phenotype with changes in fiber size, number, and type. DNA methylation measurements in 6 week old offspring showed a hypomethylation of the Nr4a1 gene in mHFD offspring leading to an increased gene expression. Since Nr4a1 plays an important role in the regulation of skeletal muscle energy metabolism and early exercise adaptation, this could affect offspring training efficiency and exercise performance in later life. Investigation of the acute response to exercise showed that mHFD offspring displayed a reduced gene expression of vascularization markers (Hif1a, Vegfb, etc) pointing towards a reduced angiogenesis which could possibly contribute to their reduced endurance capacity. Furthermore, an impaired glucose utilization of skeletal muscle during the acute exercise bout by an impaired skeletal muscle glucose handling was evidenced by higher blood glucose levels, lower GLUT4 translocation and diminished Lactate dehydrogenase activity in mHFD offspring immediately after the endurance test. These points towards a disturbed use of glucose as a substrate during endurance exercise. Prolonged HFD feeding during adulthood increases offspring fat mass gain in mHFD offspring compared to offspring from low-fat fed mothers and also reduces their insulin sensitivity pointing towards a higher obesity and diabetes susceptibility despite exercise training. Consequently, mHFD reduces offspring responsiveness to the beneficial effects of voluntary exercise training. Conclusion: The results of this PhD thesis demonstrate that mHFD consumption impairs the offspring’s training efficiency and endurance capacity, and reduced the beneficial effects of exercise on the development of diet-induced obesity and insulin resistance in the offspring. This might be due to changes in skeletal muscle epigenetic profile and/or an impaired skeletal muscle angiogenesis and glucose utilization during an acute exercise bout, which could contribute to a disturbed adaptive response to exercise training. N2 - Hintergrund: Übergewicht ist die Folge einer ungesunden Ernährung und einem Mangel an körperlicher Aktivität. Obwohl die daraus resultierenden metabolischen Veränderungen wie die beeinträchtigte Glukose-Homöostase und die Insulinsensitivität in der Regel durch körperliche Aktivität verbessert werden können, sind einige adipöse Patienten nicht in der Lage ihren Skelettmuskel-Metabolismus durch regelmäßiges Training zu verbessern. Da dies weitgehend vererbbar sein könnte, wird vermutet, dass die maternale Ernährung während der Gestation und Laktation einen beeinträchtigten Energiestoffwechsel des Skelettmuskels der Nachkommen begünstigt. Ziel: Ziel dieser Dissertation war es, den Einfluss der maternalen Hochfett-Diät (mHFD) auf den Skelettmuskel des Nachkommens zu untersuchen. Wir konnten zeigen, dass eine mHFD während der Gestation und Laktation die Trainingseffizienz und die Ausdauerleistung der Nachkommen verringert, verursacht durch die Veränderung des epigenetischen Profils des Skelettmuskels der Nachkommen und der verminderten Anpassung an eine akute Trainingsleistung, was langfristig die Anfälligkeit für die Entwicklung einer Adipositas im Nachkommen erhöht. Experimentelles Setup: Um dieses Thema ausführlich zu erforschen, hatten wir ein komplexes Studiendesign. Allen vier Studien ging dasselbe maternale Fütterungsregime voraus. Weibliche C57BL/6J Mäuse wurden entweder mit einer Niedrigfett-Diät (LFD; 10 Energie% aus Fett) oder Hochfett-Diät (HFD; 40 Energie% aus Fett) während der Gestation und Laktation gefüttert. Nach Absatz wurden die männlichen Nachkommen beider Gruppen auf eine LFD umgestellt, auf der sie bis zum Ende der jeweiligen Studie in der Woche 6, 15 oder 25 blieben. In einer Studie folgte auf die LFD-Fütterung eine HFD-Versorgung von Woche 15 bis Woche 25, um den Einfluss der maternalen Diät auf die Entwicklung einer Adipositas der Nachkommen aufzuklären. In der 7. Woche wurden alle Mäuse zufällig einer sesshaften Gruppe (ohne Laufrad) oder einer Trainingsgruppe (mit Laufrad für freiwilliges Trainingstraining) zugewiesen. Darüber hinaus wurden Laufband-Ausdauertests durchgeführt, um die Trainingsleistung und -effizienz zu untersuchen. Um die regulatorischen Mechanismen aufzudecken, wurde jede Studie mit einem spezifischen analytischen Aufbau kombiniert, wie z. B. einer Mikroarray-Analyse, Gen- und Protein-Expressionsanalysen, DNA-Methylierungsanalysen und Enzymaktivitäts-Assays. Ergebnisse: mHFD Nachkommen zeigten eine reduzierte Trainingseffizienz und Ausdauerkapazität. Dies ist nicht auf einen veränderten Skelettmuskel-Phänotyp mit Veränderungen der Muskelfasergröße, der Anzahl und der Muskelfasertypen zurückzuführen. DNA-Methylierungsmessungen bei 6 Wochen alten Nachkommen zeigten eine Hypomethylierung des Nr4a1-Gens in mHFD-Nachkommen, was wiederum in einer erhöhten Genexpression resultierte. Da Nr4a1 eine wichtige Rolle bei der Regulierung des Skelettmuskel-Energiestoffwechsels und der frühen Trainingsanpassung spielt, könnte dies die Trainingseffizienz und -leistung der Nachkommen im späteren Leben beeinflussen. Bei der Untersuchung der Reaktion auf eine akute Ausdauerleistung zeigten die mHFD-Nachkommen eine reduzierte Genexpression von Vaskularisierungsmarkern (Hif1a, Vegfb usw.), die auf eine reduzierte Angiogenese hindeuteten, welche eine Ursache für ihre verminderte Ausdauerkapazität darstellen könnte. Darüber hinaus wurde eine beeinträchtigte Glucoseverwertung des Skelettmuskels während des akuten Ausdauertrainings durch eine beeinträchtigte Glucose-Nutzung des Skelettmuskels mit erhöhten Blutzuckerwerten, einer verminderten GLUT4-Translokation und Laktatdehydrogenase-Aktivität in mHFD-Nachkommen unmittelbar nach dem Ausdauertest gezeigt. Dies weist auf eine gestörte Verwertung der Glucose als Substrat während des Ausdauertrainings hin. Länger andauernde HFD-Fütterung während des Erwachsenenalters erhöht die Fettmasse in mHFD-Nachkommen im Vergleich zu mLFD-Nachkommen und verringert zudem ihre Insulinsensitivität, was Hinweise auf eine erhöhte Adipositas- und Diabetes-Anfälligkeit gibt. Folglich führt die mHFD zu einer verminderten Anpassung der Nachkommen an die positiven Effekte des freiwilligen Laufrad-Trainings. Schlussfolgerung: Die Ergebnisse dieser Dissertation zeigen, dass der mHFD-Konsum die Trainingseffizienz und Ausdauerkapazität der Nachkommen beeinträchtigt, was die Adipositas- und Diabetes-Anfälligkeit im Erwachsenenalter erhöhen kann. Dies könnte auf Veränderungen im epigenetischen Profil des Skelettmuskels und/oder Beeinträchtigungen der Angiogenese und Glukoseverwertung im Skelettmuskel während eines akuten Ausdauertrainings zurückzuführen sein, was zu einer gestörten Anpassung der Nachkommen an das Training beitragen könnte. KW - maternal diet KW - offspring KW - exercise performance KW - skeletal muscle KW - obesity KW - maternale Ernährung KW - Nachkommen KW - Ausdauerleistung KW - Skelettmuskel KW - Adipositas Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-409703 ER - TY - THES A1 - Schraplau, Anne T1 - Regulation der Expression von Xenobiotika-metabolisierenden Enzymen und Deiodasen durch die Xenobiotika-abhängige wechselseitige Induktion von Xenosensor-Transkriptionsfaktoren und Prostaglandin E2 BT - Auswirkung auf die Aktivierung und Inaktivierung von Schilddrüsenhormonen Y1 - 2017 ER - TY - THES A1 - Wittenbecher, Clemens T1 - Linking whole-grain bread, coffee, and red meat to the risk of type 2 diabetes T1 - Der Einfluss von Vollkornbrot, Kaffee, und rotem Fleisch auf das Typ 2 Diabetesrisiko BT - using metabolomics networks to infer potential biological mechanisms BT - Verwendung von Metabolomics-Netzwerken, um auf biologische Mechanismen zu schließen N2 - Background: Consumption of whole-grain, coffee, and red meat were consistently related to the risk of developing type 2 diabetes in prospective cohort studies, but potentially underlying biological mechanisms are not well understood. Metabolomics profiles were shown to be sensitive to these dietary exposures, and at the same time to be informative with respect to the risk of type 2 diabetes. Moreover, graphical network-models were demonstrated to reflect the biological processes underlying high-dimensional metabolomics profiles. Aim: The aim of this study was to infer hypotheses on the biological mechanisms that link consumption of whole-grain bread, coffee, and red meat, respectively, to the risk of developing type 2 diabetes. More specifically, it was aimed to consider network models of amino acid and lipid profiles as potential mediators of these risk-relations. Study population: Analyses were conducted in the