TY - JOUR A1 - Karuwanarint, Piyaporn A1 - Phonrat, Benjaluck A1 - Tungtrongchitr, Anchalee A1 - Suriyaprom, Kanjana A1 - Chuengsamarn, Somlak A1 - Schweigert, Florian J. A1 - Tungtrongchitr, Rungsunn T1 - Vitamin D-binding protein and its polymorphisms as a predictor for metabolic syndrome JF - Biomarkers in medicine N2 - Aim: To investigate the relationship of vitamin D-binding protein (GC) and genetic variation of GC (rs4588, rs7041 and rs2282679) with metabolic syndrome (MetS) in the Thai population. Materials & methods: GCglobulin concentrations were measured by quantitative western blot analysis in 401 adults. All participants were genotyped using TaqMan allelic discrimination assays. Results: GC-globulin levels were significatly lower in MetS subjects than in control subjects, in which significant negative correlations of GC-globulin levels with systolic blood pressure, glucose and age were found. Male participants who carried the GT genotype for rs4588 showed an increased risk of MetS compared with the GG wild-type (odds ratio: 3.25; p = 0.004). Conclusion: GC-globulin concentrations and variation in GC rs4588 were supported as a risk factor for MetS in Thais. KW - GC gene KW - GC-globulin KW - metabolic syndrome KW - polymorphism KW - Thai population KW - vitamin D-binding protein Y1 - 2018 U6 - https://doi.org/10.2217/bmm-2018-0029 SN - 1752-0363 SN - 1752-0371 VL - 12 IS - 5 SP - 465 EP - 473 PB - Future Medicine CY - London ER - TY - JOUR A1 - Chaykovska, Lyubov A1 - Heunisch, Fabian A1 - von Einem, Gina A1 - Hocher, Carl-Friedrich A1 - Tsuprykov, Oleg A1 - Pavkovic, Mira A1 - Sandner, Peter A1 - Kretschmer, Axel A1 - Chu, Chang A1 - Elitok, Saban A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium JF - PLoS one N2 - Background The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography. Methods Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charite Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE. Results In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean +/- SD was predictive for the need of dialysis (no dialysis: 89.77 +/- 92.85 mu M/mM, n = 277; need for dialysis: 140.3 +/- 82.90 mu M/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60 +/- 92.50 mu M/mM, n = 280; death during follow-up: 169.88 +/- 81.52 mu M/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02 +/- 93.17 mu M/mM, n = 271; MARE: 146.64 +/- 74.68 mu M/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 pM/mM in patients who developed MARE, required dialysis or died. Conclusions Urinary cGMP/creatinine ratio >= 120 mu M/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes. Y1 - 2018 U6 - https://doi.org/10.1371/journal.pone.0195828 SN - 1932-6203 VL - 13 IS - 4 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Knebel, Constanze A1 - Neeb, Jannika A1 - Zahn, Elisabeth A1 - Schmidt, Flavia A1 - Carazo, Alejandro A1 - Holas, Ondej A1 - Pavek, Petr A1 - Püschel, Gerhard Paul A1 - Zanger, Ulrich M. A1 - Süssmuth, Roderich A1 - Lampen, Alfonso A1 - Marx-Stoelting, Philip A1 - Braeuning, Albert T1 - Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells JF - Toxicological sciences N2 - Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group and are therefore thought to display similar and additive behavior. Our data show that Te is an antagonist of the constitutive androstane receptor (CAR) in rats and humans, while propiconazole is an agonist of this receptor. Both substances activate the pregnane X-receptor (PXR) and further induce mRNA expression of CYP3A4. CYP3A4 enzyme activity, however, is inhibited by propiconazole. For common targets of PXR and CAR, the activation of PXR by Te overrides CAR inhibition. In summary, propiconazole and Te affect different hepatotoxicity-relevant cellular targets and, depending on the individual endpoint analyzed, act via similar or dissimilar mechanisms. The use of molecular data based on research in human cell systems extends the picture to refine cumulative assessment group grouping and substantially contributes to the understanding of mixture effects of chemicals in biological systems. KW - triazole fungicides KW - constitutive androstane receptor KW - pregnane X-receptor KW - enzyme induction KW - liver toxicity KW - mixtures Y1 - 2018 U6 - https://doi.org/10.1093/toxsci/kfy026 SN - 1096-6080 SN - 1096-0929 VL - 163 IS - 1 SP - 170 EP - 181 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Eckel, Nathalie A1 - Li, Yanping A1 - Kuxhaus, Olga A1 - Stefan, Norbert A1 - Hu, Frank B. A1 - Schulze, Matthias Bernd T1 - Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study) BT - 30 year follow-up from a prospective cohort study JF - The lancet diabetes & endocrinology N2 - Background Cardiovascular disease risk among individuals across different categories of BMI might depend on their metabolic health. It remains unclear to what extent metabolic health status changes over time and whether this affects cardiovascular disease risk. In this study, we aimed to examine the association between metabolic health and its change over time and cardiovascular disease risk across BMI categories. Findings During 2 127 391 person-years of follow-up with a median follow-up of 24 years, we documented 6306 cases of cardiovascular disease including 3304 myocardial infarction cases and 3080 strokes. Cardiovascular disease risk of women with metabolically healthy obesity was increased compared with women with metabolically healthy normal weight (HR 1.39, 95% CI 1.15-1.68), but risk was considerably higher in women with metabolically unhealthy normal weight (2.43, 2.19-2.68), overweight (2.61, 2.36-2.89) and obesity (3.15, 2.83-3.50). The majority of metabolically healthy women converted to unhealthy phenotypes (2555 [84%] of 3027 women with obesity, 22 215 [68%] of 32 882 women with normal-weight after 20 years). Women who maintained metabolically healthy obesity during follow-up were still at a higher cardiovascular disease risk compared with women with stable healthy normal weight (HR 1.57, 1.03-2.38), yet this risk was lower than for initially metabolically healthy women who converted to an unhealthy phenotype (normal-weight 1.90, 1.66-2.17 vs obesity 2.74, 2.30-3.27). Particularly incident diabetes and hypertension increased the risk among women with initial metabolic health. Interpretation Even when metabolic health is maintained during long periods of time, obesity remains a risk factor for cardiovascular disease. However, risks are highest for metabolically unhealthy women across all BMI categories. A large proportion of metabolically healthy women converted to an unhealthy phenotype over time across all BMI categories, which is associated with an increased cardiovascular disease risk. Copyright (C) 2018 Elsevier Ltd. All rights reserved. Y1 - 2018 U6 - https://doi.org/10.1016/S2213-8587(18)30137-2 SN - 2213-8587 VL - 6 IS - 9 SP - 714 EP - 724 PB - Elsevier CY - New York ER - TY - JOUR A1 - Schwingshackl, Lukas A1 - Ruzanska, Ulrike Alexandra A1 - Anton, Verena A1 - Wallroth, Raphael A1 - Ohla, Kathrin A1 - Knueppel, Sven A1 - Schulze, Matthias Bernd A1 - Pischon, Tobias A1 - Deutschbein, Johannes A1 - Schenk, Liane A1 - Warschburger, Petra A1 - Harttig, Ulrich A1 - Boeing, Heiner A1 - Bergmann, Manuela M. T1 - The NutriAct Family Study: a web-based prospective study on the epidemiological, psychological and sociological basis of food choice JF - BMC public health N2 - Background: Most studies on food choice have been focussing on the individual level but familial aspects may also play an important role. This paper reports of a novel study that will focus on the familial aspects of the formation of food choice among men and women aged 50-70 years by recruiting spouses and siblings (NutriAct Family Study; NFS). Discussion: Until August 4th 2017, 4783 EPIC-Participants were contacted by mail of which 446 persons recruited 2 to 5 family members (including themselves) resulting in 1032 participants, of whom 82% had started answering or already completed the questionnaires. Of the 4337 remaining EPIC-participants who had been contacted, 1040 (24%) did not respond at all, and 3297 (76%) responded but declined, in 51% of the cases because of the request to recruit at least 2 family members in the respective age range. The developed recruitment procedures and web-based methods of data collection are capable to generate the required study population including the data on individual and inter-personal determinants which will be linkable to food choice. The information on familial links among the study participants will show the role of familial traits in midlife for the adoption of food choices supporting healthy aging. KW - NutriAct family study KW - Study protocol KW - Food choice KW - Determinants Y1 - 2018 U6 - https://doi.org/10.1186/s12889-018-5814-x SN - 1471-2458 VL - 18 PB - BMC CY - London ER - TY - JOUR A1 - Maares, Maria A1 - Duman, Ayse A1 - Keil, Claudia A1 - Schwerdtle, Tanja A1 - Haase, Hajo T1 - The impact of apical and basolateral albumin on intestinal zinc resorption in the Caco-2/HT-29-MTX co-culture model JF - Metallomics : integrated biometal science N2 - The molecular mechanisms of intestinal zinc resorption and its regulation are still topics of ongoing research. To this end, the application of suitable in vitro intestinal models, optimized with regard to their cellular composition and medium constituents, is of crucial importance. As one vital aspect, the impact of cell culture media or buffer compounds, respectively, on the speciation and cellular availability of zinc has to be considered when investigating zinc resorption. Thus, the present study aims to investigate the impact of serum, and in particular its main constituent serum albumin, on zinc uptake and toxicity in the intestinal cell line Caco-2. Furthermore, the impact of serum albumin on zinc resorption is analyzed using a co-culture of Caco-2 cells and the mucin-producing goblet cell line HT-29-MTX. Apically