@misc{PonceSchererBoekstegersetal.2019, author = {Ponce, Carol Barahona and Scherer, Dominique and Boekstegers, Felix and Garate-Calderon, Valentina and Jenab, Mazda and Aleksandrova, Krasimira and Katzke, Verena and Weiderpass, Elisabete and Bonet, Catalina and Moradi, Tahereh and Fischer, Krista and Bossers, Willem and Brenner, Hermann and Sch{\"o}ttker, Ben and Holleczek, Bernd and Hveem, Kristian and Eklund, Niina and Voelker, Uwe and Waldenberger, Melanie and Bermejo, Justo Lorenzo}, title = {Arsenic and gallbladder cancer risk}, series = {International journal of cancer}, volume = {146}, journal = {International journal of cancer}, number = {9}, publisher = {Wiley}, address = {Hoboken}, issn = {0020-7136}, doi = {10.1002/ijc.32837}, pages = {2648 -- 2650}, year = {2019}, language = {en} } @misc{DietrichJacobsZhengetal.2019, author = {Dietrich, Stefan and Jacobs, Simone and Zheng, Ju-Sheng and Meidtner, Karina and Schwingshackl, Lukas and Schulze, Matthias Bernd}, title = {Gene-lifestyle interaction on risk of type 2 diabetes}, series = {Obesity reviews : an official journal of the International Association for the Study of Obesity}, volume = {20}, journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity}, number = {11}, publisher = {Wiley}, address = {Hoboken}, issn = {1467-7881}, doi = {10.1111/obr.12921}, pages = {1557 -- 1571}, year = {2019}, abstract = {The pathophysiological influence of gene-lifestyle interactions on the risk to develop type 2 diabetes (T2D) is currently under intensive research. This systematic review summarizes the evidence for gene-lifestyle interactions regarding T2D incidence. MEDLINE, EMBASE, and Web of Science were systematically searched until 31 January 2019 to identify publication with (a) prospective study design; (b) T2D incidence; (c) gene-diet, gene-physical activity, and gene-weight loss intervention interaction; and (d) population who are healthy or prediabetic. Of 66 eligible publications, 28 reported significant interactions. A variety of different genetic variants and dietary factors were studied. Variants at TCF7L2 were most frequently investigated and showed interactions with fiber and whole grain on T2D incidence. Further gene-diet interactions were reported for, eg, a western dietary pattern with a T2D-GRS, fat and carbohydrate with IRS1 rs2943641, and heme iron with variants of HFE. Physical activity showed interaction with HNF1B, IRS1, PPAR gamma, ADRA2B, SLC2A2, and ABCC8 variants and weight loss interventions with ENPP1, PPAR gamma, ADIPOR2, ADRA2B, TNF alpha, and LIPC variants. However, most findings represent single study findings obtained in European ethnicities. Although some interactions have been reported, their conclusiveness is still low, as most findings were not yet replicated across multiple study populations.}, language = {en} } @article{GhaffariBernhoeftEtheveetal.2019, author = {Ghaffari, Morteza Hosseini and Bernhoeft, Katrin and Etheve, Stephane and Immig, Irmgard and Hoelker, Michael and Sauerwein, Helga and Schweigert, Florian J.}, title = {Technical note: Rapid field test for the quantification of vitamin E, beta-carotene, and vitamin A in whole blood and plasma of dairy cattle}, series = {Journal of dairy science}, volume = {102}, journal = {Journal of dairy science}, number = {12}, publisher = {Elsevier}, address = {New York}, issn = {0022-0302}, doi = {10.3168/jds.2019-16755}, pages = {11744 -- 11750}, year = {2019}, abstract = {Fast and easy tests for quantifying fat-soluble vitamins such as vitamin E and vitamin A, as well as beta-carotene, in whole blood without a need to preprocess blood samples could facilitate assessment of the vitamin status of dairy cattle. The objective of this study was to validate a field-portable fluorometer/spectrophotometer assay for the rapid quantification of these vitamins in whole blood and plasma of dairy cows and calves. We measured the concentrations of vitamin E and beta-carotene in whole blood and plasma from 28 dairy cows and 11 calves using the iCheck test (Bio-Analyt GmbH, Teltow, Germany) and compared the results with the current analytical standard (HPLC) in 2 independent laboratories, one at the University of Potsdam (Germany) and at one at DSM Nutritional Products Ltd. (Kaiseraugst, Switzerland). For vitamin A, the HPLC measurements were done only in the laboratory in Germany. The whole-blood concentrations of vitamin E as determined by iCheck (blood-hematocritcorrected) ranged from 1.82 to 4.99 mg/L in dairy cows and 0.34 to 3.40 mg/L in calves. These findings were moderately correlated (R-2 = 0.66) with the values assessed by HPLC in dairy cattle (cows + calves). When calves were excluded, the correlation was higher (R-2 = 0.961). The beta-carotene and vitamin A values obtained by the reference method HPLC were highly correlated with the iCheck methods in whole blood (R-2 = 0.99 and 0.88, respectively). In plasma, we observed strong correlations between the concentrations assessed by iCheck and those of HPLC for vitamin E (R-2 = 0.97), beta-carotene (R-2 = 0.98), and vitamin A (R-2 = 0.92) in dairy cattle (cows + calves). For vitamin E, beta-carotene, and vitamin A, we compared the relationship between the differences obtained by the iCheck assay and the HPLC measurements, as well as the magnitude of measurements, using Bland-Altman plots to test for systematic bias. For all 3 vitamins, the differences values were not outside the 95\% acceptability limits; we found no systematic error between the 2 methods for all 3 analytes.}, language = {en} } @article{RundHeylmannSeiwertetal.2019, author = {Rund, Katharina M. and Heylmann, Daniel and Seiwert, Nina and Wecklein, Sabine and Oger, Camille and Galano, Jean-Marie and Durand, Thierry and Chen, Rongjun and G{\"u}ler, Faikah and Fahrer, J{\"o}rg and Bornhorst, Julia and Schebb, Nils Helge}, title = {Formation of trans-epoxy fatty acids correlates with formation of isoprostanes and could serve as biomarker of oxidative stress}, series = {Prostaglandins \& Other Lipid Mediators}, volume = {144}, journal = {Prostaglandins \& Other Lipid Mediators}, publisher = {Elsevier}, address = {New York}, issn = {1098-8823}, doi = {10.1016/j.prostaglandins.2019.04.004}, pages = {10}, year = {2019}, abstract = {In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.}, language = {en} } @article{RohnKroepflAschneretal.2019, author = {Rohn, Isabelle and Kroepfl, Nina and Aschner, Michael and Bornhorst, Julia and Kuehnelt, Doris and Schwerdtle, Tanja}, title = {Selenoneine ameliorates peroxide-induced oxidative stress in C. elegans}, series = {Journal of trace elements in medicine and biology}, volume = {55}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier GMBH}, address = {M{\"u}nchen}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2019.05.012}, pages = {78 -- 81}, year = {2019}, abstract = {Scope: Selenoneine (2-selenyl-N-alpha, N-alpha, N-alpha-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. Methods and results: Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18 h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48 h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48 h posttreatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. Conclusion: The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points.}, language = {en} } @article{GanchevaOuniJeleniketal.2019, author = {Gancheva, Sofiya and Ouni, Meriem and Jelenik, Tomas and Koliaki, Chrysi and Szendroedi, Julia and Toledo, Frederico G. S. and Markgraf, Daniel Frank and Pesta, Dominik H. and Mastrototaro, Lucia and De Filippo, Elisabetta and Herder, Christian and J{\"a}hnert, Markus and Weiss, J{\"u}rgen and Strassburger, Klaus and Schlensak, Matthias and Sch{\"u}rmann, Annette and Roden, Michael}, title = {Dynamic changes of muscle insulin sensitivity after metabolic surgery}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-12081-0}, pages = {13}, year = {2019}, abstract = {The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity.}, language = {en} } @article{WittenbecherKuxhausBoeingetal.2019, author = {Wittenbecher, Clemens and Kuxhaus, Olga and Boeing, Heiner and Stefan, Norbert and Schulze, Matthias Bernd}, title = {Associations of short stature and components of height with incidence of type 2 diabetes}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {62}, journal = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, number = {12}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, doi = {10.1007/s00125-019-04978-8}, pages = {2211 -- 2221}, year = {2019}, abstract = {Aims/hypothesis This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers. Methods A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions. Results After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 [95\% CI 0.47, 0.75] and women 0.67 [0.51, 0.88], respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women. Conclusions/interpretation We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile.}, language = {en} } @article{QuicletDittbernerGaessleretal.2019, author = {Quiclet, Charline and Dittberner, Nicole and Gaessler, Anneke and Stadion, Mandy and Gerst, Felicia and Helms, Anett and Baumeier, Christian and Schulz, Tim Julius and Schurmann, Annette}, title = {Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice}, series = {Metabolism - Clinical and experimental}, volume = {97}, journal = {Metabolism - Clinical and experimental}, publisher = {Elsevier}, address = {Philadelphia}, issn = {0026-0495}, doi = {10.1016/j.metabol.2019.05.005}, pages = {9 -- 17}, year = {2019}, abstract = {Objective: Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and beta-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function. Methods: New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lep(ob/ob) (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed. Results: NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32\%) and the liver (-35\%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty adds than adipocytes of inguinal white adipose tissue. Conclusions: These results suggest that pancreatic fat participates in diabetes development, but can be prevented by IF. (C) 2019 Published by Elsevier Inc.}, language = {en} } @article{AbebeHakiSchweigertetal.2019, author = {Abebe, Zeweter and Haki, Gulelat Desse and Schweigert, Florian J. and Henkel, Ina M. and Baye, Kaleab}, title = {Low breastmilk vitamin A concentration is prevalent in rural Ethiopia}, series = {European journal of clinical nutrition}, volume = {73}, journal = {European journal of clinical nutrition}, number = {8}, publisher = {Nature Publ. Group}, address = {London}, issn = {0954-3007}, doi = {10.1038/s41430-018-0334-4}, pages = {1110 -- 1116}, year = {2019}, abstract = {Background There is scant information on the breastmilk vitamin A (BMVA) concentration of lactating women in developing countries, partly due to lack of methods applicable in-field. Objective To assess BMVA concentrations of samples collected from lactating women of children aged 6-23 months, in Mecha district, Ethiopia. Subjects/methods Data on socio-demographic and anthropometric characteristics were collected from randomly selected lactating women (n = 104). Breast milk samples were collected and vitamin A concentrations were analyzed using HPLC and iCheck FLUORO then the two measurements were compared. Results The prevalence of underweight (BMI < 18.5 kg/m(2)) among lactating women was 17\%. Seventy six percent of the BMVA values were < 1.05 mu mol/l and 81\% were < 8 mu g/g fat. The mean BMVA concentration accounted to 41\% of the estimated average value for mothers in developing countries. The BMVA values from HPLC and iCheck were correlated (r = 0.59, p = < 0.001), but it was not strong. Conclusions The result indicates the low vitamin A status of the lactating women and their children. It further indicates that intake assessments should not use average BMVA composition. The possibility of using iCheck for monitoring interventions designed to improve vitamin A status of lactating women with low BMVA requires further investigation.}, language = {en} } @article{FranzOttenMuellerWerdanetal.2019, author = {Franz, Kristina and Otten, Lindsey and M{\"u}ller-Werdan, Ursula and D{\"o}hner, Wolfram and Norman, Kristina}, title = {Severe Weight Loss and Its Association with Fatigue in Old Patients at Discharge from a Geriatric Hospital}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {10}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11102415}, pages = {10}, year = {2019}, abstract = {Although malnutrition is frequent in the old, little is known about its association with fatigue. We evaluated the relation of self-reported severe weight loss with fatigue and the predictors for fatigue in old patients at hospital discharge. Severe weight loss was defined according to involuntary weight loss >= 5\% in the last three months. We determined fatigue with the validated Brief Fatigue Inventory questionnaire. The regression analyses were adjusted for age, sex, number of comorbidities, medications/day, and BMI. Of 424 patients aged between 61 and 98 y, 34.1\% had severe weight loss. Fatigue was higher in patients with severe weight loss (3.7 +/- 2.3 vs. 3.2 +/- 2.3 points, p = 0.021). In a multinomial regression model, weight loss was independently associated with higher risk for moderate fatigue (OR:1.172, CI:1.026-1.338, p = 0.019) and with increased risk for severe fatigue (OR:1.209, CI:1.047-1.395, p = 0.010) together with the number of medications/day (OR:1.220, CI:1.023-1.455, p = 0.027). In a binary regression model, severe weight loss predicted moderate-to-severe fatigue in the study population (OR:1.651, CI:1.052-2.590, p = 0.029). In summary, patients with self-reported severe weight loss at hospital discharge exhibited higher fatigue levels and severe weight loss was an independent predictor of moderate and severe fatigue, placing these patients at risk for impaired outcome in the post-hospital period.}, language = {en} } @article{WarringtonBeaumontHorikoshietal.2019, author = {Warrington, Nicole and Beaumont, Robin and Horikoshi, Momoko and Day, Felix R. and Helgeland, {\O}yvind and Laurin, Charles and Bacelis, Jonas and Peng, Shouneng and Hao, Ke and Feenstra, Bjarke and Wood, Andrew R. and Mahajan, Anubha and Tyrrell, Jessica and Robertson, Neil R. and Rayner, N. William and Qiao, Zhen and Moen, Gunn-Helen and Vaudel, Marc and Marsit, Carmen and Chen, Jia and Nodzenski, Michael and Schnurr, Theresia M. and Zafarmand, Mohammad Hadi and Bradfield, Jonathan P. and Grarup, Niels and Kooijman, Marjolein N. and Li-Gao, Ruifang and Geller, Frank and Ahluwalia, Tarunveer Singh and Paternoster, Lavinia and Rueedi, Rico and Huikari, Ville and Hottenga, Jouke-Jan and Lyytik{\"a}inen, Leo-Pekka and Cavadino, Alana and Metrustry, Sarah and Cousminer, Diana L. and Wu, Ying and Thiering, Elisabeth Paula and Wang, Carol A. and Have, Christian Theil and Vilor-Tejedor, Natalia and Joshi, Peter K. and Painter, Jodie N. and Ntalla, Ioanna and Myhre, Ronny and Pitk{\"a}nen, Niina and van Leeuwen, Elisabeth M. and Joro, Raimo and Lagou, Vasiliki and Richmond, Rebecca C. and Espinosa, Ana and Barton, Sheila J. and Inskip, Hazel M. and Holloway, John W. and Santa-Marina, Loreto and Estivill, Xavier and Ang, Wei and Marsh, Julie A. and Reichetzeder, Christoph and Marullo, Letizia and Hocher, Berthold and Lunetta, Kathryn L. and Murabito, Joanne M. and Relton, Caroline L. and Kogevinas, Manolis and Chatzi, Leda and Allard, Catherine and Bouchard, Luigi and Hivert, Marie-France and Zhang, Ge and Muglia, Louis J. and Heikkinen, Jani and Morgen, Camilla S. and van Kampen, Antoine H. C. and van Schaik, Barbera D. C. and Mentch, Frank D. and Langenberg, Claudia and Scott, Robert A. and Zhao, Jing Hua and Hemani, Gibran and Ring, Susan M. and Bennett, Amanda J. and Gaulton, Kyle J. and Fernandez-Tajes, Juan and van Zuydam, Natalie R. and Medina-Gomez, Carolina and de Haan, Hugoline G. and Rosendaal, Frits R. and Kutalik, Zolt{\´a}n and Marques-Vidal, Pedro and Das, Shikta and Willemsen, Gonneke and Mbarek, Hamdi and M{\"u}ller-Nurasyid, Martina and Standl, Marie and Appel, Emil V. R. and Fonvig, Cilius Esmann and Trier, Caecilie and van Beijsterveldt, Catharina E. M. and Murcia, Mario and Bustamante, Mariona and Bon{\`a}s-Guarch, S{\´i}lvia and Hougaard, David M. and Mercader, Josep M. and Linneberg, Allan and Schraut, Katharina E. and Lind, Penelope A. and Medland, Sarah Elizabeth and Shields, Beverley M. and Knight, Bridget A. and Chai, Jin-Fang and Panoutsopoulou, Kalliope and Bartels, Meike and S{\´a}nchez, Friman and Stokholm, Jakob and Torrents, David and Vinding, Rebecca K. and Willems, Sara M. and Atalay, Mustafa and Chawes, Bo L. and Kovacs, Peter and Prokopenko, Inga and Tuke, Marcus A. and Yaghootkar, Hanieh and Ruth, Katherine S. and Jones, Samuel E. and Loh, Po-Ru and Murray, Anna and Weedon, Michael N. and T{\"o}njes, Anke and Stumvoll, Michael and Michaelsen, Kim Fleischer and Eloranta, Aino-Maija and Lakka, Timo A. and van Duijn, Cornelia M. and Kiess, Wieland and Koerner, Antje