prospective EPIC-Potsdam cohort (n = 27,548), applying a nested case-cohort design (n = 2731, including 692 incident diabetes cases). Habitual diet was assessed with validated semiquantitative food-frequency questionnaires. Concentrations of 126 metabolites (acylcarnitines, phosphatidylcholines, sphingomyelins, amino acids) were determined in baseline-serum samples. Incident type 2 diabetes cases were assed and validated in an active follow-up procedure. The median follow-up time was 6.6 years. Analytical design: The methodological approach was conceptually based on counterfactual causal inference theory. Observations on the network-encoded conditional independence structure restricted the space of possible causal explanations of observed metabolomics-data patterns. Given basic directionality assumptions (diet affects metabolism; metabolism affects future diabetes incidence), adjustment for a subset of direct neighbours was sufficient to consistently estimate network-independent direct effects. Further model-specification, however, was limited due to missing directionality information on the links between metabolites. Therefore, a multi-model approach was applied to infer the bounds of possible direct effects. All metabolite-exposure links and metabolite-outcome links, respectively, were classified into one of three categories: direct effect, ambiguous (some models indicated an effect others not), and no-effect. Cross-sectional and longitudinal relations were evaluated in multivariable-adjusted linear regression and Cox proportional hazard regression models, respectively. Models were comprehensively adjusted for age, sex, body mass index, prevalence of hypertension, dietary and lifestyle factors, and medication. Results: Consumption of whole-grain bread was related to lower levels of several lipid metabolites with saturated and monounsaturated fatty acids. Coffee was related to lower aromatic and branched-chain amino acids, and had potential effects on the fatty acid profile within lipid classes. Red meat was linked to lower glycine levels and was related to higher circulating concentrations of branched-chain amino acids. In addition, potential marked effects of red meat consumption on the fatty acid composition within the investigated lipid classes were identified. Moreover, potential beneficial and adverse direct effects of metabolites on type 2 diabetes risk were detected. Aromatic amino acids and lipid metabolites with even-chain saturated (C14-C18) and with specific polyunsaturated fatty acids had adverse effects on type 2 diabetes risk. Glycine, glutamine, and lipid metabolites with monounsaturated fatty acids and with other species of polyunsaturated fatty acids were classified as having direct beneficial effects on type 2 diabetes risk. Potential mediators of the diet-diabetes links were identified by graphically overlaying this information in network models. Mediation analyses revealed that effects on lipid metabolites could potentially explain about one fourth of the whole-grain bread effect on type 2 diabetes risk; and that effects of coffee and red meat consumption on amino acid and lipid profiles could potentially explain about two thirds of the altered type 2 diabetes risk linked to these dietary exposures. Conclusion: An algorithm was developed that is capable to integrate single external variables (continuous exposures, survival time) and high-dimensional metabolomics-data in a joint graphical model. Application to the EPIC-Potsdam cohort study revealed that the observed conditional independence patterns were consistent with the a priori mediation hypothesis: Early effects on lipid and amino acid metabolism had the potential to explain large parts of the link between three of the most widely discussed diabetes-related dietary exposures and the risk of developing type 2 diabetes. N2 - Hintergrund: Evidenz aus prospektiven Kohortenstudien belegt, dass der gewohnheitsmäßige Verzehr von Vollkorn, Kaffee und rotem Fleisch mit dem Risiko an Typ 2 Diabetes zu erkranken assoziiert ist. Dieser Risikobeziehung eventuell zugrunde liegende Mechanismen sind allerdings noch weitgehend unklar. Des Weiteren wurde gezeigt, dass Metabolitenprofile im Blut durch die oben genannten Ernährungs-expositionen beeinflusst werden und außerdem in Zusammenhang mit dem Typ 2 Diabetesrisiko stehen. Zusätzlich wurde beschrieben, dass grafische Netzwerkmodelle von Metabolitenprofilen die zugrunde liegenden Stoffwechselprozesse gut abbilden. Zielstellung: Das Ziel dieser Arbeit war es, Hypothesen bezüglich biologischer Mechanismen zu generieren, die die Assoziationen des Vollkornverzehrs, des Kaffeekonsums und des Fleischverzehrs mit dem Typ 2 Diabetesrisiko erklären könnten. Im speziellen sollten Aminosäure- und Lipidprofile als mögliche Mediatoren des Risikozusammenhangs untersucht werden. Studienpopulation: Analysen wurden auf Grundlage von Daten aus der prospektiven EPIC-Potsdam Kohortenstudie (n=27,548) durchgeführt, wobei ein Fall-Kohorten-Design verwendet wurde (n=2317, darunter 692 inzidente Typ 2 Diabetesfälle). Ernährungsgewohnheiten wurden mit einem validierten, semiquantitativen Verzehrshäufigkeitsfragebogen erfasst. Die Konzentrationen von 126 Metaboliten (Aminosäuren, Acylcarnitine, Sphingomyeline und Phosphatidylcholine) wurden zur Basiserhebung genommen Blutproben gemessen. Inzidente Typ 2 Diabetesfälle wurden im Rahmen einer aktiven Folgeerhebung detektiert und verifiziert. Die mediane Dauer des berücksichtigten prospektiven Erhebungszeitraums lag für diese Studie bei 6,6 Jahren. Aufbau der Analysen: Die theoretische Grundlage für den methodischen Ansatz dieser Arbeit bildete die kontrafaktische Theorie der Kausalinferenz. Die in Netzwerken kodierte konditionale Unabhängigkeitsstruktur wurde genutzt, um den Raum möglicher Modelle zu begrenzen, die die beobachteten Zusammenhänge zwischen den Metaboliten erklären könnten. Unter Annahme weniger grundlegender Effektrichtungen (von der Ernährung auf die Netzwerke gerichtete Effekte; von den Netzwerken auf das Diabetesrisiko gerichtete Effekte) genügt die Adjustierung für eine Teilmenge der direkten Nachbarn im Netzwerk, um netzwerkunabhängige direkte Effekte konsistent zu schätzen. Eine weitere Spezifizierung der Modelle war allerdings aufgrund fehlender Richtungsinformationen zu den Metaboliten-abhängigkeiten nicht möglich. Deshalb wurde ein Multi-Modellierungsansatz gewählt, um die Grenzen möglicher Effekte zu schlussfolgern. Alle möglichen Ernährungs-Metaboliten-Beziehungen und Metaboliten-Typ 2 Diabetesrisiko-Beziehungen wurden dadurch in eine der folgenden drei Kategorien klassifiziert: Direkter Effekt, Unklar, Kein Effekt. Querschnittsbeziehungen wurden in multivariabel adjustierten linearen Regressionsmodellen untersucht. Longitudinale Zusammenhänge wurden mit Cox-Regressionsmodellen geschätzt. Alle Modelle wurden für Alter, Geschlecht, Body-Mass-Index, prävalente Hypertonie, Ernährungs- und Lebensstilfaktoren und die Einnahme von Medikamenten adjustiert. Ergebnisse: Der Verzehr von Vollkornbrot stand im Zusammenhang mit niedrigeren Konzentrationen gesättigter und einfach ungesättigter Fettsäuren. Kaffee stand in Beziehung zu niedrigeren Konzentrationen verzweigtkettiger und aromatischer Aminosäuren und hatte potentielle Effekte auf das Fettsäureprofil in den Lipidmetaboliten. Rotes Fleisch zeigte einen Zusammenhang mit niedrigeren Glyzinspiegeln und mit höheren Konzentrationen verzweigtkettiger Aminosäuren. Außerdem stand das Fettsäureprofil in den verschieden Gruppen von Lipidmetaboliten in Zusammenhang mit dem Fleischverzehr. Des Weiteren wurden potentielle Effekte der Metabolite auf das Typ 2 Diabetesrisiko gefunden. Aromatische Aminosäuren und Lipidmetabolite mit geradzahligen, gesättigten (C14-C16) und mit spezifischen mehrfach ungesättigten Fettsäureseitenketten standen mit einem erhöhten Typ 2 Diabetesrisiko in Beziehung. Glyzin, Glutamin und Lipidmetabolite mit einfach ungesättigten und anderen mehrfach ungesättigten Fettsäureseitenketten zeigten einen günstigen Zusammenhang mit dem Diabetesrisiko. Mögliche Mediatoren der Beziehung der Ernährungsexpositionen wurden identifiziert, indem diese Informationen in gemeinsamen grafischen Modellen integriert wurden. Mediationsanalysen zeigten, dass die möglichen Effekte von Vollkornverzehr auf die Lipidmetabolite ungefähr ein Viertel des günstigen Einflusses von Vollkornverzehr auf das Diabetesrisikos erklären könnten. Die möglichen Effekte von Kaffeekonsum und von Fleischverzehr auf Aminosäuren und Lipidmetabolite könnten jeweils ungefähr zwei Drittel der Zusammenhänge mit dem Diabetesrisiko