added albumin significantly impaired zinc uptake into enterocytes and buffered its cytotoxicity. Yet, undigested albumin does not occur in the intestinal lumen in vivo and impairment of zinc uptake was abrogated by digestion of albumin. Interestingly, zinc uptake, as well as gene expression studies of mt1a and selected intestinal zinc transporters after zinc incubation for 24 h, did not show significant differences between 0 and 10% serum. Importantly, the basolateral application of serum in a transport study significantly enhanced fractional apical zinc resorption, suggesting that the occurrence of a zinc acceptor in the plasma considerably affects intestinal zinc resorption. This study demonstrates that the apical and basolateral medium composition is crucial when investigating zinc, particularly its intestinal resorption, using in vitro cell culture. Y1 - 2018 U6 - https://doi.org/10.1039/c8mt00064f SN - 1756-5901 SN - 1756-591X VL - 10 IS - 7 SP - 979 EP - 991 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Werno, Martin Witold A1 - Wilhelmi, Ilka A1 - Kuropka, Benno A1 - Ebert, Franziska A1 - Freund, Christian A1 - Schürmann, Annette T1 - The GTPase ARFRP1 affects lipid droplet protein composition and triglyceride release from intracellular storage of intestinal Caco-2 cells JF - Biochemical and biophysical research communications N2 - Intestinal release of dietary triglycerides via chylomicrons is the major contributor to elevated postprandial triglyceride levels. Dietary lipids can be transiently stored in cytosolic lipid droplets (LDs) located in intestinal enterocytes for later release. ADP ribosylation factor-related protein 1 (ARFRP1) participates in processes of LD growth in adipocytes and in lipidation of lipoproteins in liver and intestine. This study aims to explore the impact of ARFRP1 on LD organization and its interplay with chylomicron-mediated triglyceride release in intestinal-like Caco-2 cells. Suppression of Arfrp1 reduced release of intracellularly derived triglycerides (0.69-fold) and increased the abundance of transitional endoplasmic reticulum ATPase TERA/VCP, fatty acid synthase-associated factor 2 (FAF2) and perilipin 2 (Plin2) at the LD surface. Furthermore, TERA/VCP and FAF2 co-occurred more frequently with ATGL at LDs, suggesting a reduced adipocyte triglyceride lipase (ATGL)-mediated lipolysis. Accordingly, inhibition of lipolysis reduced lipid release from intracellular storage pools by the same magnitude as Arfrp1 depletion. Thus, the lack of Arfrp1 increases the abundance of lipolysis-modulating enzymes TERA/VCP, FAF2 and Plin2 at LDs, which might decrease lipolysis and reduce availability of fatty acids for triglyceride synthesis and their release via chylomicrons. (C) 2018 The Authors. Published by Elsevier Inc. KW - Chylomicron KW - Lipid droplet proteome KW - Triglyceride secretion KW - Lipolysis Y1 - 2018 U6 - https://doi.org/10.1016/j.bbrc.2018.10.092 SN - 0006-291X SN - 1090-2104 VL - 506 IS - 1 SP - 259 EP - 265 PB - Elsevier CY - San Diego ER - TY - JOUR A1 - Ruszkiewicz, Joanna A. A1 - de Macedo, Gabriel Teixeira A1 - Miranda-Vizuete, Antonio A1 - Teixeira da Rocha, Joao B. A1 - Bowman, Aaron B. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Aschner, Michael T1 - The cytoplasmic thioredoxin system in Caenorhabditis elegans affords protection from methylmercury in an age-specific manner JF - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system N2 - Methylmercury (MeHg) is an environmental pollutant linked to many neurological defects, especially in developing individuals. The thioredoxin (TRX) system is a key redox regulator affected by MeHg toxicity, however the mechanisms and consequences of MeHg-induced dysfunction are not completely understood. This study evaluated the role of the TRX system in C. elegans susceptibility to MeHg during development. Worms lacking or overexpressing proteins from the TRX family were exposed to MeHg for 1 h at different developmental stage: L1, L4 and adult. Worms without cytoplasmic thioredoxin system exhibited age-specific susceptibility to MeHg when compared to wild-type (wt). This susceptibility corresponded partially to decreased total glutathione (GSH) levels and enhanced degeneration of dopaminergic neurons. In contrast, the overexpression of the cytoplasmic system TRX-1/TRXR-1 did not provide substantial protection against MeHg. Moreover, transgenic worms exhibited decreased protein expression for cytoplasmic thioredoxin reductase (TRXR-1). Both mitochondrial thioredoxin system TRX-2/TRXR-2, as well as other thioredoxin-like proteins: TRX-3, TRX-4, TRX-5 did not show significant role in C. elegans resistance to MeHg. Based on the current findings, the cytoplasmic thioredoxin system TRX-1/TRXR-1 emerges as an important age-sensitive protectant against MeHg toxicity in C. elegans. KW - Methylmercury KW - Age KW - Development KW - C. elegans KW - Thioredoxin KW - Thioredoxin reductase Y1 - 2018 U6 - https://doi.org/10.1016/j.neuro.2018.08.007 SN - 0161-813X SN - 1872-9711 VL - 68 SP - 189 EP - 202 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol JF - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - https://doi.org/10.3390/nu10091326 SN - 2072-6643 VL - 10 IS - 9 SP - 1 EP - 17 PB - Molecular Diversity Preservation International (MDPI) CY - Basel ER - TY - JOUR A1 - John, Cathleen A1 - Grune, Jana A1 - Ott, Christiane A1 - Nowotny, Kerstin A1 - Deubel, Stefanie A1 - Kühne, Arne A1 - Schubert, Carola A1 - Kintscher, Ulrich A1 - Regitz-Zagrosek, Vera A1 - Grune, Tilman T1 - Sex Differences in Cardiac Mitochondria in the New Zealand Obese Mouse JF - Frontiers in Endocrinology N2 - Background: Obesity is a risk factor for diseases including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. Diabetes itself contributes to cardiac damage. Thus, studying cardiovascular events and establishing therapeutic intervention in the period of type T2DM onset and manifestation are of highest importance. Mitochondrial dysfunction is one of the pathophysiological mechanisms leading to impaired cardiac function. Methods: An adequate animal model for studying pathophysiology of T2DM is the New Zealand Obese (NZO) mouse. These mice were maintained on a high-fat diet (HFD) without carbohydrates for 13 weeks followed by 4 week HFD with carbohydrates. NZO mice developed severe obesity and only male mice developed manifest T2DM. We determined cardiac phenotypes and mitochondrial function as well as cardiomyocyte signaling in this model. Results: The development of an obese phenotype and T2DM in male mice was accompanied by an impaired systolic function as judged by echocardiography and MyH6/7 expression. Moreover, the mitochondrial function only in male NZO hearts was significantly reduced and ERK1/2 and AMPK protein levels were altered. Conclusions: This is the first report demonstrating that the cardiac phenotype in male diabetic NZO mice is associated with impaired cardiac energy function and signaling events. KW - NZO KW - heart KW - obesity KW - mitochondrial function KW - echocardiography KW - systolic function Y1 - 2018 U6 - https://doi.org/10.3389/fendo.2018.00732 SN - 1664-2392 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Mueller, Steffen A1 - Engel, Tilman A1 - Müller, Juliane A1 - Stoll, Josefine A1 - Baur, Heiner A1 - Mayer, Frank T1 - Sensorimotor exercises and enhanced trunk function BT - a randomized controlled trial JF - International journal of sports medicine N2 - The aim of this study was to investigate the effect of a 6-week sensorimotor or resistance training on maximum trunk strength and response to sudden, high-intensity loading in athletes. Interventions showed no significant difference for maximum strength in concentric and eccentric testing (p>0.05). For perturbation compensation, higher peak torque response following SMT (Extension: +24Nm 95%CI +/- 19Nm; Rotation: + 19Nm 95%CI +/- 13Nm) and RT (Extension: +35Nm 95%CI +/- 16Nm; Rotation: +5Nm 95%CI +/- 4Nm) compared to CG (Extension: -4Nm 95%CI +/- 16Nm; Rotation: -2Nm 95%CI +/- 4Nm) was present (p<0.05). KW - core KW - training intervention KW - prevention KW - perturbation KW - MiSpEx* Y1 - 2018 U6 - https://doi.org/10.1055/a-0592-7286 SN - 0172-4622 SN - 1439-3964 VL - 39 IS - 7 SP - 555 EP - 563 PB - Thieme CY - Stuttgart ER - TY - JOUR A1 - Rohn, Isabelle A1 - Marschall, Talke Anu A1 - Kröpfl, Nina A1 - Jensen, Kenneth Bendix A1 - Aschner, Michael A1 - Tuck, Simon A1 - Kuehnelt, Doris A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans JF - Metallomics : integrated biometal science N2 - The essential micronutrient selenium (Se) is required for various systemic functions, but its beneficial range is narrow and overexposure may result in adverse health effects. Additionally, the chemical form of the ingested selenium contributes crucially to its health effects. While small Se species play a major role in Se metabolism, their toxicological effects, bioavailability and metabolic transformations following elevated uptake are poorly understood. Utilizing the tractable invertebrate Caenorhabditis elegans allowed for an alternative approach to study species-specific characteristics of organic and inorganic Se forms in vivo, revealing remarkable species-dependent differences in the toxicity and bioavailability of selenite, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys). An inverse relationship was found between toxicity and bioavailability of the Se species, with the organic species displaying a higher bioavailability than the inorganic form, yet being less toxic. Quantitative Se speciation analysis with HPLC/mass spectrometry revealed a partial metabolism of SeMet and MeSeCys. In SeMet exposed worms, identified metabolites were Se-adenosylselenomethionine (AdoSeMet) and Se-adenosylselenohomocysteine (AdoSeHcy), while worms exposed to MeSeCys produced Se-methylselenoglutathione (MeSeGSH) and -glutamyl-MeSeCys (-Glu-MeSeCys). Moreover, the possible role of