and Niinikoski, Harri and Pahkala, Katja and Raitakari, Olli T. and Jacobsson, Bo and Zeggini, Eleftheria and Dedoussis, George V. and Teo, Yik-Ying and Saw, Seang-Mei and Montgomery, Grant W. and Campbell, Harry and Wilson, James F. and Vrijkotte, Tanja G. M. and Vrijheid, Martine and de Geus, Eco J. C. N. and Hayes, M. Geoffrey and Kadarmideen, Haja N. and Holm, Jens-Christian and Beilin, Lawrence J. and Pennell, Craig E. and Heinrich, Joachim and Adair, Linda S. and Borja, Judith B. and Mohlke, Karen L. and Eriksson, Johan G. and Widen, Elisabeth E. and Hattersley, Andrew T. and Spector, Tim D. and Kaehoenen, Mika and Viikari, Jorma S. and Lehtimaeki, Terho and Boomsma, Dorret I. and Sebert, Sylvain and Vollenweider, Peter and Sorensen, Thorkild I. A. and Bisgaard, Hans and Bonnelykke, Klaus and Murray, Jeffrey C. and Melbye, Mads and Nohr, Ellen A. and Mook-Kanamori, Dennis O. and Rivadeneira, Fernando and Hofman, Albert and Felix, Janine F. and Jaddoe, Vincent W. V. and Hansen, Torben and Pisinger, Charlotta and Vaag, Allan A. and Pedersen, Oluf and Uitterlinden, Andre G. and Jarvelin, Marjo-Riitta and Power, Christine and Hypponen, Elina and Scholtens, Denise M. and Lowe, William L. and Smith, George Davey and Timpson, Nicholas J. and Morris, Andrew P. and Wareham, Nicholas J. and Hakonarson, Hakon and Grant, Struan F. A. and Frayling, Timothy M. and Lawlor, Debbie A. and Njolstad, Pal R. and Johansson, Stefan and Ong, Ken K. and McCarthy, Mark I. and Perry, John R. B. and Evans, David M. and Freathy, Rachel M.}, title = {Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors}, series = {Nature genetics}, volume = {51}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {EGG Consortium}, issn = {1061-4036}, pages = {804 -- +}, year = {2019}, abstract = {Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.}, language = {en} } @article{StarzonekRoscherBlitheretal.2019, author = {Starzonek, Janine and Roscher, Katja and Blither, Matthias and Blaue, Dominique and Schedlbauer, Carola and Hire, Manuela and Raila, Jens and Vervuert, Ingrid}, title = {Effects of a blend of green tea and curcuma extract supplementation on lipopolysaccharide-induced inflammation in horses and ponies}, series = {PeerJ}, volume = {7}, journal = {PeerJ}, publisher = {PeerJ Inc.}, address = {London}, issn = {2167-8359}, doi = {10.7717/peerj.8053}, pages = {17}, year = {2019}, abstract = {Background. In horses and ponies numerous medical conditions are known to be linked with inflammation in different tissues, especially in the liver. Besides affecting other metabolic pathways such as the expression of certain interleukins (IL), inflammation is associated with stress of the endoplasmic reticulum (ER). In particular, ER stress leads to adaptive stress response and can be measured by several markers of inflammatory and stress signalling pathways, like nuclear factor kappa B (NF-kB). Objectives. To investigate lipopolysaccharide (LPS)-induced inflammatory reactions and their modulation in horses and ponies by feeding a polyphenol-rich supplement consisting of green tea and curcuma. Methods. In a cross-over study, 11 animals were allocated to either a placebo or a supplement group and supplemented with 10 g of a blend of green tea and curcuma extract (GCE) or a placebo (calcium carbonate) once daily. After 21 days of supplementation, all animals underwent a LPS challenge to induce moderate systemic inflammation. Blood samples and liver biopsies were taken at standardized time points: 24 hours before and 12 hours after LPS challenge. Inflammatory blood parameters such as serum amyloid A (SAA), haptoglobin and retinol binding protein 4 (RBP4) were measured in serum. Hepatic mRNA levels of selected markers of inflammation such as haptoglobin, tumor necrosis factor alpha (TNF-alpha), IL-1 beta, IL-6, cluster of differentiation 68 (CD68), fibroblast growth factor 21 (FGF-21), NF-kappa B, activating transcription factor 4 (ATF4) were quantified by RT-qPCR. In addition, liver biopsies were examined histologically for inflammatory alterations. Results. Blood markers of acute inflammatory response increased after LPS challenge. In the liver, the proinflammatory cytokine IL-1 beta showed significantly lower mRNA levels after LPS challenge in the supplemented group (P = 0.04) compared to the placebo group. Levels of the hepatic CD68 mRNA increased significantly in the placebo group (P = 0.04). There were no significant differences between supplemented and placebo groups concerning other markers of inflammation and markers of ER stress within the liver. The number of hepatic macrophages were not different after LPS challenge in both feeding groups. Conclusion. LPS was able to induce inflammation but seemed less suitable to induce ER stress in the horses and ponies. The polyphenol-rich supplement showed some potential to reduce inflammatory responses. Nevertheless, the supplementation did not exert an overall anti-inflammatory effect in horses and ponies.}, language = {en} } @misc{SchwarzLossowKoppetal.2019, author = {Schwarz, Maria and Lossow, Kristina and Kopp, Johannes F. and Schwerdtle, Tanja and Kipp, Anna Patricia}, title = {Crosstalk of Nrf2 with the Trace Elements Selenium, Iron, Zinc, and Copper}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1081}, issn = {1866-8372}, doi = {10.25932/publishup-47287}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-472873}, pages = {20}, year = {2019}, abstract = {Trace elements, like Cu, Zn, Fe, or Se, are important for the proper functioning of antioxidant enzymes. However, in excessive amounts, they can also act as pro-oxidants. Accordingly, trace elements influence redox-modulated signaling pathways, such as the Nrf2 pathway. Vice versa, Nrf2 target genes belong to the group of transport and metal binding proteins. In order to investigate whether Nrf2 directly regulates the systemic trace element status, we used mice to study the effect of a constitutive, whole-body Nrf2 knockout on the systemic status of Cu, Zn, Fe, and Se. As the loss of selenoproteins under Se-deprived conditions has been described to further enhance Nrf2 activity, we additionally analyzed the combination of Nrf2 knockout with feeding diets that provide either suboptimal, adequate, or supplemented amounts of Se. Experiments revealed that the Nrf2 knockout partially affected the trace element concentrations of Cu, Zn, Fe, or Se in the intestine, liver, and/or plasma. However, aside from Fe, the other three trace elements were only marginally modulated in an Nrf2-dependent manner. Selenium deficiency mainly resulted in increased plasma Zn levels. One putative mediator could be the metal regulatory transcription factor 1, which was up-regulated with an increasing Se supply and downregulated in Se-supplemented Nrf2 knockout mice.}, language = {en} } @misc{AlkerSchwerdtleSchomburgetal.2019, author = {Alker, Wiebke and Schwerdtle, Tanja and Schomburg, Lutz and Haase, Hajo}, title = {A Zinpyr-1-based fluorimetric microassay for free zinc in human serum}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1086}, issn = {1866-8372}, doi = {10.25932/publishup-47283}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-472833}, pages = {15}, year = {2019}, abstract = {Zinc is an essential trace element, making it crucial to have a reliable biomarker for evaluating an individual's zinc status. The total serum zinc concentration, which is presently the most commonly used biomarker, is not ideal for this purpose, but a superior alternative is still missing. The free zinc concentration, which describes the fraction of zinc that is only loosely bound and easily exchangeable, has been proposed for this purpose, as it reflects the highly bioavailable part of serum zinc. This report presents a fluorescence-based method for determining the free zinc concentration in human serum samples, using the fluorescent probe Zinpyr-1. The assay has been applied on 154 commercially obtained human serum samples. Measured free zinc concentrations ranged from 0.09 to 0.42 nM with a mean of 0.22 ± 0.05 nM. It did not correlate with age or the total serum concentrations of zinc, manganese, iron or selenium. A negative correlation between the concentration of free zinc and total copper has been seen for sera from females. In addition, the free zinc concentration in sera from females (0.21 ± 0.05 nM) was significantly lower than in males (0.23 ± 0.06 nM). The assay uses a sample volume of less than 10 µL, is rapid and cost-effective and allows us to address questions regarding factors influencing the free serum zinc concentration, its connection with the body's zinc status, and its suitability as a future biomarker for an individual's zinc status.