erklären. Schlussfolgerung: Grundlage für die Ergebnisse dieser Arbeit war die Entwicklung eines Algorithmus, der externe Faktoren (kontinuierlich Expositionsvariablen, Ereigniszeit-Daten) und hochdimensionale Metabolitenprofile in einem gemeinsamen grafischen Modell integriert. Die Anwendung dieses Algorithmus auf Daten aus der EPIC-Potsdam Kohortenstudie hat gezeigt, dass die beobachteten konditionalen Unabhängigkeitsstrukturen mit der a priori Mediationshypothese konsistent waren. Der frühe Einfluss auf den Aminosäure- und Lipidstoffwechsel könnte die beobachteten Zusammenhänge zwischen drei wichtigen Ernährungsfaktoren und dem Risiko an Typ 2 Diabetes zu erkranken zu großen Teilen erklären. KW - type 2 diabetes KW - nutrition KW - lipid metabolism KW - metabolomics KW - epidemiology KW - networks KW - graphical models KW - mediation analysis KW - red meat KW - whole-grain KW - Diabetes mellitus Typ 2 KW - Ernährung KW - Fettstoffwechsel KW - Metabolomics KW - Epidemiologie KW - Netzwerke KW - grafische Modelle KW - Mediationsanalyse KW - rotes Fleisch KW - Vollkorn KW - Kaffee KW - coffee Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-404592 ER - TY - THES A1 - Jannasch, Franziska T1 - Methodological aspects of the derivation of dietary patterns and their association with type 2 diabetes N2 - Hintergrund: Die Untersuchung von Ernährungsmustern als komplementärer Ansatz zu der Untersuchung einzelner Lebensmittel nimmt stetig zu. Generell können drei verschiedene Ansätze unterschieden werden um Ernährungsmuster herzuleiten: A priori Indizes, welche das Wissen über gesundheitsförderliche und –schädliche Eigenschaften eines Lebensmittels für einen gewissen Endpunkt nutzen; A posteriori (exploratorische) Ernährungsmuster, welche die populationsspezifischen vorliegenden Daten ohne eine vorangegangene Hypothese nutzen; gemischte Methoden, die das Wissen über bestimmte Nährstoffe oder Biomarker, welche in der Krankheitsentstehung eine Rolle spielen, nutzen und mit einer exploratorischen Methode kombinieren um krankheitsrelevante Ernährungsmuster zu generieren. Vorangegangene systematische Übersichtsarbeiten, welche die Evidenz der Assoziation zwischen Ernährungsmustern und Diabetes mellitus Typ 2 zusammenfassten, waren entweder beschränkt auf eine Mustermethode oder kombinierten die Muster verschiedener Methoden, ohne die Zusammensetzung der Ernährungsmuster zu berücksichtigen. Ziel: Das Ziel dieser Dissertation war eine umfassende Untersuchung der Assoziation von Ernährungsmustern mit Diabetes mellitus Typ 2. Das erste Teilprojekt zielte auf die Erstellung einer systematischen Übersichtsarbeit von prospektiven Studien ab, unter der Berücksichtigung der verschiedenen Methoden zur Herleitung von Ernährungsmustern in der meta-analytischen Zusammenfassung, was in vorangegangen Übersichtsarbeiten eine Limitation darstellte. Das zweite Teilprojekt hatte die Untersuchung der Assoziation mit Diabetes mellitus Typ 2 von exploratorischen Ernährungsmustern, welche mit der Hauptkomponentenanalyse in einer multi-zentrischen europäischen Fall-Kohorten Studie hergeleitet wurden, zum Ziel. Des Weiteren wurde der eingeschränkten Anwendbarkeit von exploratorischen Mustern in anderen Studienpopulationen mit Methoden der Replikation dieser Ernährungsmuster begegnet. Methoden: Im ersten Teilprojekt wurde eine systematische Literatursuche in den Datenbanken MEDLINE und Web of Science vorgenommen, sowie ein dreistufiger Screeningprozess. Die identifizierten Studien wurden nach den jeweiligen Methoden zur Erstellung von Ernährungsmustern zusammengefasst und Meta-Analysen nur für diejenigen Ernährungsmuster mit vergleichbarer Zusammensetzung vorgenommen. Im zweiten Teilprojekt wurden länderspezifische Ernährungsmuster mittels Hauptkomponentenanalyse aus 36 standardisierten Lebensmittelgruppen hergeleitet. Die Assoziation mit Diabetes mellitus Typ 2 Risiko wurde mit verschieden adjustierten Cox Regressionsmodellen zur Berechnung von Hazardratenverhältnissen untersucht. Die Ernährungsmuster, welche eine signifikante Assoziation mit dem Diabetesrisiko aufzeigten, wurden anschließend über alle Länder in der EPIC-InterAct Studie repliziert: Entweder wurden Summenscores ungewichteter standardisierter Lebensmittelgruppen berechnet (wenn die Korrelation mit dem originalen Ernährungsmuster r ≥ 0.90 war) oder Summenscores der Produkte von standardisierten Scoringkoeffizienten mit standardisierten Lebensmittelgruppen (wenn die Korrelation mit dem originalen Ernährungsmuster r < 0.90). Die resultierenden Scores wurden standardisiert nach der Verteilung der gesamten EPIC-InterAct Subkohorte, dann in jedem Land angewendet und die Assoziation mit Diabetes mellitus Typ 2 anhand der Cox Regressionsmodelle berechnet. Anschließend wurden Meta-Analysen zur Berechnung der gepoolten Schätzer durchgeführt. Ergebnisse: Im ersten Teilprojekt ergab die Literatursuche 48 Artikel, welche 16 Kohorten umfassten. Die Einhaltung der Mediterranen Diät (relatives Risiko (RR) für den Vergleich der extremen Quantile: 0,87; 95%-Konfidenzintervall (KI): 0,82, 0,93), der DASH Diät (RR: 0,81; 95%-KI: 0,72, 0,92) und des Alternative Healthy Eating Index (AHEI) (RR: 0,79; 95%-KI: 0,69, 0,90) war mit einer signifikanten Reduzierung des Diabetesrisikos assoziiert. Exploratorische Ernährungsmuster, charakterisiert durch rotes und verarbeitetes Fleisch, prozessiertes Getreide, hochfette Milchprodukte, Eier und frittierte Produkte, waren positiv mit dem Diabetesrisiko assoziiert (RR: 1,44; 95%-KI: 1,27, 1,62), während Ernährungs-muster, charakterisiert durch Gemüse, Hülsenfrüchte, Obst, Geflügel und Fisch, invers mit dem Diabetesrisiko assoziiert waren (RR: 0,84; 95%-KI: 0,77, 0,91). Ernährungsmuster, welche mit reduzierter Rangregression hergeleitet wurden und charakterisiert waren durch eine hohe Aufnahme von prozessiertem Getreide, zuckergesüßten Getränken und verarbeitetem Fleisch und einen niedrigen Weinkonsum, waren alle signifikant mit dem Diabetesrisiko assoziiert. Im zweiten Teilprojekt konnten zwei wesentliche Ernährungsmuster in jedem Land mit der Hauptkomponentenanalyse hergeleitet werden. Ein Ernährungsmuster, welches in Frankreich hergeleitet wurde und charakterisiert war durch Nüsse, andere Früchte, verarbeitetes Fleisch, Fisch, Eier, Kuchen und Kekse, Kaffee und andere alkoholische Getränke, war signifikant assoziiert mit einem erniedrigten Diabetesrisiko. Drei andere Ernährungsmuster, hergeleitet in Spanien, Norfolk und Oxford, welche sich erheblich in ihrer Zusammensetzung unterschieden, waren mit einem erhöhten Diabetesrisiko assoziiert. Keine der Replikationen dieser vier Ernährungsmuster konnte die signifikante Assoziation mit Diabetes mellitus Typ 2 über andere Länder bestätigen. Schlussfolgerung: Aus der systematischen Übersichtsarbeit ließ sich schlussfolgern, dass Ernährungsweisen gemäß der Mediterranen Diät, DASH und AHEI ein starkes Potenzial zur Prävention von Diabetes mellitus Typ 2 zu haben, obwohl sie sich in einigen Komponenten unterscheiden. Exploratorische Ernährungsmuster wurden basierend auf konkordanten Lebensmitteln gruppiert und waren signifikant mit dem Diabetesrisiko assoziiert, auch wenn die Untersuchungen einzelner Lebensmittel eher begrenzte Evidenz für einen Zusammenhang aufwiesen. Trotzdem bleiben sie populationsspezifische Beobachtungen. Das wurde auch in dem zweiten Teilprojekt unterstrichen, als länderspezifische Ernährungsmuster generiert wurden und keines der Ernährungsmuster, welches signifikant mit dem Diabetesrisiko assoziiert war, durch Simplifizierung oder Replikation der Musterstruktur des Originalmusters über alle Länder bestätigt werden konnte. Für drei RRR-Muster konnten konsistente positive Assoziationen mit dem Diabetesrisiko über verschiedene Studienpopulationen beobachtet werden. N2 - Hintergrund: Die Untersuchung von Ernährungsmustern als komplementärer Ansatz zu der Untersuchung einzelner Lebensmittel nimmt stetig zu. Generell können drei verschiedene Ansätze unterschieden werden um Ernährungsmuster herzuleiten: A priori Indizes, welche das Wissen über gesundheitsförderliche und –schädliche Eigenschaften eines Lebensmittels für einen gewissen Endpunkt nutzen; A posteriori (exploratorische) Ernährungsmuster, welche die populationsspezifischen vorliegenden Daten ohne eine vorangegangene Hypothese nutzen; gemischte Methoden, die das Wissen über bestimmte Nährstoffe oder Biomarker, welche in der Krankheitsentstehung eine Rolle spielen, nutzen und mit einer exploratorischen Methode kombinieren um krankheitsrelevante Ernährungsmuster zu generieren. Vorangegangene systematische Übersichtsarbeiten, welche