the sole selenoprotein in the nematode, thioredoxin reductase-1 (TrxR-1), was studied comparing wildtype and trxr-1 deletion mutants. Although a lower basal Se level was detected in trxr-1 mutants, Se toxicity and bioavailability following acute exposure was indistinguishable from wildtype worms. Altogether, the current study demonstrates the suitability of C. elegans as a model for Se species dependent toxicity and metabolism, while further research is needed to elucidate TrxR-1 function in the nematode. Y1 - 2018 U6 - https://doi.org/10.1039/c8mt00066b SN - 1756-5901 SN - 1756-591X VL - 10 IS - 6 SP - 818 EP - 827 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Baldermann, Susanne A1 - Homann, Thomas A1 - Neugart, Susanne A1 - Chmielewski, Frank M. A1 - Götz, Klaus-Peter A1 - Gödeke, Kristin A1 - Huschek, Gerd A1 - Morlock, Gertrud E. A1 - Rawel, Harshadrai Manilal T1 - Selected Plant Metabolites Involved in Oxidation-Reduction Processes during Bud Dormancy and Ontogenetic Development in Sweet Cherry Buds (Prunus avium L.) JF - Molecules N2 - Many biochemical processes are involved in regulating the consecutive transition of different phases of dormancy in sweet cherry buds. An evaluation based on a metabolic approach has, as yet, only been partly addressed. The aim of this work, therefore, was to determine which plant metabolites could serve as biomarkers for the different transitions in sweet cherry buds. The focus here was on those metabolites involved in oxidation-reduction processes during bud dormancy, as determined by targeted and untargeted mass spectrometry-based methods. The metabolites addressed included phenolic compounds, ascorbate/dehydroascorbate, reducing sugars, carotenoids and chlorophylls. The results demonstrate that the content of phenolic compounds decrease until the end of endodormancy. After a long period of constancy until the end of ecodormancy, a final phase of further decrease followed up to the phenophase open cluster. The main phenolic compounds were caffeoylquinic acids, coumaroylquinic acids and catechins, as well as quercetin and kaempferol derivatives. The data also support the protective role of ascorbate and glutathione in the para- and endodormancy phases. Consistent trends in the content of reducing sugars can be elucidated for the different phenophases of dormancy, too. The untargeted approach with principle component analysis (PCA) clearly differentiates the different timings of dormancy giving further valuable information. KW - dormancy KW - redox-metabolites KW - phenolics KW - ascorbate KW - anti-oxidative capacity KW - Prunus avium L. KW - flower buds Y1 - 2018 U6 - https://doi.org/10.3390/molecules23051197 SN - 1420-3049 VL - 23 IS - 5 SP - 1 EP - 19 PB - Molecular Diversity Preservation International CY - Basel ER - TY - JOUR A1 - Peres, Tanara Vieira A1 - Arantes, Leticia P. A1 - Miah, Mahfuzur R. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Bowman, Aaron B. A1 - Leal, Rodrigo B. A1 - Aschner, Michael T1 - Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity JF - Neurotoxicity Research N2 - Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson’s disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration. KW - Manganese . C. elegans KW - Signaling pathways KW - DAF-16 KW - Akt/PKB KW - SGK-1 Y1 - 2018 U6 - https://doi.org/10.1007/s12640-018-9915-1 SN - 1029-8428 SN - 1476-3524 VL - 34 IS - 3 SP - 584 EP - 596 PB - Springer CY - New York ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Buse, Claudia A1 - Skoblo, Roman A1 - Haq, Afrozul A1 - Hocher, Berthold T1 - Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - The determination of free 25-hydroxyvitamin D (25(OH)D) as compared to the analysis of total 25-hydroxyvitamin D might reflect better the vitamin D status during pregnancy, since vitamin D-binding protein (DBP) concentrations increase throughout pregnancy and the vast majority of 25(OH)D is tightly bound to DBP thus strongly influencing total 25(OH)D. The concentration of the biologically active free 25(OH)D - on the other hand - is much less dependent on the DBP concentrations. The study was conducted in May-June 2016 in 368 Caucasian pregnant healthy women - residents of Northeastern Germany. Free 25(OH)D was either measured directly by commercial ELISA kit or assessed by calculation via total 25(OH)D, DBP, and albumin serum concentrations. Regardless of the detection method, free 25(OH)D lowers in the 3rd trimester comparing to the 1st trimester (by 12% and 21%, p < 0.05 and p < 0.001, for measured and calculated free 25(OH)D, respectively), whereas total 25(OH)D was not decreased in late pregnancy. DBP rises with gestational age. Total 25(OH)D was not correlated with serum calcium (p = 0.251), whereas free 25(OH)D was significantly (p = 0.007 for measured free 25(OH)D and p < 0.001 for calculated free 25(OH)D) positively correlated with calcium. All 25(OH) D isoforms were significantly negatively correlated with bone-specific alkaline phosphatase (BSAP), however the correlation strength was the lowest with total 25(OH)D (rho = -0.108, p = 0.038), whereas both measured and calculated free 25(OH)D revealed better associations with BSAP (rho = -0.203 and rho = -0.211 for measured and calculated free 25(OH)D, respectively, p < 0.001 for both). We established pregnancy trimester specific reference intervals for free measured and calculated 25(OH)D and DBP. Both measured and calculated free 25(OH)D showed better correlations with parameters of the endocrine vitamin D system (calcium and BSAP). Both ways of measuring free 25(OH)D in pregnant women are suitable as novel laboratory parameter for vitamin D status monitoring during human pregnancy and might replace in the future the routine total 25(OH)D assessment. KW - Measured free 25-hydroxyvitamin D KW - Calculated free 25-hydroxyvitamin D KW - Vitamin D-binding protein KW - Pregnancy KW - Reference intervals Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2018.03.005 SN - 0960-0760 VL - 181 SP - 80 EP - 87 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Neuschäfer-Rube, Frank A1 - Pathe-Neuschäfer-Rube, Andrea A1 - Hippenstiel, Stefan A1 - Püschel, Gerhard Paul T1 - PGE(2) enhanced TNF alpha-mediated IL-8 induction in monocytic cell lines and PBMC JF - Cytokine N2 - Background & purpose: Recent studies suggested a role of prostaglandin E-2 (PGE(2)) in the expression of the chemokine IL-8 by monocytes. The function of EP4 receptor for TNF alpha-induced IL-8 expression was studied in monocytic cell lines. Experimental approach: IL-8 mRNA and protein induction as well as IL-8 promoter activity and transcription factor activation were assessed in monocytic cell lines, primary blood mononuclear cells (PBMC) and transgenic HEK293 cells expressing the EP4 receptor. Key results: In monocytic cell lines THP-1, MonoMac and U937 PGE(2) had only a marginal impact on IL-8 induction but strongly enhanced TNFa-induced IL-8 mRNA and protein synthesis. Similarly, in PBMC IL-8 mRNA induction was larger by simultaneous stimulation with TNF alpha and PGE(2) than by either stimulus alone. The EP4 receptor subtype was the most abundant EP receptor in all three cell lines and in PBMC. Stimulation of THP-1 cells with an EP4 specific agonist enhanced TNF alpha-induced IL-8 mRNA and protein formation to the same extent as PGE(2). In HEK293 cells expressing EP4, but not in wild type HEK293 cells lacking EP4, PGE(2) enhanced TNFainduced IL-8 protein and mRNA synthesis. In THP-1 cells, the enhancement of TNF alpha-mediated IL-8 mRNA induction by PGE(2) was mimicked by a PICA-activator. Furthermore in these cells PGE(2) induced expression of transcription factor C/EBPS, enhanced NF-KB activation by TNFa and inhibited TNF alpha-mediated AP-1 activation. PGE(2) and TNF alpha synergistically activated transcription factor CREB, induced C/EBPS expression and enhanced the activity of an IL-8 promoter fragment containing-223 bp upstream of the transcription start site. Conclusions and implications: These findings suggest that a combined stimulation of TNF alpha and PGE(2)/EP4 signal chains in monocytic cells leads to maximal IL-8 promoter activity, as well as IL-8 mRNA and protein induction, by activating the PICA/CREB/C/EB1313 as well as NF-kappa B signal chains. KW - Monocyte KW - Prostaglandin receptor EP4 KW - IL-8 transcription KW - Signal transduction KW - Tumor necrosis factor alpha Y1 - 2018 U6 - https://doi.org/10.1016/j.cyto.2018.06.020 SN - 1043-4666 SN - 1096-0023 VL - 113 SP - 105 EP - 116 PB - Elsevier CY - London ER - TY - JOUR A1 - Nowotny, Kerstin A1 - Castro, Jose Pedro A1 - Hugo, Martin A1 - Braune, Sabine A1 - Weber, Daniela A1 - Pignitter, Marc A1 - Somoza, Veronika A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Grune, Tilman T1 - Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2 alpha pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging. KW - Advanced glycation end products KW - Aging KW - Apoptosis KW - Collagen KW - ER stress KW - Methylglyoxal KW - Redox homeostasis Y1 - 2018 U6 - https://doi.org/10.1016/j.freeradbiomed.2018.03.022 SN - 0891-5849 SN - 1873-4596 VL - 120 SP - 102 EP - 113 PB - Elsevier CY - New York ER - TY - JOUR A1 - Galbete, Cecilia A1 - Kröger, Janine A1 - Jannasch, Franziska A1 - Iqbal, Khalid A1 - Schwingshackl, Lukas A1 - Schwedhelm, Carolina A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Schulze, Matthias Bernd T1 - Nordic diet, Mediterranean diet, and the risk of chronic diseases BT - the EPIC-Potsdam study JF - BMC Medicine N2 - Background: The Mediterranean Diet (MedDiet) has been acknowledged as a healthy diet. However, its relation with risk of major chronic diseases in non-Mediterranean countries is inconclusive. The Nordic diet is proposed as an alternative across Northern Europe, although its associations with the risk of chronic diseases remain controversial. We aimed to investigate the association between the Nordic diet and the MedDiet with the