}, language = {en} } @phdthesis{Kochlik2019, author = {Kochlik, Bastian Max}, title = {Relevance of biomarkers for the diagnosis of the frailty syndrome}, doi = {10.25932/publishup-44118}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-441186}, school = {Universit{\"a}t Potsdam}, pages = {IV, 99}, year = {2019}, abstract = {Frailty and sarcopenia share some underlying characteristics like loss of muscle mass, low muscle strength, and low physical performance. Imaging parameters and functional examinations mainly assess frailty and sarcopenia criteria; however, these measures can have limitations in clinical settings. Therefore, finding suitable biomarkers that reflect a catabolic muscle state e.g. an elevated muscle protein turnover as suggested in frailty, are becoming more relevant concerning frailty diagnosis and risk assessment. 3-Methylhistidine (3-MH) and its ratios 3-MH-to-creatinine (3-MH/Crea) and 3 MH-to-estimated glomerular filtration rate (3-MH/eGFR) are under discussion as possible biomarkers for muscle protein turnover and might support the diagnosis of frailty. However, there is some skepticism about the reliability of 3-MH measures since confounders such as meat and fish intake might influence 3-MH plasma concentrations. Therefore, the influence of dietary habits and an intervention with white meat on plasma 3-MH was determined in young and healthy individuals. In another study, the cross-sectional associations of plasma 3-MH, 3-MH/Crea and 3-MH/eGFR with the frailty status (robust, pre-frail and frail) were investigated. Oxidative stress (OS) is a possible contributor to frailty development, and high OS levels as well as low micronutrient levels are associated with the frailty syndrome. However, data on simultaneous measures of OS biomarkers together with micronutrients are lacking in studies including frail, pre-frail and robust individuals. Therefore, cross-sectional associations of protein carbonyls (PrCarb), 3-nitrotyrosine (3-NT) and several micronutrients with the frailty status were determined. A validated UPLC-MS/MS (ultra-performance liquid chromatography tandem mass spectrometry) method for the simultaneous quantification of 3-MH and 1-MH (1 methylhistidine, as marker for meat and fish consumption) was presented and used for further analyses. Omnivores showed higher plasma 3-MH and 1-MH concentrations than vegetarians and a white meat intervention resulted in an increase in plasma 3-MH, 3 MH/Crea, 1-MH and 1-MH/Crea in omnivores. Elevated 3-MH and 3-MH/Crea levels declined significantly within 24 hours after this white meat intervention. Thus, 3-MH and 3-MH/Crea might be used as biomarker for muscle protein turnover when subjects did not consume meat 24 hours prior to blood samplings. Plasma 3-MH, 3-MH/Crea and 3-MH/eGFR were higher in frail individuals than in robust individuals. Additionally, these biomarkers were positively associated with frailty in linear regression models, and higher odds to be frail were found for every increase in 3 MH and 3-MH/eGFR quintile in multivariable logistic regression models adjusted for several confounders. This was the first study using 3-MH/eGFR and it is concluded that plasma 3-MH, 3-MH/Crea and 3-MH/eGFR might be used to identify frail individuals or individuals at higher risk to be frail, and that there might be threshold concentrations or ratios to support these diagnoses. Higher vitamin D3, lutein/zeaxanthin, γ-tocopherol, α-carotene, β-carotene, lycopene and β-cryptoxanthin concentrations and additionally lower PrCarb concentrations were found in robust compared to frail individuals in multivariate linear models. Frail subjects had higher odds to be in the lowest than in the highest tertile for vitamin D3 α-tocopherol, α-carotene, β-carotene, lycopene, lutein/zeaxanthin, and β cryptoxanthin, and had higher odds to be in the highest than in the lowest tertile for PrCarb than robust individuals in multivariate logistic regression models. Thus, a low micronutrient together with a high PrCarb status is associated with pre-frailty and frailty.}, language = {en} } @article{DrobyshevKybarskayaDagaevetal.2019, author = {Drobyshev, Evgenii J. and Kybarskaya, Larisa and Dagaev, Sergey and Solovyev, Nikolay}, title = {New insight in beryllium toxicity excluding exposure to beryllium-containing dust}, series = {Archives of toxicology : official journal of EUROTOX}, volume = {93}, journal = {Archives of toxicology : official journal of EUROTOX}, number = {4}, publisher = {Springer}, address = {Heidelberg}, issn = {0340-5761}, doi = {10.1007/s00204-019-02432-7}, pages = {859 -- 869}, year = {2019}, abstract = {There is much contradiction between different experimental studies on beryllium (Be) toxicity. The majority of studies focus on occupational pathologies, caused by the exposure to Be dust. However, Be pollution may affect wide population groups through other exposure routes. The discrepancies between experimental studies may be attributed to the lack of adequate Be toxicity model since conventional administration routes are hampered by high acidity and low solubility of Be compounds. This study was aimed to develop a novel way to implement Be toxicity avoiding side effects, related to high acidity or low solubility of Be salts. Intraperitoneal injection of Be-glycine composition (containing BeSO4, glycine, purified water, pH adjusted to 5.5 with NaOH) was tested in the dose range 238-7622 mu molBekg(-1) (body weight, b/w) in full-grown Wistar male rats. The model provided reliable uptake of Be from the peritoneum into general circulation for at least 48h. LD50 was found to be 687 mu molBekg(-1) (b/w). The established LD50 value differed from previous data on gastrointestinal, intramuscular or intravenous administration of Be compounds. The liver was found to act as a primary elimination route for Be and related to the highest Be content in the animal. However, it had no signs of morphological damage, which was observed only in the testes (deterioration of germinal epithelium). At the same time, the lungs, stated as a primary target tissue for Be in the models of chronic beryllium disease, did not show strong Be accumulation nor morphological changes. Survived animals showed behavioral changes, including increased motor activity and aggressive reactions in some cases, and complete spasticity in other. The obtained data show the applicability of the established modeling protocol and testified for the independence of chronic beryllium disease on Be2+ ion toxicity per se.}, language = {en} } @article{HasanvonWebskyReichetzederetal.2019, author = {Hasan, Ahmed Abdallah Abdalrahman Mohamed and von Websky, Karoline and Reichetzeder, Christoph and Tsuprykov, Oleg and Gaballa, Mohamed Mahmoud Salem Ahmed and Guo, Jingli and Zeng, Shufei and Delic, Denis and Tammen, Harald and Klein, Thomas and Kleuser, Burkhard and Hocher, Berthold}, title = {Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy}, series = {Kidney international : official journal of the International Society of Nephrology}, volume = {95}, journal = {Kidney international : official journal of the International Society of Nephrology}, number = {6}, publisher = {Elsevier}, address = {New York}, issn = {0085-2538}, doi = {10.1016/j.kint.2019.01.010}, pages = {1373 -- 1388}, year = {2019}, abstract = {Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham + wild type + placebo; 5/6Nx+ wild type + placebo; 5/6Nx+ wild type + linagliptin; sham + knock out+ placebo; 5/6Nx + knock out+ placebo; 5/6Nx + knock out+ linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin beta 4 and heterogeneous nuclear ribonucleoprotein Al (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-beta 1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and GIplr-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1,YB-1,thymosin beta 4 and TGF-beta 1) influenced by DPP-4 inhibition.