die Evidenz der Assoziation zwischen Ernährungsmustern und Diabetes mellitus Typ 2 zusammenfassten, waren entweder beschränkt auf eine Mustermethode oder kombinierten die Muster verschiedener Methoden, ohne die Zusammensetzung der Ernährungsmuster zu berücksichtigen. Ziel: Das Ziel dieser Dissertation war eine umfassende Untersuchung der Assoziation von Ernährungsmustern mit Diabetes mellitus Typ 2. Das erste Teilprojekt zielte auf die Erstellung einer systematischen Übersichtsarbeit von prospektiven Studien ab, unter der Berücksichtigung der verschiedenen Methoden zur Herleitung von Ernährungsmustern in der meta-analytischen Zusammenfassung, was in vorangegangen Übersichtsarbeiten eine Limitation darstellte. Das zweite Teilprojekt hatte die Untersuchung der Assoziation mit Diabetes mellitus Typ 2 von exploratorischen Ernährungsmustern, welche mit der Hauptkomponentenanalyse in einer multi-zentrischen europäischen Fall-Kohorten Studie hergeleitet wurden, zum Ziel. Des Weiteren wurde der eingeschränkten Anwendbarkeit von exploratorischen Mustern in anderen Studienpopulationen mit Methoden der Replikation dieser Ernährungsmuster begegnet. Methoden: Im ersten Teilprojekt wurde eine systematische Literatursuche in den Datenbanken MEDLINE und Web of Science vorgenommen, sowie ein dreistufiger Screeningprozess. Die identifizierten Studien wurden nach den jeweiligen Methoden zur Erstellung von Ernährungsmustern zusammengefasst und Meta-Analysen nur für diejenigen Ernährungsmuster mit vergleichbarer Zusammensetzung vorgenommen. Im zweiten Teilprojekt wurden länderspezifische Ernährungsmuster mittels Hauptkomponentenanalyse aus 36 standardisierten Lebensmittelgruppen hergeleitet. Die Assoziation mit Diabetes mellitus Typ 2 Risiko wurde mit verschieden adjustierten Cox Regressionsmodellen zur Berechnung von Hazardratenverhältnissen untersucht. Die Ernährungsmuster, welche eine signifikante Assoziation mit dem Diabetesrisiko aufzeigten, wurden anschließend über alle Länder in der EPIC-InterAct Studie repliziert: Entweder wurden Summenscores ungewichteter standardisierter Lebensmittelgruppen berechnet (wenn die Korrelation mit dem originalen Ernährungsmuster r ≥ 0.90 war) oder Summenscores der Produkte von standardisierten Scoringkoeffizienten mit standardisierten Lebensmittelgruppen (wenn die Korrelation mit dem originalen Ernährungsmuster r < 0.90). Die resultierenden Scores wurden standardisiert nach der Verteilung der gesamten EPIC-InterAct Subkohorte, dann in jedem Land angewendet und die Assoziation mit Diabetes mellitus Typ 2 anhand der Cox Regressionsmodelle berechnet. Anschließend wurden Meta-Analysen zur Berechnung der gepoolten Schätzer durchgeführt. Ergebnisse: Im ersten Teilprojekt ergab die Literatursuche 48 Artikel, welche 16 Kohorten umfassten. Die Einhaltung der Mediterranen Diät (relatives Risiko (RR) für den Vergleich der extremen Quantile: 0,87; 95%-Konfidenzintervall (KI): 0,82, 0,93), der DASH Diät (RR: 0,81; 95%-KI: 0,72, 0,92) und des Alternative Healthy Eating Index (AHEI) (RR: 0,79; 95%-KI: 0,69, 0,90) war mit einer signifikanten Reduzierung des Diabetesrisikos assoziiert. Exploratorische Ernährungsmuster, charakterisiert durch rotes und verarbeitetes Fleisch, prozessiertes Getreide, hochfette Milchprodukte, Eier und frittierte Produkte, waren positiv mit dem Diabetesrisiko assoziiert (RR: 1,44; 95%-KI: 1,27, 1,62), während Ernährungs-muster, charakterisiert durch Gemüse, Hülsenfrüchte, Obst, Geflügel und Fisch, invers mit dem Diabetesrisiko assoziiert waren (RR: 0,84; 95%-KI: 0,77, 0,91). Ernährungsmuster, welche mit reduzierter Rangregression hergeleitet wurden und charakterisiert waren durch eine hohe Aufnahme von prozessiertem Getreide, zuckergesüßten Getränken und verarbeitetem Fleisch und einen niedrigen Weinkonsum, waren alle signifikant mit dem Diabetesrisiko assoziiert. Im zweiten Teilprojekt konnten zwei wesentliche Ernährungsmuster in jedem Land mit der Hauptkomponentenanalyse hergeleitet werden. Ein Ernährungsmuster, welches in Frankreich hergeleitet wurde und charakterisiert war durch Nüsse, andere Früchte, verarbeitetes Fleisch, Fisch, Eier, Kuchen und Kekse, Kaffee und andere alkoholische Getränke, war signifikant assoziiert mit einem erniedrigten Diabetesrisiko. Drei andere Ernährungsmuster, hergeleitet in Spanien, Norfolk und Oxford, welche sich erheblich in ihrer Zusammensetzung unterschieden, waren mit einem erhöhten Diabetesrisiko assoziiert. Keine der Replikationen dieser vier Ernährungsmuster konnte die signifikante Assoziation mit Diabetes mellitus Typ 2 über andere Länder bestätigen. Schlussfolgerung: Aus der systematischen Übersichtsarbeit ließ sich schlussfolgern, dass Ernährungsweisen gemäß der Mediterranen Diät, DASH und AHEI ein starkes Potenzial zur Prävention von Diabetes mellitus Typ 2 zu haben, obwohl sie sich in einigen Komponenten unterscheiden. Exploratorische Ernährungsmuster wurden basierend auf konkordanten Lebensmitteln gruppiert und waren signifikant mit dem Diabetesrisiko assoziiert, auch wenn die Untersuchungen einzelner Lebensmittel eher begrenzte Evidenz für einen Zusammenhang aufwiesen. Trotzdem bleiben sie populationsspezifische Beobachtungen. Das wurde auch in dem zweiten Teilprojekt unterstrichen, als länderspezifische Ernährungsmuster generiert wurden und keines der Ernährungsmuster, welches signifikant mit dem Diabetesrisiko assoziiert war, durch Simplifizierung oder Replikation der Musterstruktur des Originalmusters über alle Länder bestätigt werden konnte. Für drei RRR-Muster konnten konsistente positive Assoziationen mit dem Diabetesrisiko über verschiedene Studienpopulationen beobachtet werden. KW - Epidemiologie KW - Ernährungsmuster KW - systematischer Review KW - Typ-2-Diabetes mellitus Y1 - 2017 ER - TY - THES A1 - Graja, Antonia T1 - Aging-related changes of progenitor cell function and microenvironment impair brown adipose tissue regeneration Y1 - 2017 ER - TY - GEN A1 - Raila, Jens A1 - Schweigert, Florian J. A1 - Kohn, Barbara T1 - C-reactive protein concentrations in serum of dogs with naturally occurring renal disease N2 - The current study was undertaken to investigate the relation between serum C-reactive protein (CRP) concentrations and parameters of renal function in dogs with naturally occurring renal disease. Dogs were assigned to groups according to plasma creatinine concentration, urinary protein-to-creatinine ratio (UP/UC), and exogenous plasma creatinine clearance (P-Cl(Cr)) rates. Group A (healthy control dogs; n = 8): non-azotemic (plasma creatinine <125 mu mol/l) and nonproteinuric (UP/UC <0.2), with P-Cl(Cr) rates >90 ml/min/m(2); group B (n = 11): non-azotemic, nonproteinuric dogs with reduced P-Cl(Cr) rates (50-89 ml/min/m(2)); group C (n = 7): azotemic, borderline proteinuric dogs (P-Cl(Cr) rates: 22-67 ml/min/m(2)); and group D (n = 6): uremic, proteinuric dogs (not tested for P-Cl(Cr)). The serum CRP concentrations were measured via commercial enzyme-linked immunosorbent assay. The CRP concentrations in the clinically healthy dogs (group A) ranged from 2.09 mg/l to 8.60 mg/l (median: 3.21 mg/l). In comparison with dogs of group A, median CRP concentrations were significantly (P < 0.01) elevated in dogs of group B (17.6 mg/l, range: 17.0-19.2 mg/l), group C (24.8 mg/l, range: 18.0-32.5 mg/l), and group D (59.7 mg/l, range: 17.7-123 mg/l). Serum CRP was significantly related to P-Cl(Cr) (r = -0.83; P < 0.001), plasma creatinine (r = 0.81; P < 0.001), UP/UC (r = 0.70; P < 0.001), and leukocytes (r = 0.49; P < 0.01). The significant relations between serum CRP concentrations and biochemical parameters of kidney function in plasma and urine suggest that a stimulation of the acute phase response is implicated in the pathogenesis of canine renal disease. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 407 KW - C-reactive protein KW - dogs KW - proteinuria KW - renal disease Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-402942 ER - TY - GEN A1 - Lohren, Hanna A1 - Bornhorst, Julia A1 - Fitkau, Romy A1 - Pohl, Gabriele A1 - Galla, Hans-Joachim A1 - Schwerdtle, Tanja T1 - Effects on and transfer across the blood-brain barrier in vitro BT - Comparison of organic and inorganic mercury species N2 - Background: Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods: This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl2) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results: With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions: In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl2, our data provide first evidence that the blood-brain barrier transfers mercury out of the brain. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 406 KW - organic mercury KW - inorganic mercury KW - methylmercury KW - thiomersal KW - mercuric mercury KW - in vitro blood-brain barrier model Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-401776 ER - TY - THES A1 - Trendelenburg, Valérie T1 - Therapie der Erdnussallergie durch orale Immuntherapie T1 - Oral immunotherapy for the treatment of peanut allergy BT - eine randomisierte Placebo-kontrollierte Studie N2 - Einleitung: Die Erdnussallergie zählt zu den häufigsten Nahrungsmittelallergien im Kindesalter. Bereits kleine Mengen Erdnuss (EN) können zu schweren allergischen Reaktionen führen. EN ist der häufigste Auslöser einer lebensbedrohlichen Anaphylaxie bei Kindern und Jugendlichen. Im Gegensatz zu anderen frühkindlichen Nahrungsmittelallergien entwickeln Patienten mit einer EN-Allergie nur selten eine natürliche Toleranz. Seit mehreren Jahren wird daher an kausalen Therapiemöglichkeiten für EN-Allergiker, insbesondere an der oralen Immuntherapie (OIT), geforscht. Erste kleinere Studien zur OIT bei EN-Allergie zeigten erfolgsversprechende Ergebnisse. Im Rahmen einer randomisierten, doppelblind, Placebo-kontrollierten Studie mit größerer Fallzahl werden in der vorliegenden Arbeit die klinische Wirksamkeit und Sicherheit dieser Therapieoption bei Kindern mit EN-Allergie genauer evaluiert. Des Weiteren werden immunologische Veränderungen sowie die Lebensqualität und Therapiebelastung unter OIT untersucht. Methoden: Kinder zwischen 3-18 Jahren mit einer IgE-vermittelten EN-Allergie wurden in die Studie eingeschlossen. Vor Beginn der OIT wurde eine orale Provokation mit EN durchgeführt. Die Patienten wurden 1:1 randomisiert und entsprechend der Verum- oder Placebogruppe zugeordnet. Begonnen wurde mit 2-120 mg EN bzw. Placebo pro Tag, abhängig von der Reaktionsdosis bei der oralen Provokation. Zunächst wurde die tägliche OIT-Dosis alle zwei Wochen über etwa 14 Monate langsam bis zu einer Erhaltungsdosis von mindestens 500 mg EN (= 125 mg EN-Protein, ~ 1 kleine EN) bzw. Placebo gesteigert. Die maximal erreichte Dosis wurde dann über zwei Monate täglich zu Hause verabreicht. Im Anschluss erfolgte erneut eine orale Provokation mit EN. Der primäre Endpunkt der Studie war die Anzahl an Patienten der Verum- und Placebogruppe, die unter oraler Provokation nach OIT ≥1200 mg EN vertrugen (=„partielle Desensibilisierung“). Sowohl vor als auch nach OIT wurde ein Hautpricktest mit EN durchgeführt und EN-spezifisches IgE und IgG4 im Serum bestimmt. Außerdem wurden die Basophilenaktivierung sowie die Ausschüttung von T-Zell-spezifischen Zytokinen nach Stimulation mit EN in vitro gemessen. Anhand von Fragebögen wurde die Lebensqualität vor und nach OIT sowie die Therapiebelastung während OIT erfasst. Ergebnisse: 62 Patienten wurden in die Studie eingeschlossen und randomisiert. Nach etwa 16 Monaten unter OIT zeigten 74,2% (23/31) der Patienten der Verumgruppe und nur 16,1% (5/31) der Placebogruppe eine „partielle Desensibilisierung“ gegenüber EN (p<0,001). Im Median vertrugen Patienten der Verumgruppe 4000 mg EN (~8 kleine EN) unter der Provokation nach OIT wohingegen Patienten der Placebogruppe nur 80 mg EN (~1/6 kleine EN) vertrugen (p<0,001). Fast die Hälfte der Patienten der Verumgruppe (41,9%) tolerierten die Höchstdosis von 18 g EN unter Provokation („komplette Desensibilisierung“). Es zeigte sich ein vergleichbares Sicherheitsprofil unter Verum- und Placebo-OIT in Bezug auf objektive Nebenwirkungen. Unter Verum-OIT kam es jedoch signifikant häufiger zu subjektiven Nebenwirkungen wie oralem Juckreiz oder Bauchschmerzen im Vergleich zu Placebo (3,7% der Verum-OIT-Gaben vs. 0,5% der Placebo-OIT-Gaben, p<0,001). Drei Kinder der Verumgruppe (9,7%) und sieben Kinder der Placebogruppe (22,6%) beendeten die Studie vorzeitig, je zwei Patienten beider Gruppen aufgrund von Nebenwirkungen. Im Gegensatz zu Placebo, zeigten sich unter Verum-OIT signifikante immunologische Veränderungen. So kam es zu einer Abnahme des EN-spezifischen Quaddeldurchmessers im Hautpricktest, einem Anstieg der EN-spezifischen IgG4-Werte im Serum sowie zu einer verminderten EN-spezifischen Zytokinsekretion, insbesondere der Th2-spezifischen Zytokine IL-4 und IL-5. Hinsichtlich der EN-spezifischen IgE-Werte sowie der EN-spezifischen Basophilenaktivierung zeigten sich hingegen keine Veränderungen unter OIT. Die Lebensqualität von Kindern der Verumgruppe war nach OIT signifikant verbessert, jedoch nicht bei Kindern der Placebogruppe. Während der OIT wurde die Therapie von fast allen Kindern (82%) und Müttern (82%) als positiv bewertet (= niedrige Therapiebelastung). Diskussion: Die EN-OIT führte bei einem Großteil der EN-allergischen Kinder zu einer Desensibilisierung und einer deutlich erhöhten Reaktionsschwelle auf EN. Somit sind die Kinder im Alltag vor akzidentellen Reaktionen auf EN geschützt, was die Lebensqualität der Kinder deutlich verbessert. Unter den kontrollierten Studienbedingungen zeigte sich ein akzeptables Sicherheitsprofil, mit vorrangig milder Symptomatik. Die klinische Desensibilisierung ging mit Veränderungen auf immunologischer Ebene einher. Langzeitstudien zur EN-OIT müssen jedoch abgewartet werden, um die klinische und immunologische Wirksamkeit hinsichtlich einer möglichen langfristigen oralen Toleranzinduktion sowie die Sicherheit unter langfristiger OIT zu untersuchen, bevor das Therapiekonzept in die Praxis übertragen werden kann. N2 - Background: Peanut (PN) allergy is one of the most common food allergies in childhood. Even very small amounts of PN can elicit severe allergic reactions in patients. PN is the most common cause of life-threatening anaphylaxis in children and adolescents. A natural oral tolerance development in patients with PN allergy is rare when compared to other food allergies in early childhood. Over the last years, a lot of research has been conducted on causal treatment options for food allergy, especially on oral immunotherapy (OIT). First small trials on OIT for PN with small sample size showed promising results. This randomized, double blind, placebo-controlled study with a larger sample size aims to investigate the clinical efficacy and safety of this treatment option in children with PN allergy. In addition, effects of OIT on immunological parameters and the quality of life as well as the burden of treatment will be examined. Methods: Children aged 3-18 years with IgE-mediated PN allergy were included in the study. Before starting OIT an oral food challenge with PN was performed. Patients were randomly assigned (1:1) to receive verum- or placebo-OIT. Depending on the eliciting dose during the oral food challenge, OIT started with 2-120 mg PN or placebo on a daily basis. OIT-doses were gradually increased every two weeks up to a maintenance dose of at least 500 mg PN (= 125 mg PN protein, ~1 small PN) or placebo over a period of approximately 14 months. After reaching the highest dose, patients ingested the dose daily for two months at home followed by a repeated oral food challenge with PN. The primary endpoint of the study was the proportion of patients in the verum- and placebo group tolerating ≥1200 mg PN at final food challenge after OIT (=„partial desensitization“). Before and after OIT a skin prick test (SPT) with PN was conducted and PN -specific IgE and IgG4-levels were measured in serum. In addition, mechanistic studies on basophil reactivity and cytokine production of T-cells were performed after stimulation with PN in vitro. Disease-specific questionnaires were used to measure quality of life before and after OIT and burden of treatment during OIT. Results: 62 patients were included in the study and randomized. After a median of 16 months on OIT 74.2% (23/32) of PN OIT subjects and only 16.1% (5/31) of placebo subjects showed a partial desensitization to PN (p<0,001). During oral food challenge after OIT, PN OIT patients tolerated a median dose of 4000 mg PN (~8 small PN) whereas placebo subjects tolerated only 80 mg PN (~1/6 small PN) (p<0.001). Almost half of the PN OIT subjects (41.9%) tolerated the highest dose of 18 g PN during final food challenge (=„complete desensitization”). There was a comparable safety profile during verum and placebo OIT regarding objective adverse events. However, subjective symptoms as oral pruritus or abdominal pain occurred significantly more often during verum OIT compared to placebo (3.7% of verum OIT-doses vs. 0.52% of placebo OIT-doses, p<0.001). Three PN OIT subjects (9.7%) and seven placebo subjects (22.6%) discontinued the study, two subjects of each group due to allergic