risk of chronic disease (type 2 diabetes (T2D), myocardial infarction (MI), stroke, and cancer) in the EPIC-Potsdam cohort. Methods: The EPIC-Potsdam cohort recruited 27,548 participants between 1994 and 1998. After exclusion of prevalent cases, we evaluated baseline adherence to a score reflecting the Nordic diet and two MedDiet scores (tMDS, reflecting the traditional MedDiet score, and the MedPyr score, reflecting the MedDiet Pyramid). Cox regression models were applied to examine the association between the diet scores and the incidence of major chronic diseases. Results: During a follow-up of 10.6 years, 1376 cases of T2D, 312 of MI, 321 of stroke, and 1618 of cancer were identified. The Nordic diet showed a statistically non-significant inverse association with incidence of MI in the overall population and of stroke in men. Adherence to the MedDiet was associated with lower incidence of T2D (HR per 1 SD 0.93, 95% CI 0.88-0.98 for the tMDS score and 0.92, 0.87-0.97 for the MedPyr score). In women, the MedPyr score was also inversely associated with MI. No association was observed for any of the scores with cancer. Conclusions: In the EPIC-Potsdam cohort, the Nordic diet showed a possible beneficial effect on MI in the overall population and for stroke in men, while both scores reflecting the MedDiet conferred lower risk of T2D in the overall population and of MI in women. KW - Mediterranean diet KW - Nordic diet KW - regional diets KW - chronic diseases KW - diabetes KW - myocardial infarction KW - stroke KW - cancer KW - EPIC-Potsdam study KW - longitudinal analysis Y1 - 2018 U6 - https://doi.org/10.1186/s12916-018-1082-y SN - 1741-7015 VL - 16 PB - BMC CY - London ER - TY - JOUR A1 - Castro, Jose Pedro A1 - Wardelmann, Kristina A1 - Grune, Tilman A1 - Kleinridders, Andre T1 - Mitochondrial Chaperones in the Brain BT - safeguarding Brain Health and Metabolism? JF - Frontiers in Endocrinology N2 - The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurode-generative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases. KW - insulin signaling KW - brain KW - chaperones KW - mitochondria homeostasis KW - mitochondrial dysfunction KW - neurodegeneration Y1 - 2018 U6 - https://doi.org/10.3389/fendo.2018.00196 SN - 1664-2392 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Gubert, Priscila A1 - Puntel, Bruna A1 - Lehmen, Tassia A1 - Fessel, Joshua P. A1 - Cheng, Pan A1 - Bornhorst, Julia A1 - Trindade, Lucas Siqueira A1 - Avila, Daiana S. A1 - Aschner, Michael A1 - Soares, Felix A. A. T1 - Metabolic effects of manganese in the nematode Caenorhabditis elegans through DAergic pathway and transcription factors activation JF - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system N2 - Manganese (Mn) is an essential trace element for physiological functions since it acts as an enzymatic co-factor. Nevertheless, overexposure to Mn has been associated with a pathologic condition called manganism. Furthermore, Mn has been reported to affect lipid metabolism by mechanisms which have yet to be established. Herein, we used the nematode Caenorhabditis elegans to examine Mn’s effects on the dopaminergic (DAergic) system and determine which transcription factors that regulate with lipid metabolism are affected by it. Worms were exposed to Mn for four hours in the presence of bacteria and in a liquid medium (85 mM NaCl). Mn increased fat storage as evidenced both by Oil Red O accumulation and triglyceride levels. In addition, metabolic activity was reduced as a reflection of decreased oxygen consumption caused by Mn. Mn also affected feeding behavior as evidenced by decreased pharyngeal pumping rate. DAergic neurons viability were not altered by Mn, however the dopamine levels were significantly reduced following Mn exposure. Furthermore, the expression of sbp-1 transcription factor and let-363 protein kinase responsible for lipid accumulation control was increased and decreased, respectively, by Mn. Altogether, our data suggest that Mn increases the fat storage in C. elegans, secondary to DAergic system alterations, under the control of SBP-1 and LET-363 proteins. KW - Manganese KW - Caenorhabditis elegans KW - Lipid metabolism KW - Dopaminergic system KW - Manganism Y1 - 2018 U6 - https://doi.org/10.1016/j.neuro.2018.04.008 SN - 0161-813X SN - 1872-9711 VL - 67 SP - 65 EP - 72 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Fernando, Raquel A1 - Drescher, Cathleen A1 - Deubel, Stefanie A1 - Jung, Tobias A1 - Ost, Mario A1 - Klaus, Susanne A1 - Grune, Tilman A1 - Castro, Jose Pedro T1 - Low proteasomal activity in fast skeletal muscle fibers is not associated with increased age-related oxidative damage JF - Experimental gerontology N2 - The skeletal muscle is a crucial tissue for maintaining whole body homeostasis. Aging seems to have a disruptive effect on skeletal muscle homeostasis including proteostasis. However, how aging specifically impacts slow and fast twitch fiber types remains elusive. Muscle proteostasis is largely maintained by the proteasomal system. Here we characterized the proteasomal system in two different fiber types, using a non-sarcopenic aging model. By analyzing the proteasomal activity and amount, as well as the polyubiquitinated proteins and the level of protein oxidation in Musculus soleus (Sol) and Musculus extensor digitorum longus (EDL), we found that the slow twitch Sol muscle shows an overall higher respiratory and proteasomal activity in young and old animals. However, especially during aging the fast twitch EDL muscle reduces protein oxidation by an increase of antioxidant capacity. Thus, under adaptive non-sarcopenic conditions, the two fibers types seem to have different strategies to avoid age-related changes. KW - Proteasomal system KW - Skeletal muscle KW - Fast and slow fibers KW - Polyubiquitination KW - Oxidized proteins KW - Antioxidants KW - Aging KW - Mitochondrial respiration Y1 - 2018 U6 - https://doi.org/10.1016/j.exger.2018.10.018 SN - 0531-5565 SN - 1873-6815 VL - 117 SP - 45 EP - 52 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Maares, Maria A1 - Keil, Claudia A1 - Koza, Jenny A1 - Straubing, Sophia A1 - Schwerdtle, Tanja A1 - Haase, Hajo T1 - In Vitro Studies on Zinc Binding and Buffering by Intestinal Mucins JF - International Journal of Molecular Sciences N2 - The investigation of luminal factors influencing zinc availability and accessibility in the intestine is of great interest when analyzing parameters regulating intestinal zinc resorption. Of note, intestinal mucins were suggested to play a beneficial role in the luminal availability of zinc. Their exact zinc binding properties, however, remain unknown and the impact of these glycoproteins on human intestinal zinc resorption has not been investigated in detail. Thus, the aim of this study is to elucidate the impact of intestinal mucins on luminal uptake of zinc into enterocytes and its transfer into the blood. In the present study, in vitro zinc binding properties of mucins were analyzed using commercially available porcine mucins and secreted mucins of the goblet cell line HT-29-MTX. The molecular zinc binding capacity and average zinc binding affinity of these glycoproteins demonstrates that mucins contain multiple zinc-binding sites with biologically relevant affinity within one mucin molecule. Zinc uptake into the enterocyte cell line Caco-2 was impaired by zinc-depleted mucins. Yet this does not represent their form in the intestinal lumen in vivo under zinc adequate conditions. In fact, zinc-uptake studies into enterocytes in the presence of mucins with differing degree of zinc saturation revealed zinc buffering by these glycoproteins, indicating that mucin-bound zinc is still available for the cells. Finally, the impact of mucins on zinc resorption using three-dimensional cultures was studied comparing the zinc transfer of a Caco-2/HT-29-MTX co-culture and conventional Caco-2 monoculture. Here, the mucin secreting co-cultures yielded higher fractional zinc resorption and elevated zinc transport rates, suggesting that intestinal mucins facilitate the zinc uptake into enterocytes and act as a zinc delivery system for the intestinal epithelium. KW - intestinal zinc resorption KW - zinc binding KW - mucus layer KW - intestinal mucins KW - in vitro intestinal model KW - goblet cells KW - Caco-2/HT-29-MTX-model Y1 - 2018 U6 - https://doi.org/10.3390/ijms19092662 SN - 1422-0067 VL - 19 IS - 9 ER - TY - JOUR A1 - Fernando, Raquel A1 - Drescher, Cathleen A1 - Nowotny, Kerstin A1 - Grune, Tilman A1 - Castro, Jose Pedro T1 - Impaired proteostasis during skeletal muscle aging JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - Aging is a complex phenomenon that has detrimental effects on tissue homeostasis. The skeletal muscle is one of the earliest tissues to be affected and to manifest age-related changes such as functional impairment and the loss of mass. Common to these alterations and to most of tissues during aging is the disruption of the proteostasis network by detrimental changes in the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal system (ALS). In fact, during aging the accumulation of protein aggregates, a process mainly driven by increased levels of oxidative stress, has been observed, clearly demonstrating UPS and ALS dysregulation. Since the UPS and ALS are the two most important pathways for the removal of misfolded and aggregated proteins and also of damaged organelles, we provide here an overview on the current knowledge regarding the connection between the loss of proteostasis and skeletal muscle functional impairment and also how redox regulation can play a role during aging. Therefore, this review serves for a better understanding of skeletal muscle aging in regard to the loss of proteostasis and how redox regulation can impact its function and maintenance. KW - Skeletal muscle KW - Proteostasis KW - Proteasome and lysosome KW - Oxidative stress KW - Redox regulation KW - Aging Y1 - 