}, language = {en} } @article{SchenkEichelmannSchulzeetal.2019, author = {Schenk, Matthew and Eichelmann, Fabian and Schulze, Matthias Bernd and Rudovich, Natalia and Pfeiffer, Andreas F. H. and di Giuseppe, Romina and B{\"o}ing, Heiner and Aleksandrova, Krasimira}, title = {Reproducibility of novel immune-inflammatory biomarkers over 4 months}, series = {Biomarkers in medicine}, volume = {13}, journal = {Biomarkers in medicine}, number = {8}, publisher = {Future Medicine}, address = {London}, issn = {1752-0363}, doi = {10.2217/bmm-2018-0351}, pages = {639 -- 648}, year = {2019}, abstract = {Aim: Assessment of the feasibility and reliability of immune-inflammatory biomarker measurements. Methods: The following biomarkers were assessed in 207 predominantly healthy participants at baseline and after 4 months: MMF, TGF-beta, suPAR and clusterin. Results: Intraclass correlation coefficients (95\% CIs) ranged from good for TGF-beta (0.75 [95\% CI: 0.33-0.90]) to excellent for MMF (0.81 [95\% CI: 0.64-0.90]), clusterin (0.83 [95\% CI: 0.78-0.87]) and suPAR (0.91 [95\% CI: 0.88-0.93]). Measurement of TGF-beta was challenged by the large number of values below the detection limit. Conclusion: Single measurements of suPAR, clusterin and MMF could serve as feasible and reliable biomarkers of immune-inflammatory pathways in biomedical research.}, language = {en} } @article{RohnKroepflBornhorstetal.2019, author = {Rohn, Isabelle and Kroepfl, Nina and Bornhorst, Julia and K{\"u}hnelt, Doris and Schwerdtle, Tanja}, title = {Side-directed transfer and presystemic metabolism of selenoneine in a human intestinal barrier model}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {63}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {12}, publisher = {Wiley}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201900080}, pages = {11}, year = {2019}, abstract = {Scope: Selenoneine, a recently discovered selenium (Se) species mainly present in marine fish, is the Se analogue of ergothioneine, a sulfur-containing purported antioxidant. Although similar properties have been proposed for selenoneine, data on its relevance to human health are yet scarce. Here, the transfer and presystemic metabolism of selenoneine in an in vitro model of the human intestinal barrier are investigated. Methods and results: Selenoneine and the reference species Se-methylselenocysteine (MeSeCys) and selenite are applied to the Caco-2 intestinal barrier model. Selenoneine is transferred in higher amounts, but with similar kinetics as selenite, while MeSeCys shows the highest permeability. In contrast to the reference species, transfer of selenoneine is directed toward the blood side. Cellular Se contents demonstrate that selenoneine is efficiently taken up by Caco-2 cells. Moreover, HPLC/MS-based Se speciation studies reveal a partial metabolism to Se-methylselenoneine, a metabolite previously detected in human blood and urine. Conclusions: Selenoneine is likely to pass the intestinal barrier via transcellular, carrier-mediated transport, is highly bioavailable to Caco-2 cells and undergoes metabolic transformations. Therefore, further studies are needed to elucidate its possible health effects and to characterize the metabolism of selenoneine in humans.}, language = {en} } @misc{TianReichetzederLietal.2019, author = {Tian, Mei and Reichetzeder, Christoph and Li, Jian and Hocher, Berthold}, title = {Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth}, series = {Journal of hypertension}, volume = {37}, journal = {Journal of hypertension}, number = {11}, publisher = {Kluwer}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0000000000002156}, pages = {2123 -- 2134}, year = {2019}, abstract = {Low birth weight (LBW) is associated with diseases in adulthood. The birthweight attributed risk is independent of confounding such as gestational age, sex of the newborn but also social factors. The birthweight attributed risk for diseases in later life holds for the whole spectrum of birthweight. This raises the question what pathophysiological principle is actually behind the association. In this review, we provide evidence that LBW is a surrogate of insulin resistance. Insulin resistance has been identified as a key factor leading to type 2 diabetes, cardiovascular disease as well as kidney diseases. We first provide evidence linking LBW to insulin resistance during intrauterine life. This might be caused by both genetic (genetic variations of genes controlling glucose homeostasis) and/or environmental factors (due to alterations of macronutrition and micronutrition of the mother during pregnancy, but also effects of paternal nutrition prior to conception) leading via epigenetic modifications to early life insulin resistance and alterations of intrauterine growth, as insulin is a growth factor in early life. LBW is rather a surrogate of insulin resistance in early life - either due to inborn genetic or environmental reasons - rather than a player on its own.}, language = {en} } @misc{ZeiherDuchKrolletal.2019, author = {Zeiher, Johannes and Duch, M. and Kroll, Lars Eric and Mensink, Gerhardus Bernardus Maria and Finger, Jonas David and Keil, Thomas}, title = {Domain-specific physical activity patterns and cardiorespiratory fitness among adults in Germany}, series = {The European Journal of Public Health}, volume = {29}, journal = {The European Journal of Public Health}, number = {Supplement. 4}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1101-1262}, pages = {1}, year = {2019}, abstract = {Background Studies show that occupational physical activity (OPA) has less health-enhancing effects than leisure-time physical activity (LTPA). The spare data available suggests that OPA rarely includes aerobic PAs with little or no enhancing effects on cardiorespiratory fitness (CRF) as a possible explanation. This study aims to investigate the associations between patterns of OPA and LTPA and CRF among adults in Germany. Methods 1,204 men and 1,303 women (18-64 years), who participated in the German Health Interview and Examination Survey 2008-2011, completed a standardized sub-maximal cycle ergometer test to estimate maximal oxygen consumption (VO2max). Job positions were coded according to the level of physical effort to construct an occupational PA index and categorized as low vs. high OPA. LTPA was assessed via questionnaires and dichotomized in no vs. any LTPA participation. A combined LTPA/OPA variable was used (high OPA/ LTPA, low OPA/LTPA, high OPA/no LTPA, low OPA/no LTPA). Information on potential confounders was obtained via questionnaires (e.g., smoking and education) or physical measurements (e.g., waist circumference). Multi-variable logistic regression was used to analyze associations between OPA/LTPA patterns and VO2max. Results Preliminary analyses showed that less-active men were more likely to have a low VO2max with odds ratios (ORs) of 0.80 for low OPA/LTPA, 1.84 for high OPA/no LTPA and 3.46 for low OPA/no LTPA compared to high OPA/LTPA. The corresponding ORs for women were 1.11 for low OPA/LTPA, 3.99 for high OPA/no LTPA and 2.44 for low OPA/no LTPA, indicating the highest likelihood of low fitness for women working in physically demanding jobs and not engaging in LTPA. Conclusions Findings confirm a strong association between LTPA and CRF and suggest an interaction between OPA and LTPA patterns on CRF within the workforce in Germany. Women without LTPA are at high risk of having a low CRF, especially if they work in physically demanding jobs. Key messages Women not practicing leisure-time physical activity are at risk of having a low cardiorespiratory fitness, especially if they work in physically demanding jobs. Different impact of domains of physical activity should be considered when planning interventions to enhance fitness among the adult population.}, language = {en} } @misc{NormanOtten2019, author = {Norman, Kristina and Otten, Lindsey}, title = {Financial impact of sarcopenia or low muscle mass - a short review}, series = {Clinical Nutrition}, volume = {38}, journal = {Clinical Nutrition}, number = {4}, publisher = {Churchill Livingstone}, address = {Edinburgh}, issn = {0261-5614}, doi = {10.1016/j.clnu.2018.09.026}, pages = {1489 -- 1495}, year = {2019}, abstract = {Background \& aims: Low muscle mass is associated with increased falls, medical complications, length of hospital stay and loss of independence. An increasing number of studies has also shown the association between sarcopenia and health care expenditure. The following narrative review summarizes the current evidence on the economic relevance of low muscle mass (MM) or sarcopenia. Methods: An extensive search of the literature in Medline identified twelve studies in English, which evaluated direct and indirect health care expenditure in patients with low muscle mass or sarcopenia (low MM and strength or mobility). Results: Three studies analysed the cost of age-related loss of MM or strength in large surveys of the general, older population. Six retrospective analyses evaluated perioperative medical costs related to low MM in primarily older patients from different medical areas. One prospective study presented hospital costs related to sarcopenia in patients with gastric cancer. Two studies presented data from general hospital patients. Despite the difference in diagnostic criteria, study population and statistical design, low MM and sarcopenia were consistently identified as predictors of increased health care expenditure in community, perioperative and general hospital settings. Conclusions: Low MM and sarcopenia are prevalent and associated with significantly higher health care costs. Considering the demographic change, which will lead to an increasing number of patients with sarcopenia, every effort should be made to identify and treat patients with sarcopenia. The use of a unified definition and diagnostic criteria would allow a better comparison of data. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.}, language = {en} } @article{KoppMuellerPohletal.2019, author = {Kopp, Johannes Florian and M{\"u}ller, Sandra Marie and Pohl, Gabriele and Lossow, Kristina and Kipp, Anna Patricia and Schwerdtle, Tanja}, title = {A quick and simple method for the determination of six trace elements in mammalian serum samples using ICP-MS/MS}, series = {Journal of trace elements in medicine and biology}, volume = {54}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier}, address = {M{\"u}nchen}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2019.04.015}, pages = {221 -- 225}, year = {2019}, abstract = {In order to assess the individual trace element status of humans for either medical or scientific purposes, amongst others, blood serum levels are determined. Furthermore, animal models are used to study interactions of trace elements. Most published methods require larger amounts (500-1000 mu L) of serum to achieve a reliable determination of multiple trace elements. However, oftentimes, these amounts of serum cannot be dedicated to a single analysis and the amount available for TE-determination is much lower. Therefore, a published ICP-MS/MS method for trace element determination in serum was miniaturized, optimized and validated for the measurement of Mn, Fe, Cu Zn, I and Se in as little as 50 mu L of human and murine serum and is presented in this work. For validation, recoveries of multiple LOTs and levels from commercially available human reference serum samples were determined, infra- and inter-day variations were assessed and limits of detection and quantification determined. It is shown, that the method is capable of giving accurate and reproducible results for all six elements within the relevant concentration ranges for samples from humans living in central Europe as well as from laboratory mice. As a highlight, the achieved limits of detection and quantification for Mn were found to be at 0.02 mu g/L serum and 0.05 mu g/L serum, respectively, while using an alkaline diluent for the parallel determination of iodine.}, language = {en} } @misc{PlankYeallandMicelietal.2019, author = {Plank, Roswitha and Yealland, Guy and Miceli, Enrico and Cunha, Dulce Lima and Graff, Patrick and Thomforde, Sari and Gruber, Robert and Moosbrugger-Martinz, Verena and Eckl, Katja and Calderon, Marcelo and Hennies, Hans Christian and Hedtrich, Sarah}, title = {Transglutaminase 1 Replacement Therapy Successfully Mitigates the Autosomal Recessive Congenital Ichthyosis Phenotype in Full-Thickness Skin Disease Equivalents}, series = {The journal of investigative dermatology}, volume = {139}, journal = {The journal of investigative dermatology}, number = {5}, publisher = {Elsevier}, address = {New York}, issn = {0022-202X}, doi = {10.1016/j.jid.2018.11.002}, pages = {1191 -- 1195}, year = {2019}, language = {en} } @article{BasaranDuyduUstundagetal.2019, author = {Basaran, Nursen and Duydu, Yalcin and Ustundag, Aylin and Taner, Gokce and Aydin, Sevtap and Anlar, Hatice Gul and Yalcin, Can {\"O}zg{\"u}r and Bacanli, Merve and Aydos, Kaan and Atabekoglu, Cem Somer and Golka, Klaus and Ickstadt, Katja and Schwerdtle, Tanja and Werner, Matthias and Meyer, S{\"o}ren and Bolt, Hermann M.}, title = {Evaluation of the DNA damage in lymphocytes, sperm and buccal cells of workers under environmental and occupational boron exposure conditions}, series = {Mutation Research/Genetic Toxicology and Environmental Mutagenesis}, volume = {843}, journal = {Mutation Research/Genetic Toxicology and Environmental Mutagenesis}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1383-5718}, doi = {10.1016/j.mrgentox.2018.12.013}, pages = {33 -- 39}, year = {2019}, abstract = {Industrial production and use of boron compounds have increased during the last decades, especially for the manufacture of borosilicate glass, fiberglass, metal alloys and flame retardants. This study was conducted in two districts of Balikesir; Bandirma and Bigadic, which geographically belong to the Marmara Region of Turkey. Bandirma is the production and exportation zone for the produced boric acid and some borates and Bigadic has the largest B deposits in Turkey. 102 male workers who were occupationally exposed to boron from Bandirma and 110 workers who were occupationally and environmentally exposed to boron from Bigadic participated to our study. In this study the DNA damage in the sperm, blood and buccal cells of 212 males was evaluated by comet and micronucleus assays. No significant increase in the DNA damage in blood, sperm and buccal cells was observed in the residents exposed to boron both occupationally and environmentally (p = 0.861) for Comet test in the sperm samples, p = 0.116 for Comet test in the lymphocyte samples, p = 0.042 for micronucleus (MN) test, p = 0.955 for binucleated cells (BN), p = 1.486 for condensed chromatin (CC), p = 0.455 for karyorrhectic cells (KHC), p = 0.541 for karyolitic cells (KLY), p = 1.057 for pyknotic cells (PHC), p = 0.331 for nuclear bud (NBUD)). No correlations were seen between blood boron levels and tail intensity values of the sperm samples, lymphocyte samples, frequencies of MN, BN, KHC, KYL, PHC and NBUD. The results of this study came to the same conclusions of the previous studies that boron does not induce DNA damage even under extreme exposure conditions.}, language = {en} } @article{KhozroughiBragaWagneretal.2019, author = {Khozroughi, Amin Ghadiri and Braga, Tess Waldbach and Wagner, Janine and Rawel, Harshadrai Manilal}, title = {Investigation of the post mortem zinc protoporphyrin IX fluorescence with respect to its protein-bound and unbound occurrence in aqueous meat extracts}, series = {Food chemistry}, volume = {283}, journal = {Food chemistry}, publisher = {Elsevier}, address = {Oxford}, issn = {0308-8146}, doi = {10.1016/j.foodchem.2019.01.080}, pages = {462 -- 467}, year = {2019}, abstract = {Zinc protoporphyrin IX (ZnPP) is known to accumulate in most meat products during storage. However, the pathway of its formation is not yet completely clarified. To gain more insights into the specificity of ZnPP occurrence, a SEC-HPLC-UV-fluorescence setup was established to screen the proteins in aqueous meat extracts for their ZnPP fluorescence during incubation. In accordance with previous studies it was identified by SDS-PAGE and MALDI-TOF-MS that ZnPP formation takes place in myoglobin. In this study, valuable new insights into the ZnPP forming pathway were gained, as our results indicated that a significant part of ZnPP - after being formed within the protein - is transitioned into free ZnPP during incubation. Additionally, the obtained results implied that ZnPP may also occur in proteins of higher molecular weight (> 100 kDa).