side effects. In contrast to placebo, significant immunological changes could be shown during verum OIT with a reduction in PN-specific SPT wheal size, an increase in PN -specific IgG4-serum levels and a decrease in PN-specific cytokine production, especially of Th2-specific cytokines IL-4 and IL-5. With regard to PN-specific IgE levels and PN-specific basophil reactivity, no changes were observed during OIT. Quality of life in PN OIT children significantly improved after treatment but not in placebo. During OIT almost all children (82%) and mothers (82%) were positive about this treatment option (= low burden of treatment). Discussion: PN-OIT successfully induced desensitization in most of the PN-allergic children with a marked increase in the threshold to PN. Consequently, children will be protected from accidental reaction to PN in everyday life, leading to a significant improvement of their quality of life. OIT showed an acceptable safety profile under strict conditions of this clinical trial, with mainly mild symptoms. Clinical desensitization came along with immunological changes. However, long-term studies on PN-OIT are warranted, in order to investigate the clinical and immunological efficacy regarding a possible long-term oral tolerance induction as well as long-term safety, before this treatment option may be implemented as part of routine practice. KW - Erdnussallergie KW - Nahrungsmittelallergie KW - orale Immuntherapie KW - Desensibilisierung KW - Anaphylaxie KW - peanut allergy KW - food allergy KW - oral immunotherapy KW - desensitization KW - anaphylaxis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-403557 ER - TY - THES A1 - Weitkunat, Karolin T1 - Dietary fibers and short-chain fatty acids in the development of diet-induced obesity Y1 - 2017 ER - TY - THES A1 - Nitezki, Tina T1 - Charakterisierung von Stereotypien bei der FVB/NJ-Maus hinsichtlich metabolischer und immunologischer Aspekte auf die Stoffwechselleistung T1 - Characterization of stereotypies in FVB/NJ mice and their impact on metabolism and immune system N2 - Im Sinne des Refinements von Tierversuchen sollen alle Bedingungen während der Zucht, der Haltung und des Transports von zu Versuchszwecken gehaltenen Tieren und alle Methoden während des Versuchs so verbessert werden, dass die verwendeten Tiere ein minimales Maß an potentiellem Distress, Schmerzen oder Leiden erfahren. Zudem soll ihr Wohlbefinden durch die Möglichkeit des Auslebens speziesspezifischer Verhaltensweisen und die Anwendung tierschonender Verfahren maximal gefördert werden. Zur Etablierung von Grundsätzen des Refinements sind grundlegende Kenntnisse über die physiologischen Bedürfnisse und Verhaltensansprüche der jeweiligen Spezies unabdingbar. Die Experimentatoren sollten das Normalverhalten der Tiere kennen, um potentielle Verhaltensabweichungen, wie Stereotypien, zu verstehen und interpretieren zu können. Standardisierte Haltungsbedingungen von zu Versuchszwecken gehaltenen Mäusen weichen in diversen Aspekten von der natürlichen Umgebung ab und erfordern eine gewisse Adaptation. Ist ein Tier über einen längeren Zeitraum unfähig, sich an die gegebenen Umstände anzupassen, können abnormale Verhaltensweisen, wie Stereotypien auftreten. Stereotypien werden definiert als Abweichungen vom Normalverhalten, die repetitiv und ohne Abweichungen im Ablauf ausgeführt werden, scheinbar keiner Funktion dienen und der konkreten Umweltsituation nicht immer entsprechen. Bisher war unklar, in welchem Ausmaß stereotypes Verhalten den metabolischen Phänotyp eines Individuums beeinflusst. Ziel dieser Arbeit war es daher, das stereotype Verhalten der FVB/NJ-Maus erstmals detailliert zu charakterisieren, systematisch zusammenzutragen, welche metabolischen Konsequenzen dieses Verhalten bedingt und wie sich diese auf das Wohlbefinden der Tiere und die Verwendung stereotyper Tiere in Studien mit tierexperimentellem Schwerpunkt auswirken. Der Versuch begann mit der Charakterisierung der mütterlichen Fürsorge in der Parentalgeneration. Insgesamt wurden 35 Jungtiere der F1-Generation vom Absatz an, über einen Zeitraum von 11 Wochen einzeln gehalten, kontinuierlich beobachtet, bis zum Versuchsende wöchentlich Kotproben gesammelt und das Körpergewicht bestimmt. Zusätzlich erfolgten begleitende Untersuchungen wie Verhaltenstests und die Erfassung der physischen Aktivität und metabolischer Parameter. Anschließend wurden u.a. die zerebralen Serotonin- und Dopamingehalte, fäkale Glucocorticoidlevels, hepatisches Glykogen und muskuläre Glykogen- und Triglyceridlevels bestimmt. Nahezu unabhängig von der mütterlichen Herkunft entwickelte sich bei mehr als der Hälfte der 35 Jungtiere in der F1-Generation stereotypes Verhalten. Diese Daten deuten darauf hin, dass es keine Anzeichen für das Erlernen oder eine direkte genetische Transmission stereotypen Verhaltens bei der FVB/NJ-Maus gibt. Über den gesamten Beobachtungszeitraum zeichneten sich die stereotypen FVB/NJ-Mäuse durch ein eingeschränktes Verhaltensrepertoire aus. Zu Gunsten der erhöhten Aktivität und des Ausübens stereotypen Verhaltens lebten sie insgesamt weniger andere Verhaltensweisen (Klettern, Graben, Nagen) aus. Darüber hinaus waren Stereotypien sowohl im 24-Stunden Open Field Test als auch in der Messeinrichtung der indirekten Tierkalorimetrie mit einer erhöhten Aktivität und Motilität assoziiert, während die circadiane Rhythmik nicht divergierte. Diese erhöhte körperliche Betätigung spiegelte sich in den niedrigeren Körpergewichtsentwicklungen der stereotypen Tiere wieder. Außerdem unterschieden sich die Körperfett- und Körpermuskelanteile. Zusammenfassend lässt sich sagen, dass das Ausüben stereotypen Verhaltens zu Differenzen im metabolischen Phänotyp nicht-stereotyper und stereotyper FVB/NJ-Mäuse führt. Im Sinne der „Guten Wissenschaftlichen Praxis“ sollte das zentrale Ziel jedes Wissenschaftlers sein, aussagekräftige und reproduzierbare Daten hervorzubringen. Jedoch können keine validen Resultate von Tieren erzeugt werden, die in Aspekten variieren, die für den vorgesehenen Zweck der Studie nicht berücksichtigt wurden. Deshalb sollten nicht-stereotype und stereotype Individuen nicht innerhalb einer Versuchsgruppe randomisiert werden. Stereotype Tiere demzufolge von geplanten Studien auszuschließen, würde allerdings dem Gebot des zweiten R’s – der Reduction – widersprechen. Um Refinement zu garantieren, sollte der Fokus auf der maximal erreichbaren Prävention stereotypen Verhaltens liegen. Diverse Studien haben bereits gezeigt, dass die Anreicherung der Haltungsumwelt (environmental enrichment) zu einer Senkung der Prävalenz von Stereotypien bei Mäusen führt, dennoch kommen sie weiterhin vor. Daher sollte environmental enrichment zukünftig weniger ein „Kann“, sondern ein „Muss“ sein – oder vielmehr: der Goldstandard. Zudem würde eine profunde phänotypische Charakterisierung dazu beitragen, Mausstämme zu erkennen, die zu Stereotypien neigen und den für den spezifischen Zweck am besten geeigneten Mausstamm zu identifizieren, bevor ein Experiment geplant wird. N2 - In the sense of refinement animal experimentation, all conditions during breeding, husbandry and transport of animals used for experimental purposes and all methods during the experiment should be improved to reduce the degree of potential distress, pain or suffering. In addition, their well-being should be guaranteed by the possibility of expressing natural and species-specific behavioural patterns and by the application of considerate procedures. In order to establish principles for refinement, basic knowledge about the physiological needs and behavioural requirements of the respective species is indispensable. The experimenters should know the normal behaviour of animals in order to understand and interpret potential behavioural deviations, such as stereotypies. Standardized housing conditions of laboratory mice deviate from the natural environment in various aspects and might require a certain adaptation. Behavioural adaptation allows animals to adjust to environmental changes and leads to species’ characteristic behaviour. If an animal is unable to adapt to environmental conditions, abnormal behaviours like stereotypies might occur. Stereotypies are defined as deviations from normal behaviour, which are executed repetitively and without deviations in the performance, seem to serve no function and do not always correspond to the concrete environmental situation. Since it remains unclear to what extend stereotypic behaviour influences the individual’s metabolic phenotype, this study investigated behaviour of FVB/NJ mice in detail, exemplarily for