2018 U6 - https://doi.org/10.1016/j.freeradbiomed.2018.08.037 SN - 0891-5849 SN - 1873-4596 VL - 132 SP - 58 EP - 66 PB - Elsevier CY - New York ER - TY - JOUR A1 - von Websky, Karoline A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Impact of vitamin D on pregnancy-related disorders and on offspring outcome JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for pre-eclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases. KW - Vitamin D deficiency KW - Free vitamin D KW - Vitamin D binding protein KW - Epigenetics KW - DNA methylation KW - Single nucleotide polymorphism KW - Preeclampsia KW - Gestational diabetes mellitus KW - Small for gestational age KW - Long term health Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2017.11.008 SN - 0960-0760 VL - 180 SP - 51 EP - 64 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Franz, Kristina A1 - Ost, Mario A1 - Otten, Lindsey A1 - Herpich, Catrin A1 - Coleman, Verena A1 - Endres, Anne-Sophie A1 - Klaus, Susanne A1 - Müller-Werdan, Ursula A1 - Norman, Kristina T1 - Higher serum levels of fibroblast growth factor 21 in old patients with cachexia JF - Nutrition : the international journal of applied and basic nutritional sciences N2 - Objective: Fibroblast growth factor (FGF)21 is promptly induced by short fasting in animal models to regulate glucose and fat metabolism. Data on FGF21 in humans are inconsistent and FGF21 has not yet been investigated in old patients with cachexia, a complex syndrome characterized by inflammation and weight loss. The aim of this study was to explore the association of FGF21 with cachexia in old patients compared with their healthy counterparts. Methods: Serum FGF21 and its inactivating enzyme fibroblast activation protein (FAP)-cc were measured with enzyme-linked immunoassays. Cachexia was defined as >= 5% weight loss in the previous 3 mo and concurrent anorexia (Council on Nutrition appetite questionnaire). Results: We included 103 patients with and without cachexia (76.9 +/- 5.2 y of age) and 56 healthy controls (72.9 +/- 5.9 y of age). Cachexia was present in 16.5% of patients. These patients had significantly higher total FGF21 levels than controls (952.1 +/- 821.3 versus 525.2 +/- 560.3 pg/mL; P= 0.012) and the lowest FGF21 levels (293.3 +/- 150.9 pg/mL) were found in the control group (global P < 0.001). Although FAP-alpha did not differ between the three groups (global P = 0.082), bioactive FGF21 was significantly higher in patients with cachexia (global P = 0.002). Risk factor-adjusted regression analyses revealed a significant association between cachexia and total ((beta = 649.745 pg/mL; P < 0.001) and bioactive FGF21 (beta = 393.200 pg/mL; P <0.001), independent of sex, age, and body mass index. Conclusions: Patients with cachexia exhibited the highest FGF21 levels. Clarification is needed to determine whether this is an adaptive response to nutrient deprivation in disease-related cachexia or whether the increased FGF21 values contribute to the catabolic state. (C) 2018 Elsevier Inc. All rights reserved. KW - Fibroblast growth factor 21 KW - Cachexia KW - Anorexia KW - Aging KW - Biomarker Y1 - 2018 U6 - https://doi.org/10.1016/j.nut.2018.11.004 SN - 0899-9007 SN - 1873-1244 VL - 63-64 SP - 81 EP - 86 PB - Elsevier CY - New York ER - TY - JOUR A1 - Gao, Lin-rui A1 - Wang, Guang A1 - Zhang, Jing A1 - Li, Shuai A1 - Chuai, Manli A1 - Bao, Yongping A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation JF - Journal of Cellular Physiology N2 - An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI(+) cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes. KW - cardiac progenitor migration and differentiation KW - chick embryo KW - heart tube KW - high salt KW - reactive oxygen species Y1 - 2018 U6 - https://doi.org/10.1002/jcp.26528 SN - 0021-9541 SN - 1097-4652 VL - 233 IS - 9 SP - 7120 EP - 7133 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Nitezki, Tina A1 - Kleuser, Burkhard A1 - Krämer, Stephanie T1 - Fatal gastric distension in a gold thioglucose mouse model of obesity JF - Laboratory Animals N2 - This case report addresses the problem of underreporting negative results and adverse side effects in animal testing. We present our findings regarding a hyperphagic mouse model associated with unforeseen high mortality. The results outline the necessity of reporting detailed information in the literature to avoid duplication. Obese mouse models are essential in the study of obesity, metabolic syndrome and diabetes mellitus. An experimental model of obesity can be induced by the administration of gold thioglucose (GTG). After transcending the blood-brain barrier, the GTG molecule interacts with regions of the ventromedial hypothalamus, thereby primarily targeting glucose-sensitive neurons. When these neurons are impaired, mice become insensitive to the satiety effects of glucose and develop hyperphagia. In a pilot study for optimising dosage and body weight development, C57BL/6 mice were treated with GTG (0.5 mg/g body weight) or saline, respectively. Animals were provided a physiological amount of standard diet (5 g per animal) for the first 24 hours after treatment to prevent gastric dilatation. Within 24 hours after GTG injection, all GTG-treated animals died of gastric overload and subsequent circulatory shock. Animals developed severe attacks of hyperphagia, and as the amount of provided chow was restricted, mice exhibited unforeseen pica and ingested bedding material. These observations strongly suggest that restricted feeding is contraindicated concerning GTG application. Presumably, the impulse of excessive food intake was a strong driving force. Therefore, the actual degree of suffering in the GTG-induced model of hyperphagia should be revised from moderate to severe. KW - appetite KW - distress KW - refinement KW - mortality Y1 - 2018 U6 - https://doi.org/10.1177/0023677218803384 SN - 0023-6772 SN - 1758-1117 VL - 53 IS - 1 SP - 89 EP - 94 PB - Sage Publ. CY - Thousand Oaks ER - TY - JOUR A1 - Giulbudagian, Michael A1 - Hönzke, Stefan A1 - Bergueiro, Julián A1 - Işık, Doğuş A1 - Schumacher, Fabian A1 - Saeidpour, Siavash A1 - Lohan, Silke A1 - Meinke, Martina A1 - Teutloff, Christian A1 - Schäfer-Korting, Monika A1 - Yealland, Guy A1 - Kleuser, Burkhard A1 - Hedtrich, Sarah A1 - Calderón, Marcelo T1 - Enhanced topical delivery of dexamethasone by beta-cyclodextrin decorated thermoresponsive nanogels JF - Nanoscale N2 - Highly hydrophilic, responsive nanogels are attractive as potential systems for the topical delivery of bioactives encapsulated in their three-dimensional polymeric scaffold. Yet, these drug carrier systems suffer from drawbacks for efficient delivery of hydrophobic drugs. Addressing this, β-cyclodextrin (βCD) could be successfully introduced into the drug carrier systems by exploiting its unique affinity toward dexamethasone (DXM) as well as its role as topical penetration enhancer. The properties of βCD could be combined with those of thermoresponsive nanogels (tNGs) based on dendritic polyglycerol (dPG) as a crosslinker and linear thermoresponsive polyglycerol (tPG) inducing responsiveness to temperature changes. Electron paramagnetic resonance (EPR) studies localized the drug within the hydrophobic cavity of βCD by differences in its mobility and environmental polarity. In fact, the fabricated carriers combining a particulate delivery system with a conventional penetration enhancer, resulted in an efficient delivery of DXM to the epidermis and the dermis of human skin ex vivo (enhancement compared to commercial DXM cream: ∼2.5 fold in epidermis, ∼30 fold in dermis). Furthermore, DXM encapsulated in βCD tNGs applied to skin equivalents downregulated the expression of proinflammatory thymic stromal lymphopoietin (TSLP) and outperformed a commercially available DXM cream. Y1 - 2017 U6 - https://doi.org/10.1039/c7nr04480a SN - 2040-3364 SN - 2040-3372 VL - 10 IS - 1 SP - 469 EP - 479 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Müller, Sandra Marie A1 - Ebert, Franziska A1 - Raber, Georg A1 - Meyer, Sören A1 - Bornhorst, Julia A1 - Hüwel, Stephan A1 - Galla, Hans-Joachim A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Effects of arsenolipids on in vitro blood-brain barrier model JF - Archives of toxicology : official journal of EUROTOX N2 - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids (AsLs) occurring in fish and edible algae, possess a substantial neurotoxic potential in fully differentiated human brain cells. Previous in vivo studies indicating that AsHCs cross the blood–brain barrier of the fruit fly Drosophila melanogaster raised the question whether AsLs could also cross the vertebrate blood–brain barrier (BBB). In the present study, we investigated the impact of several representatives of AsLs (AsHC 332, AsHC 360, AsHC 444, and two arsenic-containing fatty acids, AsFA 362 and AsFA 388) as well as of their metabolites (thio/oxo-dimethylpropionic acid, dimethylarsinic acid) on porcine brain capillary endothelial cells (PBCECs, in vitro model for the blood–brain barrier). AsHCs exerted the strongest cytotoxic effects of all investigated arsenicals as they were up to fivefold more potent than the toxic reference species arsenite (iAsIII). In our in vitro BBB-model, we observed a slight transfer of AsHC 332 across the BBB after 6 h at concentrations that do not affect the barrier integrity. Furthermore, incubation with AsHCs for 72 h led to a disruption of the barrier at sub-cytotoxic concentrations. The subsequent immunocytochemical staining of three tight junction proteins revealed a significant impact on the cell membrane. Because AsHCs enhance the permeability of the in vitro blood–brain barrier, a similar behavior in an in vivo system cannot be excluded. Consequently, AsHCs might facilitate the transfer of accompanying foodborne toxicants into the brain. KW - Arsenolipids KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids KW - In vitro blood-brain barrier