}, language = {en} } @article{LiSchlaichKulkaetal.2019, author = {Li, Mingjun and Schlaich, Christoph and Kulka, Michael Willem and Donskyi, Ievgen S. and Schwerdtle, Tanja and Unger, Wolfgang E. S. and Haag, Rainer}, title = {Mussel-inspired coatings with tunable wettability, for enhanced antibacterial efficiency and reduced bacterial adhesion}, series = {Journal of materials chemistry : B, Materials for biology and medicine}, volume = {7}, journal = {Journal of materials chemistry : B, Materials for biology and medicine}, number = {21}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2050-750X}, doi = {10.1039/c9tb00534j}, pages = {3438 -- 3445}, year = {2019}, abstract = {Over the last few decades, there has been a tremendous increase in research on antibacterial surface coatings as an alternative strategy against bacterial infections. Although there are several examples of effective strategies to prevent bacterial adhesion, the effect of the wetting properties on the coating was rarely considered as a crucial factor. Here we report an in-depth study on the effect of extreme wettability on the antibacterial efficiency of a silver nanoparticles ( AgNPs)-based coating. By controlling surface polymerization of mussel-inspired dendritic polyglycerol ( MI-dPG) and post-functionalization, surfaces with wetting properties ranging from superhydrophilic to superhydrophobic were fabricated. Subsequently, AgNPs were embedded into the coatings by applying in situ reduction using the free catechols-moieties present in the MI-dPG coating. The resulting polymer coatings exhibited excellent antibacterial ability against planktonic Escherichia coli ( E. coli) DH5a and Staphylococcus aureus ( S. aureus) SH1000. The antibacterial efficiency of the coatings was analyzed by using inductively coupled plasma mass spectrometry ( ICP-MS) and bacterial viability tests. Furthermore, the antifouling properties of the coatings in relation to the antibacterial properties were evaluated.}, language = {en} } @misc{VolkertBeckCederholmetal.2019, author = {Volkert, Dorothee and Beck, Anne Marie and Cederholm, Tommy and Cereda, Emanuele and Cruz-Jentoft, Alfonso J. and Goisser, Sabine and de Groot, Lisette and Grosshauser, Franz and Kiesswetter, Eva and Norman, Kristina and Pourhassan, Maryam and Reinders, Ilse and Roberts, Helen C. and Rolland, Yves and Schneider, St{\´e}phane M. and Sieber, Cornel and Thiem, Ulrich and Visser, Marjolein and Wijnhoven, Hanneke and Wirth, Rainer}, title = {Management of malnutrition in older patients}, series = {Journal of Clinical Medicine : open access journal}, volume = {8}, journal = {Journal of Clinical Medicine : open access journal}, number = {7}, publisher = {MDPI}, address = {Basel}, issn = {2077-0383}, doi = {10.3390/jcm8070974}, pages = {16}, year = {2019}, abstract = {Malnutrition is widespread in older people and represents a major geriatric syndrome with multifactorial etiology and severe consequences for health outcomes and quality of life. The aim of the present paper is to describe current approaches and evidence regarding malnutrition treatment and to highlight relevant knowledge gaps that need to be addressed. Recently published guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) provide a summary of the available evidence and highlight the wide range of different measures that can be taken—from the identification and elimination of potential causes to enteral and parenteral nutrition—depending on the patient's abilities and needs. However, more than half of the recommendations therein are based on expert consensus because of a lack of evidence, and only three are concern patient-centred outcomes. Future research should further clarify the etiology of malnutrition and identify the most relevant causes in order to prevent malnutrition. Based on limited and partly conflicting evidence and the limitations of existing studies, it remains unclear which interventions are most effective in which patient groups, and if specific situations, diseases or etiologies of malnutrition require specific approaches. Patient-relevant outcomes such as functionality and quality of life need more attention, and research methodology should be harmonised to allow for the comparability of studies.}, language = {en} } @article{JannaschKroegerAgnolietal.2019, author = {Jannasch, Franziska and Kr{\"o}ger, Janine and Agnoli, Claudia and Barricarte, Aurelio and Boeing, Heiner and Cayssials, Val{\´e}rie and Colorado-Yohar, Sandra and Dahm, Christina C. and Dow, Courtney and Fagherazzi, Guy and Franks, Paul W. and Freisling, Heinz and Gunter, Marc J. and Kerrison, Nicola D. and Key, Timothy J. and Khaw, Kay-Tee and K{\"u}hn, Tilman and Kyro, Cecilie and Mancini, Francesca Romana and Mokoroa, Olatz and Nilsson, Peter and Overvad, Kim and Palli, Domenico and Panico, Salvatore and Quiros Garcia, Jose Ramon and Rolandsson, Olov and Sacerdote, Carlotta and Sanchez, Maria-Jose and Sahrai, Mohammad Sediq and Sch{\"u}bel, Ruth and Sluijs, Ivonne and Spijkerman, Annemieke M. W. and Tjonneland, Anne and Tong, Tammy Y. N. and Tumino, Rosario and Riboli, Elio and Langenberg, Claudia and Sharp, Stephen J. and Forouhi, Nita G. and Schulze, Matthias Bernd and Wareham, Nicholas J.}, title = {Generalizability of a Diabetes-Associated Country-Specific Exploratory Dietary Pattern Is Feasible Across European Populations}, series = {The Journal of Nutrition}, volume = {149}, journal = {The Journal of Nutrition}, number = {6}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0022-3166}, doi = {10.1093/jn/nxz031}, pages = {1047 -- 1055}, year = {2019}, abstract = {Background: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence. Objective: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries. Methods: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association. Results: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95\% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95\% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95\% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea. Conclusions: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.}, language = {en} } @article{SpiraBuchmannKoenigetal.2019, author = {Spira, Dominik and Buchmann, Nikolaus and Koenig, Maximilian and Rosada, Adrian and Steinhagen-Thiessen, Elisabeth and Demuth, Ilja and Norman, Kristina}, title = {Sex-specific differences in the association of vitamin D with low lean mass and frailty}, series = {Nutrition}, volume = {62}, journal = {Nutrition}, publisher = {Elsevier}, address = {New York}, issn = {0899-9007}, doi = {10.1016/j.nut.2018.11.020}, pages = {1 -- 6}, year = {2019}, abstract = {Background: Sex-specific differences in factors associated with aging and lifespan, such as sarcopenia and disease development, are increasingly recognized. The study aims to assess sex-specific aspects of the association between vitamin D insufficiency and low lean mass as well as between vitamin D insufficiency and the frailty phenotype. Methods: A total of 1102 participants (51\% women) from the Berlin Aging Study II were included in this cross-sectional study. Vitamin D insufficiency was defined as a 25(OH)D level <50 nmol/L. Lean mass was assessed with dual-energy x-ray absorptiometry and corrected by body mass index. Low lean mass was defined according to the Foundations for the National Institutes of Health Sarcopenia Project criteria (appendicular lean mass/body mass index <0.789 in men and <0.512 in women) and frailty defined according to the Fried criteria. Results: In a risk factor adjusted analysis, the association of vitamin D insufficiency was significantly influenced by sex (P for interaction < 0.001). Men with vitamin D insufficiency had 1.8 times higher odds of having low lean mass, with no association between vitamin D insufficiency and low lean mass in women. Participants with vitamin D insufficiency had 1.5 higher odds of being prefrail/frail with no significant effect modification by sex. Conclusions: We found notable sex-specific differences in the association of vitamin D insufficiency with low lean mass but not of vitamin D insufficiency with frailty. Vitamin D might play a relevant role in the loss of lean mass in men but not women and might be a biological marker of an unfavorable aging process associated with early development of frailty regardless of sex.}, language = {en} } @article{WillmannHeniLinderetal.2019, author = {Willmann, Caroline and Heni, Martin and Linder, Katarzyna and Wagner, Robert and Stefan, Norbert and Machann, J{\"u}rgen and Schulze, Matthias Bernd and Joost, Hans-Georg and Haring, Hans-Ulrich and Fritsche, Andreas}, title = {Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content}, series = {The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.}, volume = {109}, journal = {The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.}, number = {2}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0002-9165}, doi = {10.1093/ajcn/nqy307}, pages = {288 -- 296}, year = {2019}, abstract = {Background: Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk. Objectives: We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes. Methods: This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy. Results: Participants in all groups lost weight (mean 3.3 +/- 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r(2) = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084). Conclusions: Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters. This trial was registered at clinicaltrials.gov as NCT03231839.