stereotypy-prone mouse strains, and compiled the impact of behavioural deviations on physical activity, animal metabolism, animal welfare and on results obtained from studies with an animal specific focus. To detect early indicators for the later development of stereotypic behaviour in the F1 generation, this study started with investigating maternal care in the parental generation. Overall, 35 animals of the F1 generation were kept individually from weaning age. For 11 weeks they were observed, faecal samples were obtained and body weight was determined. Additionally, behavioural tests, metabolic parameters and physical activity were investigated. Furthermore, among others, cerebral serotonin and dopamine contents, faecal glucocorticoid levels and hepatic glycogen, muscular triglyceride and glycogen levels were assessed. Almost independently of the mother's origin, more than half of the 35 pups developed stereotypic behavior in the F1 generation. Data suggest that there is obviously no evidence of learning or a direct genetic transmission of stereotypic behavior in the FVB/NJ-mouse. The predominant portion of stereotypic animals performed the stereotypy of back-flipping (backwards jumping), some animals demonstrated stereotypic circuit running (running in circles on the cage bottom) and wire gnawing (persistent gnawing on the cage grid while hanging with the forelimbs on it). Because of the increased activity and the performance of stereotypic behaviour, stereotypic mice displayed a restricted behavioural repertoire (reduced climbing, digging, gnawing). Moreover, stereotypies were associated with increased activity and motility, both in the 24-hours open field test and in the ITK system, while the circadian rhythm did not diverge. This elevated physical activity was reflected in the expected gender-dependent lower body weight development of stereotypic animals. In addition, stereotypic FVB/NJ-mice contained more relative muscle mass and less fat mass compared to non-stereotypic FVB/NJ-mice in experimental weeks 7 and 12. Besides, significant differences in relative organ weights were found. In conclusion, the performance of stereotypic behaviour leads to differences in the metabolic phenotype between non-stereotypic and stereotypic FVB/NJ mice. In the sense of "Good Scientific Practice", the central aim of any scientist should be to generate meaningful and reproducible data. However, no valid results can be generated with data derived from animals which differ in aspects that were not considered for the designated purpose of the study. Therefore, stereotypic and non-stereotypic individuals should not be randomized within one trial group. To generally exclude stereotypic animals from further studies, though, would interfere with the commandment of the second "R" - the reduction. To guarantee a maximum refinement, the focus should be the highest achievable prevention of stereotypies. Multiple studies indicate that environmental enrichment decreases the prevalence of stereotypic behaviour in mice, nevertheless they still occur. Thus, environmental enrichment of animal housing should not be a "can" but a "must", or rather the “golden standard”. Moreover, a profound phenotypic characterization would help to identify a stereotypy-prone mouse strain and to determine the mouse strain most suitable for the specific purpose before planning an experiment. KW - Stereotypien KW - Verhalten KW - FVB/NJ Maus KW - Versuchstierkunde KW - stereotypy KW - behaviour KW - FVB/NJ mouse KW - laboratory animal sciences Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-402265 ER - TY - THES A1 - Stadion, Mandy T1 - Validation and Characterization of lfi202b and Zfp69, two Novel Disease Genes in Obesity-Associated Insulin Resistance Y1 - 2017 ER - TY - THES A1 - König, Jeannette T1 - Lipofuscin - Entstehung und Rolle in der Zellalterung Y1 - 2017 ER - TY - GEN A1 - Raila, Jens A1 - Kawashima, Chiho A1 - Sauerwein, Helga A1 - Hülsmann, Nadine A1 - Knorr, Christoph A1 - Myamoto, Akio A1 - Schweigert, Florian J. T1 - Validation of blood vitamin A concentrations in cattle: comparison of a new cow-side test (iCheck™ FLUORO) with high-performance liquid chromatography (HPLC) N2 - Background: Plasma concentration of retinol is an accepted indicator to assess the vitamin A (retinol) status in cattle. However, the determination of vitamin A requires a time consuming multi-step procedure, which needs specific equipment to perform extraction, centrifugation or saponification prior to high-performance liquid chromatography (HPLC). Methods: The concentrations of retinol in whole blood (n = 10), plasma (n = 132) and serum (n = 61) were measured by a new rapid cow-side test (iCheck™ FLUORO) and compared with those by HPLC in two independent laboratories in Germany (DE) and Japan (JP). Results: Retinol concentrations in plasma ranged from 0.033 to 0.532 mg/L, and in serum from 0.043 to 0.360 mg/L (HPLC method). No significant differences in retinol levels were observed between the new rapid cow-side test and HPLC performed in different laboratories (HPLC vs. iCheck™ FLUORO: 0.320 ± 0.047 mg/L vs. 0.333 ± 0.044 mg/L, and 0.240 ± 0.096 mg/L vs. 0.241 ± 0.069 mg/L, lab DE and lab JP, respectively). A similar comparability was observed when whole blood was used (HPLC vs. iCheck™ FLUORO: 0.353 ± 0.084 mg/L vs. 0.341 ± 0.064 mg/L). Results showed a good agreement between both methods based on correlation coefficients of r2 = 0.87 (P < 0.001) and Bland-Altman blots revealed no significant bias for all comparison. Conclusions: With the new rapid cow-side test (iCheck™ FLUORO) retinol concentrations in cattle can be reliably assessed within a few minutes and directly in the barn using even whole blood without the necessity of prior centrifugation. The ease of the application of the new rapid cow-side test and its portability can improve the diagnostic of vitamin A status and will help to control vitamin A supplementation in specific vitamin A feeding regimes such as used to optimize health status in calves or meat marbling in Japanese Black cattle. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 381 KW - Biomarker KW - Blood KW - Cattle KW - Cow-side assay KW - Method comparison KW - Vitamin A Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-401978 ER - TY - JOUR A1 - Raila, Jens A1 - Kawashima, Chiho A1 - Sauerwein, Helga A1 - Hülsmann, Nadine A1 - Knorr, Christoph A1 - Myamoto, Akio A1 - Schweigert, Florian J. T1 - Validation of blood vitamin A concentrations in cattle: comparison of a new cow-side test (iCheck™ FLUORO) with high-performance liquid chromatography (HPLC) JF - BMC veterinary research N2 - Background: Plasma concentration of retinol is an accepted indicator to assess the vitamin A (retinol) status in cattle. However, the determination of vitamin A requires a time consuming multi-step procedure, which needs specific equipment to perform extraction, centrifugation or saponification prior to high-performance liquid chromatography (HPLC). Methods: The concentrations of retinol in whole blood (n = 10), plasma (n = 132) and serum (n = 61) were measured by a new rapid cow-side test (iCheck™ FLUORO) and compared with those by HPLC in two independent laboratories in Germany (DE) and Japan (JP). Results: Retinol concentrations in plasma ranged from 0.033 to 0.532 mg/L, and in serum from 0.043 to 0.360 mg/L (HPLC method). No significant differences in retinol levels were observed between the new rapid cow-side test and HPLC performed in different laboratories (HPLC vs. iCheck™ FLUORO: 0.320 ± 0.047 mg/L vs. 0.333 ± 0.044 mg/L, and 0.240 ± 0.096 mg/L vs. 0.241 ± 0.069 mg/L, lab DE and lab JP, respectively). A similar comparability was observed when whole blood was used (HPLC vs. iCheck™ FLUORO: 0.353 ± 0.084 mg/L vs. 0.341 ± 0.064 mg/L). Results showed a good agreement between both methods based on correlation coefficients of r2 = 0.87 (P < 0.001) and Bland-Altman blots revealed no significant bias for all comparison. Conclusions: With the new rapid cow-side test (iCheck™ FLUORO) retinol concentrations in cattle can be reliably assessed within a few minutes and directly in the barn using even whole blood without the necessity of prior centrifugation. The ease of the application of the new rapid cow-side test and its portability can improve the diagnostic of vitamin A status and will help to control vitamin A supplementation in specific vitamin A feeding regimes such as used to optimize health status in calves or meat marbling in Japanese Black cattle. KW - Cattle KW - Vitamin A KW - Biomarker KW - Blood KW - Method comparison