model Y1 - 2017 SN - 0340-5761 SN - 1432-0738 VL - 92 IS - 2 SP - 823 EP - 832 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Odongo, Grace Akinyi A1 - Schlotz, Nina A1 - Baldermann, Susanne A1 - Neugart, Susanne A1 - Ngwene, Benard A1 - Schreiner, Monika A1 - Lamy, Evelyn T1 - Effects of Amaranthus cruentus L. on aflatoxin B1- and oxidative stress-induced DNA damage in human liver (HepG2) cells JF - Food bioscience N2 - Amaranth is presently an underutilized crop despite its high content of micronutrients/bioactive phytochemicals and its capacity to thrive in harsh environmental condition. The present study aimed at determining the health benefits of Amaranthus cruentus L. in terms of protection against DNA damage induced by the mycotoxin aflatoxin B1 (AFB1) and oxidative stress using comet assay. The antioxidant potential was further investigated using electron paramagnetic resonance spectroscopy (EPR) and an ARE/Nrf2 reporter gene assay in vitro in a human liver model using the HepG2 cell line. Ethanolic extracts from fresh leaves grown under controlled conditions were used and additionally analyzed for their phytochemical content using liquid chromatography-mass spectrometry (LC-MS). The extracts inhibited both AFB1- and oxidative stress-induced DNA damage in a concentration dependent way with a maximum effect of 57% and 81%, respectively. Oxidative stress triggered using ferrous sulfate was blocked by up to 38% (EPR); the potential to induce antioxidant enzymes using ARE/Nrf2-mediated gene expression was also confirmed. Based on these in vitro findings, further studies on the health-protecting effects of A. cruentus are encouraged to fully explore its health promoting potential and provide the scientific basis for encouraging its cultivation and consumption. KW - African indigenous vegetables KW - Aflatoxin B1 KW - Amaranthaceae KW - Amaranth KW - Aspergillus KW - Cancer prevention Y1 - 2018 U6 - https://doi.org/10.1016/j.fbio.2018.09.006 SN - 2212-4292 SN - 2212-4306 VL - 26 SP - 42 EP - 48 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Tao, Ting A1 - Su, Qiongli A1 - Xu, Simeng A1 - Deng, Jun A1 - Zhou, Sichun A1 - Zhuang, Yu A1 - Huang, Yanjun A1 - He, Caimei A1 - He, Shanping A1 - Peng, Mei A1 - Hocher, Berthold A1 - Yang, Xiaoping T1 - Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis JF - Journal of cellular physiology N2 - Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer. KW - bladder cancer cells KW - FASN KW - p-AKT KW - PKM2 KW - p-mTOR KW - SREBP-1c Y1 - 2018 U6 - https://doi.org/10.1002/jcp.27129 SN - 0021-9541 SN - 1097-4652 VL - 234 IS - 3 SP - 3088 EP - 3104 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Laeger, Thomas A1 - Castano-Martinez, Teresa A1 - Werno, Martin W. A1 - Japtok, Lukasz A1 - Baumeier, Christian A1 - Jonas, Wenke A1 - Kleuser, Burkhard A1 - Schürmann, Annette T1 - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se. KW - Energy expenditure KW - FGF21 KW - Hyperglycaemia KW - Insulin resistance KW - NZO KW - Obesity KW - Protein restriction Y1 - 2018 U6 - https://doi.org/10.1007/s00125-018-4595-1 SN - 0012-186X SN - 1432-0428 VL - 61 IS - 6 SP - 1459 EP - 1469 PB - Springer CY - New York ER - TY - JOUR A1 - Meyer, Sören A1 - Markova, Mariya A1 - Pohl, Gabriele A1 - Marschall, Talke Anu A1 - Pivovarova, Olga A1 - Pfeiffer, Andreas F. H. A1 - Schwerdtle, Tanja T1 - Development, validation and application of an ICP-MS/MS method to quantify minerals and (ultra-)trace elements in human serum JF - Journal of trace elements in medicine and biology N2 - Multi-element determination in human samples is very challenging. Especially in human intervention studies sample volumes are often limited to a few microliters and due to the high number of samples a high-throughput is indispensable. Here, we present a state-of-the-art ICP-MS/MS-based method for the analysis of essential (trace) elements, namely Mg, Ca, Fe, Cu, Zn, Mo, Se and I, as well as food-relevant toxic elements such as As and Cd. The developed method was validated regarding linearity of the calibration curves, method LODs and LOQs, selectivity and trueness as well as precision. The established reliable method was applied to quantify the element serum concentrations of participants of a human intervention study (LeguAN). The participants received isocaloric diets, either rich in plant protein or in animal protein. While the serum concentrations of Mg and Mo increased in participants receiving the plant protein-based diet (above all legumes), the Se concentration in serum decreased. In contrast, the animal protein-based diet, rich in meat and dairy products, resulted in an increased Se concentration in serum. KW - ICP-MS KW - Elemental blood serum concentration KW - Human nutritional intervention Y1 - 2018 U6 - https://doi.org/10.1016/j.jtemb.2018.05.012 SN - 0946-672X VL - 49 SP - 157 EP - 163 PB - Elsevier GMBH CY - München ER - TY - JOUR A1 - Wirsching, Jan A1 - Grassmann, Sophie A1 - Eichelmann, Fabian A1 - Harms, Laura Malin A1 - Schenk, Matthew A1 - Barth, Eva A1 - Berndzen, Alide A1 - Olalekan, Moses A1 - Sarmini, Leen A1 - Zuberer, Hedwig A1 - Aleksandrova, Krasimira T1 - Development and reliability assessment of a new quality appraisal tool for cross-sectional studies using biomarker data (BIOCROSS) JF - BMC Medical Research Methodology N2 - Background Biomarker-based analyses are commonly reported in observational epidemiological studies; however currently there are no specific study quality assessment tools to assist evaluation of conducted research. Accounting for study design and biomarker measurement would be important for deriving valid conclusions when conducting systematic data evaluation. Methods We developed a study quality assessment tool designed specifically to assess biomarker-based cross-sectional studies (BIOCROSS) and evaluated its inter-rater reliability. The tool includes 10-items covering 5 domains: ‘Study rational’, ‘Design/Methods’, ‘Data analysis’, ‘Data interpretation’ and ‘Biomarker measurement’, aiming to assess different quality features of biomarker cross-sectional studies. To evaluate the inter-rater reliability, 30 studies were distributed among 5 raters and intraclass correlation coefficients (ICC-s) were derived from respective ratings. Results The estimated overall ICC between the 5 raters was 0.57 (95% Confidence Interval (CI): 0.38–0.74) indicating a good inter-rater reliability. The ICC-s ranged from 0.11 (95% CI: 0.01–0.27) for the domain ‘Study rational’ to 0.56 (95% CI: 0.40–0.72) for the domain ‘Data interpretation’. Conclusion BIOCROSS is a new study quality assessment tool suitable for evaluation of reporting quality from cross-sectional epidemiological studies employing biomarker data. The tool proved to be reliable for use by biomedical scientists with diverse backgrounds and could facilitate comprehensive review of biomarker studies in human research. KW - BIOCROSS KW - Quality appraisal KW - Evaluation tool KW - Cross-sectional studies Y1 - 2018 U6 - https://doi.org/10.1186/s12874-018-0583-x SN - 1471-2288 VL - 18 PB - BMC CY - London ER - TY - JOUR A1 - Edlich, Alexander A1 - Volz, Pierre A1 - Brodwolf, Robert A1 - Unbehauen, Michael A1 - Mundhenk, Lars A1 - Gruber, Achim D. A1 - Hedtrich, Sarah A1 - Haag, Rainer A1 - Alexiev, Ulrike A1 - Kleuser, Burkhard T1 - Crosstalk between core-multishell nanocarriers for cutaneous drug delivery and antigen-presenting cells of the skin JF - Biomaterials : biomaterials reviews online N2 - Owing their unique chemical and physical properties core-multishell (CMS) nanocarriers are thought to underlie their exploitable biomedical use for a topical treatment of skin diseases. This highlights the need to consider not only the efficacy of CMS nanocarriers but also the potentially unpredictable and adverse consequences of their exposure thereto. As CMS nanocarriers are able to penetrate into viable layers of normal and stripped human skin ex vivo as well as in in vitro skin disease models the understanding of nanoparticle crosstalk with components of the immune system requires thorough investigation. Our studies highlight the biocompatible properties of CMS nanocarriers on Langerhans cells of the skin as they did neither induce cytotoxicity and genotoxicity nor cause reactive oxygen species (ROS) or an immunological response. Nevertheless, CMS nanocarriers were efficiently taken up by Langerhans cells via divergent endocytic pathways. Bioimaging of CMS nanocarriers by fluorescence lifetime imaging microscopy (FLIM) and flow cytometry indicated not only a localization within the lysosomes but also an energy-dependent exocytosis of unmodified CMS nanocarriers into the extracellular environment. (C) 2018 Elsevier Ltd. All rights reserved. KW - Core-multishell nanocarriers KW - Fluorescence lifetime imaging microscopy KW - Langerhans cells KW - Nanoparticle uptake KW - Nanotoxicology Y1 - 2018 U6 - https://doi.org/10.1016/j.biomaterials.2018.01.058 SN - 0142-9612 SN - 1878-5905 VL - 162 SP - 60 EP - 70 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Nitezki, Tina A1 - Schulz, Nadja A1 - Krämer, Stephanie T1 - Color matters BT - They would choose if they could (see)! JF - Laboratory animals : the international journal of laboratory animal science and welfare N2 - Concerning standardization of laboratory animal husbandry, only exiguous changes of habitat can potentially influence animal physiology or results of behavioral tests. Routinely, mice chow is dyed when different types of diets are dispensed. Given the fact that the dye itself has no effects on food odor or flavor, we wanted to test the hypothesis that the color of chow has an impact on food uptake in mice. Twelve-week-old male mice of different strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ; n = 12/strain) were single-housed in PhenoMaster (R) cages. After acclimatization standard mice chow in different colors was administered. Food intake was monitored as a two-alternative choice test of different color combinations. All animals had an average food intake of 3 g/d and no preferences were observed when a combination of identically colored food was offered. Preference tests yielded significant aversion to blue food and significant attraction to yellow and green food in C57BL/6 and DBA/2J mice. In C3H/HeJ and BALB/cJ mice no color-related pattern occurred. Selected mice strains have known differences concerning functionality of their visual sense. C57BL/6 and DBA/2 mice are considered to be normal sighted at testing age, BALB/c is representative for albino strains and C3H mice carry mutations resulting in retinal alterations. Results suggesting that normal-sighted mice would be selective concerning food color when given the choice. Nevertheless, this does not influence overall quantity of food intake when animals were provided solely with food colored with a single dye. Moreover, visually impaired mice showed no color-related food preferences. N2 - Concernant la normalisation des élevages d’animaux de laboratoire, seuls des changements mineurs de leur habitat peuvent potentiellement influencer la physiologie des animaux ou les résultats des tests comportementaux. Habituellement, la nourriture des souris show est colorée en fonction des différents types de régimes administrés. Étant donné que la couleur n’a aucun effet sur l’odeur ou le goût des aliments, nous avons souhaité vérifier l’hypothèse selon laquelle la couleur des aliments a un impact sur la quantité consommée par les souris. Des souris mâles âgés de 12 semaines issus de différentes souches (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ; n = 12/souche) ont été hébergés individuellement dans des cages PhenoMaster®. Après une phase d’acclimatation, des aliments normaux de couleurs différentes ont été administrés. La consommation alimentaire a été mesurée dans le cadre d’un test permettant aux souris de choisir entre deux combinaisons de couleurs différentes. Tous les animaux ont consommé en moyenne 3 g de nourriture par jour et aucune préférence n’a été remarquée lorsqu’une combinaison d’aliments de couleur identique était offerte. Les tests de préférence ont révélé une forte aversion aux aliments de couleur bleue et une attirance importante envers les aliments de couleurs jaune et verte chez les souris C57BL/6 et DBA/2J. Chez les souris C3H/HeJ et BALB/cJ, aucune préférence basée sur les couleurs n’a été observée. Les lignées de souris sélectionnées présentent des différences connues en ce qui concerne la fonctionnalité de leur sens visuel. Il est considéré que les souris C57BL/6 et DBA/2 possèdent une vue normale au moment du test. La lignée BALB/c représente les souches de souris albinos et les souris C3H sont porteuses de mutations entraînant des modifications de la rétine. Les résultats suggèrent que les souris possédant une vue normale sont sélectives en ce qui concerne la couleur des aliments lorsqu’on leur donne le choix. De manière générale, ceci n’influence toutefois pas la quantité de nourriture consommée lorsque les animaux reçoivent uniquement des aliments ne présentant qu’une seule couleur. Par ailleurs, les souris malvoyantes n’ont affiché aucune préférence alimentaire associée aux couleurs. N2 - Bei der Standardisierung der Labortierhaltung können schon geringfügige Veränderungen des Habitats die Physiologie des Tieres oder die Ergebnisse von Verhaltenstests beeinflussen. Routinemäßig wird das Futter von Mäusen gefärbt, wenn verschiedene Arten von Diäten verabreicht werden. Angesichts der Tatsache, dass der Farbstoff selbst keine Auswirkungen auf den Lebensmittelgeruch oder -geschmack hat, wollten wir die Hypothese testen, dass die Futterfarbe einen Einfluss auf die Nahrungsaufnahme bei Mäusen hat. 12 Wochen alte männliche Mäuse verschiedener Stämme (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ; n = 12/Stamm) wurden einzeln in PhenoMaster® Käfigen untergebracht. Nach der Akklimatisierung wurde Standard-Mäusefutter in verschiedenen Farben verabreicht. Die Nahrungsaufnahme wurde als ein Zwei-Alternativen-Wahltest verschiedener Farbkombinationen überwacht. Alle Tiere nahmen durchschnittlich 3 g/Tag Nahrung auf und es wurden keine Präferenzen beobachtet, wenn eine Kombination von gleichfarbigen Futtermitteln angeboten wurde. Präferenztests ergaben eine signifikante Abneigung gegen blaues Futter und eine signifikante Vorliebe für gelbes und grünes Futter bei C57BL/6- und DBA/2J-Mäusen. Bei C3H/HeJ- und BALB/cJ-Mäusen waren keine farbbezogenen Muster erkennbar. Ausgewählte Stämme von Mäusen weisen bekanntermaßen Unterschiede in der Funktionalität ihres Sehsinns auf. C57BL/6- und DBA/2-Mäuse gelten im Testalter als normalsichtig, BALB/c sind repräsentativ für Albino-Stämme und C3H-Mäuse sind von Mutationen betroffen, die zu Netzhautveränderungen führen. Die Ergebnisse legen nahe, dass normalsichtige Mäuse selektiv in Bezug auf die Futterfarbe sein dürften, sofern sie die Wahl haben. Dies hat jedoch keinen Einfluss auf die Gesamtmenge der Nahrungsaufnahme, wenn die Tiere ausschließlich mit durch einen einzigen Farbstoff gefärbtem Futter versorgt wurden. Außerdem zeigten sehbehinderte Mäuse keine farbbezogenen Futtervorlieben. KW - refinement KW - color vision KW - food choice KW - color preference KW - eating Y1 - 2018 U6 - https://doi.org/10.1177/0023677218766370 SN - 0023-6772 SN - 1758-1117 VL - 52 IS - 6 SP - 611 EP - 620 PB - Sage Publ. CY - Thousand Oaks ER - TY - JOUR A1 - Reichel, Martin A1 - Rhein, Cosima A1 - Hofmann, Lena M. A1 - Monti, Juliana A1 - Japtok, Lukasz A1 - Langgartner, Dominik A1 - Füchsl, Andrea M. A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Hellerbrand, Claus A1 - Reber, Stefan O. A1 - Kornhuber, Johannes T1 - Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation JF - Frontiers in Psychiatry N2 - Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-alpha (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders. KW - chronic psychosocial stress KW - acid sphingomyelinase KW - ceramide KW - sphingolipid metabolism KW - chronic subordinate colony housing (CSC) KW - liver metabolism Y1 - 2018 U6 - https://doi.org/10.3389/fpsyt.2018.00496 SN - 1664-0640 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Prommer, Hans-Ulrich A1 - Maurer, Johannes A1 - von Websky, Karoline A1 - Freise, Christian A1 - Sommer, Kerstin A1 - Nasser, Hamoud A1 - Samapati, Rudi A1 - Reglin, Bettina A1 - Guimaraes, Pedro A1 - Pries, Axel Radlach A1 - Querfeld, Uwe T1 - Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis JF - Scientific reports N2 - Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1 alpha, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis. Y1 - 2018 U6 - https://doi.org/10.1038/s41598-018-23663-1 SN - 2045-2322 VL - 8 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Pathe-Neuschäfer-Rube, Andrea A1 - Neuschäfer-Rube, Frank A1 - Haas, Gerald A1 - Langoth-Fehringer, Nina A1 - Püschel, Gerhard Paul T1 - Cell-Based Reporter Release Assay to Determine the Potency of Proteolytic Bacterial Neurotoxins JF - Toxins N2 - Despite the implementation of cell-based replacement methods, the mouse lethality assay is still frequently used to determine the activity of botulinum toxin (BoNT) for medical use. One explanation is that due to the use of neoepitope-specific antibodies to detect the cleaved BoNT substrate, the currently devised assays can detect only one specific serotype of the toxin. Recently, we developed a cell-based functional assay, in which BoNT activity is determined by inhibiting the release of a reporter enzyme that is liberated concomitantly with the neurotransmitter from neurosecretory vesicles. In theory, this assay should be suitable to detect the activity of any BoNT serotype. Consistent with this assumption, the current study shows that the stimulus-dependent release of a luciferase from a differentiated human neuroblastoma-based reporter cell line (SIMA-hPOMC1-26-GLuc cells) was inhibited by BoNT-A and-C. Furthermore, this was also inhibited by BoNT-B and tetanus toxin to a lesser extent and at higher concentrations. In order to provide support for the suitability of this technique in practical applications, a dose–response curve obtained with a pharmaceutical preparation of BoNT-A closely mirrored the activity determined in the mouse lethality assay. In summary, the newly established cell-based assay may represent a versatile and specific alternative to the mouse lethality assay and other currently established cell-based assays. KW - botulinum toxin KW - BoNT KW - tetanus toxin KW - RRR KW - replacement Y1 - 2018 U6 - https://doi.org/10.3390/toxins10090360 SN - 2072-6651 VL - 10 IS - 9 SP - 1 EP - 10 PB - Molecular Diversity Preservation International (MDPI) CY - Basel ER - TY - JOUR A1 - Plöhn, Svenja A1 - Edelmann, Bärbel A1 - Japtok, Lukasz A1 - He, Xingxuan A1 - Hose, Matthias A1 - Hansen, Wiebke A1 - Schuchman, Edward H. A1 - Eckstein, Anja A1 - Berchner-Pfannschmidt, Utta T1 - CD40 enhances sphingolipids in orbital fibroblasts BT - potential role of sphingosine-1-phosphate in inflammatory T-Cell migration in graves' orbitopathy JF - Investigative ophthalmology & visual science N2 - METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. KW - inflammation Y1 - 2018 U6 - https://doi.org/10.1167/iovs.18-25466 SN - 0146-0404 SN - 1552-5783 VL - 59 IS - 13 SP - 5391 EP - 5397 PB - Association for Research in Vision and Opthalmology CY - Rockville ER - TY - JOUR A1 - Huschek, Gerd A1 - Bönick, Josephine A1 - Merkel, Dietrich A1 - Huschek, Doreen A1 - Rawel, Harshadrai Manilal T1 - Authentication of leguminous-based products by targeted biomarkers using high resolution time of flight mass spectrometry 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 - A growing number of health-conscious individuals supplements their diet with protein-rich plant-based products to reduce their meat consumption. Analytical methods are needed to authenticate these new