KW - Cow-side assay Y1 - 2017 U6 - https://doi.org/10.1186/s12917-017-1042-3 VL - 13 PB - BioMed Central CY - London ER - TY - THES A1 - Neuber, Corinna T1 - Analytik zur Biotransformation des Sphingosin 1-phosphat-abbauproduktes (2E)-Hexadecenal Y1 - 2017 ER - TY - GEN A1 - Henze, Andrea A1 - Raila, Jens A1 - Kempf, Caroline A1 - Reinke, Petra A1 - Sefrin, Anett A1 - Querfeld, Uwe A1 - Schweigert, Florian J. T1 - Vitamin A metabolism is changed in donors after living-kidney transplantation BT - an observational study N2 - Background The kidneys are essential for the metabolism of vitamin A (retinol) and its transport proteins retinol-binding protein 4 (RBP4) and transthyretin. Little is known about changes in serum concentration after living donor kidney transplantation (LDKT) as a consequence of unilateral nephrectomy; although an association of these parameters with the risk of cardiovascular diseases and insulin resistance has been suggested. Therefore we analyzed the concentration of retinol, RBP4, apoRBP4 and transthyretin in serum of 20 living-kidney donors and respective recipients at baseline as well as 6 weeks and 6 months after LDKT. Results As a consequence of LDKT, the kidney function of recipients was improved while the kidney function of donors was moderately reduced within 6 weeks after LDKT. With regard to vitamin A metabolism, the recipients revealed higher levels of retinol, RBP4, transthyretin and apoRBP4 before LDKT in comparison to donors. After LDKT, the levels of all four parameters decreased in serum of the recipients, while retinol, RBP4 as well as apoRBP4 serum levels of donors increased and remained increased during the follow-up period of 6 months. Conclusion LDKT is generally regarded as beneficial for allograft recipients and not particularly detrimental for the donors. However, it could be demonstrated in this study that a moderate reduction of kidney function by unilateral nephrectomy, resulted in an imbalance of components of vitamin A metabolism with a significant increase of retinol and RBP4 and apoRBP4 concentration in serum of donors. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 373 KW - Donors KW - glomerular filtration rate KW - kidney transplantation KW - retinol KW - retinol-binding protein 4 KW - transthyretin Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400942 ER - TY - GEN A1 - Hocher, Berthold A1 - Reichetzeder, Christoph A1 - Dwi Putra, Sulistyo Emantoko A1 - Slowinski, Torsten A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Pfab, Thiemo T1 - Increased global placental DNA methylation levels are associated with gestational diabetes N2 - Background: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. Methods: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. Results: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46 %; p = 0.013; ±SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1–4 (2.9–5.3 %), whereas the frequency in the fifth quintile was significantly higher (10.7 %; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. Conclusions: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 370 KW - Placenta KW - Gestational diabetes KW - Insulin resistance KW - LC-MS/MS KW - Global DNA methylation KW - Epigenetics KW - Hypermethylation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400914 ER - TY - GEN A1 - Camargo, Rodolfo Gonzalez A1 - Riccardi, Daniela Mendes dos Reis A1 - Ribeiro, Henrique Quintas Teixeira A1 - Carnevali Junior, Luiz Carlos A1 - Matos-Neto, Emidio Marques de A1 - Enjiu, Lucas A1 - Neves, Rodrigo Xavier A1 - Lima, Joanna Darck Carola Correia A1 - Figuerêdo, Raquel Galvão A1 - Alcântara, Paulo Sérgio Martins de A1 - Maximiano, Linda A1 - Otoch, José A1 - Batista Jr., Miguel Luiz A1 - Püschel, Gerhard Paul A1 - Seelaender, Marilia T1 - NF-kappa Bp65 and expression of its pro-inflammatory target genes are upregulated in the subcutaneous adipose tissue of cachectic cancer patients N2 - Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1β, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1β, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 349 KW - cancer cachexia KW - inflammation KW - white adipose tissue KW - NF-κB KW - IκB Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400163 ER - TY - THES A1 - Rödiger, Maria T1 - The Impact of the ARFRP1 Action at the Golgi Apparatus on Adipocyte Function Y1 - 2017 ER - TY - THES A1 - Trenkmann, Tom T1 - Bedeutung von Sphingosin-1-Phosphat in der Pathogenese des Morbus Crohn und Entwicklung und Charakterisierung eines murinen Colitis-Modells Y1 - 2017 ER - TY - GEN A1 - Hocher, Berthold A1 - Oberthür, Dominik A1 - Slowinski, Torsten A1 - Querfeld, Uwe A1 - Schaefer, Franz A1 - Doyon, Anke A1 - Tepel, Martin A1 - Roth, Heinz J. A1 - Grön, Hans J. A1 - Reichetzeder, Christoph A1 - Betzel, Christian A1 - Armbruster, Franz Paul T1 - Modeling of oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) receptor binding and relationship of oxidized to non-oxidized PTH in children with chronic renal failure, adult patients on hemodialysis and kidney transplant recipients N2 - Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 343 KW - n-oxPTH KW - chronic renal failure KW - kidney transplantation KW - hemodialysis KW - oxidation KW - PTH KW - chronic renal failure in children Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-399980 ER - TY - GEN A1 - Schmiedchen, Bettina A1 - Longardt, Ann Carolin A1 - Bührer, Christoph A1 - Raila, Jens A1 - Loui, Andrea A1 - Schweigert, Florian J. T1 - The Relative Dose Response Test Based on Retinol-Binding Protein 4 Is Not Suitable to Assess Vitamin A Status in Very Low Birth Weight Infants N2 - Background: The relative dose response (RDR) test, which quantifies the increase in serum retinol after vitamin A administration, is a qualitative measure of liver vitamin A stores. Particularly in preterm infants, the feasibility of the RDR test involving blood is critically dependent on small sample volumes. Objectives: This study aimed to assess whether the RDR calculated with retinol-binding protein 4 (RBP4) might be a substitute for the classical retinol-based RDR test for assessing vitamin A status in very preterm infants. Methods: This study included preterm infants with a birth weight below 1,500 g (n = 63, median birth weight 985 g, median gestational age 27.4 weeks) who were treated with 5,000 IU retinyl palmitate intramuscularly 3 times a week for 4 weeks. On day 3 (first vitamin A injection) and day 28 of life (last vitamin A injection), the RDR was calculated and compared using serum retinol and RBP4 concentrations. Results: The concentrations of retinol (p < 0.001) and RBP4 (p < 0.01) increased significantly from day 3 to day 28. On day 3, the median (IQR) retinol-RDR was 27% (8.4-42.5) and the median RBP4-RDR was 8.4% (-3.4 to 27.9), compared to 7.5% (-10.6 to 20.8) and -0.61% (-19.7 to 15.3) on day 28. The results for retinol-RDR and RBP4-RDR revealed no significant correlation. The agreement between retinol-RDR and RBP4-RDR was poor (day 3: Cohen's κ = 0.12; day 28: Cohen's κ = 0.18). Conclusion: The RDR test based on circulating RBP4 is unlikely to reflect the hepatic vitamin A status in preterm infants. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 342 KW - relative dose response test KW - vitamin A KW - preterm infant Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-399853 ER - TY - GEN A1 - Castro, José Pedro A1 - Grune, Tilman A1 - Speckmann, Bodo T1 - The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction N2 - White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 339 KW - adipogenesis KW - adipose tissue dysregulation KW - antioxidants KW - metabolic disorders KW - oxidative stress Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-398039 ER - TY - THES A1 - Marschall, Talke Anu T1 - Zytotoxizität, Bioverfügbarkeit und Metabolismus kleiner Selenspezies in humanen Zellen und Entwicklung von ICP-QQQ-MS-basierten Methoden für deren Nachweis Y1 - 2017 ER - TY - GEN A1 - Gerecke, Christian A1 - Edlich, Alexander A1 - Giulbudagian, Michael A1 - Schumacher, Fabian A1 - Zhang, Nan A1 - Said, Andre A1 - Yealland, Guy A1 - Lohan, Silke B. A1 - Neumann, Falko A1 - Meinke, Martina C. A1 - Ma, Nan A1 - Calderón, Marcelo A1 - Hedtrich, Sarah A1 - Schäfer-Korting, Monika A1 - Kleuser, Burkhard T1 - Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes N2 - Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 335 KW - Drug delivery KW - nanoparticles KW - particle characterization KW - keratinocytes KW - nanotoxicology Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-395325 ER -