vegetarian products not only for the correct labelling of ingredients according to European legislation but also to discourage food fraud. This paper presents new biomarkers for a targeted proteomics LC-MS/MS work-flow that can simultaneously prove the presence/absence of garden pea, a protein-rich legume, meat and honey and quantify their content in processed vegan food. We show a novel rapid strategy to identify biomarkers for species authentication and the steps for the multi-parameter LC-MS/MS method validation and quantification. A high resolution triple time of flight mass spectrometer (HRMS) with SWATH Acquisition was used for the rapid discovery of all measurable trypsin-digested proteins in the individual ingredients. From these proteins, species-selective biomarkers were identified with BLAST and Skyline. Vicilin and convicilin (UniProt: D3VND9, Q9M3X6) allow pea authentication with regard to other legume species. Myostatin (UniProt: 018831) is a single biomarker for all meat types. For honey, we identified three selective proteins (UniProt: C6K481, C6K482, Q3L6329). The final LC-MS/MS method can identity and quantify these markers simultaneously. Quantification occurs via external matrix calibration. KW - Vegan KW - Food authentication KW - Legume KW - Honey KW - Meat peptide biomarker KW - MS quantification of leguminous additives KW - Food labelling Y1 - 2018 U6 - https://doi.org/10.1016/j.lwt.2017.12.034 SN - 0023-6438 SN - 1096-1127 VL - 90 SP - 164 EP - 171 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Henkel, Janin A1 - Coleman Mac Gregor of Inneregny, Charles Dominic A1 - Schraplau, Anne A1 - Jöhrens, Korinna A1 - Weiss, Thomas Siegfried A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Püschel, Gerhard Paul T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model JF - Scientific Reports N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH. KW - suppress VLDL secretion KW - mice lacking KW - nonalcoholic steatohepatthis KW - insulin-resistance KW - rat hepatocytes KW - kupffer cells KW - E-2 KW - disease KW - expression KW - accumulation Y1 - 2018 U6 - https://doi.org/10.1038/s41598-018-34633-y SN - 2045-2322 IS - 8 SP - 1 EP - 11 PB - Nature Research CY - London ER - TY - JOUR A1 - Müller, Sandra Marie A1 - Ebert, Franziska A1 - Bornhorst, Julia A1 - Galla, Hans-Joachim A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Arsenic-containing hydrocarbons disrupt a model in vitro blood-cerebrospinal fluid barrier JF - Journal of trace elements in medicine and biology N2 - Lipid-soluble arsenicals, so-called arsenolipids, have gained a lot of attention in the last few years because of their presence in many seafoods and reports showing substantial cytotoxicity emanating from arsenic-containing hydrocarbons (AsHCs), a prominent subgroup of the arsenolipids. More recent in vivo and in vitro studies indicate that some arsenolipids might have adverse effects on brain health. In the present study, we focused on the effects of selected arsenolipids and three representative metabolites on the blood-cerebrospinal fluid barrier (B-CSF-B), a brain-regulating interface. For this purpose, we incubated an in vitro model of the B-CSF-B composed of porcine choroid plexus epithelial cells (PCPECs) with three AsHCs, two arsenic-containing fatty acids (AsFAs) and three representative arsenolipid metabolites (dimethylarsinic acid, thio/oxo-dimethylpropanoic acid) to examine their cytotoxic potential and impact on barrier integrity. The toxic arsenic species arsenite was also tested in this way and served as a reference substance. While AsFAs and the metabolites showed no cytotoxic effects in the conducted assays, AsHCs showed a strong cytotoxicity, being up to 1.5-fold more cytotoxic than arsenite. Analysis of the in vitro B-CSF-B integrity showed a concentration dependent disruption of the barrier within 72 h. The correlation with the decreased plasma membrane surface area (measured as capacitance) indicates cytotoxic effects. These findings suggest exposure to elevated levels of certain arsenolipids may have detrimental consequences for the central nervous system. KW - Arsenolipids KW - Blood-liquor barrier KW - Blood-cerebrospinal fluid barrier KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids Y1 - 2018 U6 - https://doi.org/10.1016/j.jtemb.2018.01.020 SN - 0946-672X VL - 49 SP - 171 EP - 177 PB - Elsevier GMBH CY - München ER - TY - JOUR A1 - Gulbins, Anne A1 - Schumacher, Fabian A1 - Becker, Katrin Anne A1 - Wilker, Barbara A1 - Soddemann, Matthias A1 - Boldrin, Francesco A1 - Müller, Christian P. A1 - Edwards, Michael J. A1 - Goodman, Michael A1 - Caldwell, Charles C. A1 - Kleuser, Burkhard A1 - Kornhuber, Johannes A1 - Szabo, Ildiko A1 - Gulbins, Erich T1 - Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide JF - Molecular psychiatry N2 - Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days. Y1 - 2018 U6 - https://doi.org/10.1038/s41380-018-0090-9 SN - 1359-4184 SN - 1476-5578 VL - 23 IS - 12 SP - 2324 EP - 2346 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Odongo, Grace Akinyi A1 - Schlotz, Nina A1 - Baldermann, Susanne A1 - Neugart, Susanne A1 - Huyskens-Keil, Susanne A1 - Ngwene, Benard A1 - Trierweiler, Bernhard A1 - Schreiner, Monika A1 - Lamy, Evelyn T1 - African Nightshade (Solanum scabrum Mill.) BT - Impact of Cultivation and Plant Processing on Its Health Promoting Potential as Determined in a Human Liver Cell Model JF - Nutrients N2 - Plant cultivation and processing may impact nutrient and phytochemical content of vegetables. The present study aimed at determining the influence of cultivation and processing on the health promoting capacity of African nightshade (Solanum scabrum Mill.) leaves, an indigenous vegetable, rich in nutrients and phytochemicals. Anti-genotoxicity against the human liver carcinogen aflatoxin B1 (AFB(1)) as determined by the comet assay and radical oxygen species (ROS) scavenging capacity of ethanolic and aqueous extracts were investigated in human derived liver (HepG2) cells. ROS scavenging activity was assessed using electron paramagnetic spin resonance and quantification of ARE/Nrf2 mediated gene expression. The cultivation was done under different environmental conditions. The processing included fermentation and cooking; postharvest ultraviolet irradiation (UV-C) treatment was also investigated. Overall, S. scabrum extracts showed strong health promoting potential, the highest potential was observed with the fermented extract, which showed a 60% reduction of AFB(1) induced DNA damage and a 38% reduction in FeSO4 induced oxidative stress. The content of total polyphenols, carotenoids and chlorophylls was indeed affected by cultivation and processing. Based on the present in vitro findings consumption of S. scabrum leaves could be further encouraged, preferentially after cooking or fermentation of the plant. KW - aflatoxin B1 KW - African indigenous vegetables KW - anti-genotoxicity KW - anti-oxidant activity KW - cancer chemoprevention KW - Solanaceae Y1 - 2018 U6 - https://doi.org/10.3390/nu10101532 SN - 2072-6643 VL - 10 IS - 10 PB - MDPI CY - Basel ER - TY - JOUR A1 - Vogel, Heike A1 - Kamitz, Anne A1 - Hallahan, Nicole A1 - Lebek, Sandra A1 - Schallschmidt, Tanja A1 - Jonas, Wenke A1 - Jähnert, Markus A1 - Gottmann, Pascal A1 - Zellner, Lisa A1 - Kanzleiter, Timo A1 - Damen, Mareike A1 - Altenhofen, Delsi A1 - Burkhardt, Ralph A1 - Renner, Simone A1 - Dahlhoff, Maik A1 - Wolf, Eckhard A1 - Müller, Timo Dirk A1 - Blüher, Matthias A1 - Joost, Hans-Georg A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Schürmann, Annette T1 - A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes JF - Human molecular genetics N2 - To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes. Y1 - 2018 U6 - https://doi.org/10.1093/hmg/ddy217 SN - 0964-6906 SN - 1460-2083 VL - 27 IS - 17 SP - 3099 EP - 3112 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Sammoud, Senda A1 - Nevill, Alan Michael A1 - Negra, Yassine A1 - Bouguezzi, Raja A1 - Chaabene, Helmi A1 - Hachana, Younes T1 - 100-m Breaststroke Swimming Performance in Youth Swimmers BT - the predictive value of anthropometrics JF - Pediatric exercise science N2 - This study aimed to estimate the optimal body size, limb segment length, and girth or breadth ratios of 100-m breaststroke performance in youth swimmers. In total, 59 swimmers [male: n= 39, age = 11.5 (1.3) y; female: n= 20, age = 12.0 (1.0) y] participated in this study. To identify size/shape characteristics associated with 100-m breaststroke swimming performance, we computed a multiplicative allometric log-linear regression model, which was refined using backward elimination. Results showed that the 100-m breaststroke performance revealed a significant negative association with fat mass and a significant positive association with the segment length ratio (arm ratio = hand length/forearm length) and limb girth ratio (girth ratio = forearm girth/wrist girth). In addition, leg length, biacromial breadth, and biiliocristal breadth revealed significant positive associations with the 100-m breaststroke performance. However, height and body mass did not contribute to the model, suggesting that the advantage of longer levers was limb-specific rather than a general whole-body advantage. In fact, it is only by adopting multiplicative allometric models that the previously mentioned ratios could have been derived. These results highlighted the importance of considering anthropometric characteristics of youth breaststroke swimmers for talent identification and/or athlete monitoring purposes. In addition, these findings may assist orienting swimmers to the appropriate stroke based on their anthropometric characteristics. KW - allometric model KW - maturity KW - limb lengths KW - girths and breadths Y1 - 2018 U6 - https://doi.org/10.1123/pes.2017-0220 SN - 0899-8493 SN - 1543-2920 VL - 30 IS - 3 SP - 393 EP - 401 PB - Human Kinetics Publ. CY - Champaign ER -