}, language = {en} } @article{CastroFernandoReegetal.2019, author = {Castro, Jose Pedro and Fernando, Raquel and Reeg, Sandra and Meinl, Walter and Almeida, Henrique and Grune, Tilman}, title = {Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation}, series = {Redox Biology}, volume = {21}, journal = {Redox Biology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {2213-2317}, doi = {10.1016/j.redox.2019.101108}, pages = {10}, year = {2019}, abstract = {Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation, whereas transfection of the cleaved form of Hsp90 leads to an enhanced accumulation of oxidized actin. This indicates a clear role of the Hsp90cl in the aggregation of oxidized proteins.}, language = {en} } @article{SchroeterNeugartSchreineretal.2019, author = {Schr{\"o}ter, David and Neugart, Susanne and Schreiner, Monika and Grune, Tilman and Rohn, Sascha and Ott, Christiane}, title = {Amaranth's 2-Caffeoylisocitric Acid—An Anti-Inflammatory Caffeic Acid Derivative That Impairs NF-κB Signaling in LPS-Challenged RAW 264.7 Macrophages}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {3}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11030571}, pages = {14}, year = {2019}, abstract = {For centuries, Amaranthus sp. were used as food, ornamentals, and medication. Molecular mechanisms, explaining the health beneficial properties of amaranth, are not yet understood, but have been attributed to secondary metabolites, such as phenolic compounds. One of the most abundant phenolic compounds in amaranth leaves is 2-caffeoylisocitric acid (C-IA) and regarding food occurrence, C-IA is exclusively found in various amaranth species. In the present study, the anti-inflammatory activity of C-IA, chlorogenic acid, and caffeic acid in LPS-challenged macrophages (RAW 264.7) has been investigated and cellular contents of the caffeic acid derivatives (CADs) were quantified in the cells and media. The CADs were quantified in the cell lysates in nanomolar concentrations, indicating a cellular uptake. Treatment of LPS-challenged RAW 264.7 cells with 10 µM of CADs counteracted the LPS effects and led to significantly lower mRNA and protein levels of inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin 6, by directly decreasing the translocation of the nuclear factor κB/Rel-like containing protein 65 into the nucleus. This work provides new insights into the molecular mechanisms that attribute to amaranth's anti-inflammatory properties and highlights C-IA's potential as a health-beneficial compound for future research.}, language = {en} } @article{DuyduBasaranYalcinetal.2019, author = {Duydu, Yalcin and Basaran, Nursen and Yalcin, Can {\"O}zg{\"u}r and Ustundag, Aylin and Aydin, Sevtap and Anlar, Hatice Gul and Bacanli, Merve and Aydos, Kaan and Atabekoglu, Cem Somer and Golka, Klaus and Ickstadt, Katja and Schwerdtle, Tanja and Werner, Matthias and Bolt, Hermann M.}, title = {Boron-exposed male workers in Turkey}, series = {Archives of toxicology : official journal of EUROTOX}, volume = {93}, journal = {Archives of toxicology : official journal of EUROTOX}, number = {3}, publisher = {Springer}, address = {Heidelberg}, issn = {0340-5761}, doi = {10.1007/s00204-019-02391-z}, pages = {743 -- 751}, year = {2019}, abstract = {Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 +/- 18.32 mg B/day, 1643.23 +/- 965.44 ng B/g semen and 553.83 +/- 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions.}, language = {en} } @article{EichelmannSchulzeWittenbecheretal.2019, author = {Eichelmann, Fabian and Schulze, Matthias Bernd and Wittenbecher, Clemens and Menzel, Juliane and Weikert, Cornelia and di Giuseppe, Romina and Biemann, Ronald and Isermann, Berend and Fritsche, Andreas and Boeing, Heiner and Aleksandrova, Krasimira}, title = {Association of Chemerin Plasma Concentration With Risk of Colorectal Cancer}, series = {JAMA network open}, volume = {2}, journal = {JAMA network open}, number = {3}, publisher = {American Veterinary Medical Association}, address = {Chicago}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2019.0896}, pages = {14}, year = {2019}, abstract = {IMPORTANCE Inflammatory processes have been suggested to have an important role in colorectal cancer (CRC) etiology. Chemerin is a recently discovered inflammatory biomarker thought to exert chemotactic, adipogenic, and angiogenic functions. However, its potential link with CRC has not been sufficiently explored. OBJECTIVE To evaluate the prospective association of circulating plasma chemerin concentrations with incident CRC. DESIGN, SETTING, AND PARTICIPANTS Prospective case-cohort study based on 27 548 initially healthy participants from the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort who were followed for up to 16 years. Baseline study information and samples were collected between August 23, 1994, and September 25, 1998. Recruitment was according to random registry sampling from the geographical area of Potsdam, Germany, and surrounding municipalities. The last date of study follow-up was May 10, 2010. Statistical analysis was conducted in 2018. MAIN OUTCOMES AND MEASURES Incident CRC, colon cancer, and rectal cancer. Baseline chemerin plasma concentrations were measured by enzyme-linked immunosorbent assay. CONCLUSIONS AND RELEVANCE This study found that the association between chemerin concentration and the risk of incident CRC was linear and independent of established CRC risk factors. Further studies are warranted to evaluate chemerin as a novel immune-inflammatory agent in colorectal carcinogenesis.}, language = {en} } @article{BornhorstNustedeFudickar2019, author = {Bornhorst, Julia and Nustede, Eike Jannik and Fudickar, Sebastian}, title = {Mass Surveilance of C. elegans-Smartphone-Based DIY Microscope and Machine-Learning-Based Approach for Worm Detection}, series = {Sensors}, volume = {19}, journal = {Sensors}, number = {6}, publisher = {MDPI}, address = {Basel}, issn = {1424-8220}, doi = {10.3390/s19061468}, pages = {14}, year = {2019}, abstract = {The nematode Caenorhabditis elegans (C. elegans) is often used as an alternative animal model due to several advantages such as morphological changes that can be seen directly under a microscope. Limitations of the model include the usage of expensive and cumbersome microscopes, and restrictions of the comprehensive use of C. elegans for toxicological trials. With the general applicability of the detection of C. elegans from microscope images via machine learning, as well as of smartphone-based microscopes, this article investigates the suitability of smartphone-based microscopy to detect C. elegans in a complete Petri dish. Thereby, the article introduces a smartphone-based microscope (including optics, lighting, and housing) for monitoring C. elegans and the corresponding classification via a trained Histogram of Oriented Gradients (HOG) feature-based Support Vector Machine for the automatic detection of C. elegans. Evaluation showed classification sensitivity of 0.90 and specificity of 0.85, and thereby confirms the general practicability of the chosen approach.}, language = {en} } @misc{WellenbergWeidesBornhorstetal.2019, author = {Wellenberg, Anna and Weides, L. and Bornhorst, Julia and Crone, Barbara and Karst, U. and Fritz, G. and Honnen, S.}, title = {Molecular and electrophysiological analysis of platinum-induced neurotoxicity using the model organism C. elegans}, series = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {392}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, doi = {10.1007/s00210-019-01621-6}, pages = {S63 -- S63}, year = {2019}, language = {en} } @article{SaussenthalerOuniBaumeieretal.2019, author = {Saussenthaler, Sophie and Ouni, Meriem and Baumeier, Christian and Schwerbel, Kristin and Gottmann, Pascal and Christmann, Sabrina and Laeger, Thomas and Sch{\"u}rmann, Annette}, title = {Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein}, series = {The journal of nutritional biochemistry}, volume = {63}, journal = {The journal of nutritional biochemistry}, publisher = {Elsevier}, address = {New York}, issn = {0955-2863}, doi = {10.1016/j.jnutbio.2018.09.025}, pages = {109 -- 116}, year = {2019}, abstract = {Dipeptidyl peptidase 4 (DPP4) is known to be elevated in metabolic disturbances such as obesity, type 2 diabetes and fatty liver disease. Lowering DPP4 concentration by pharmacological inhibition improves glucose homeostasis and exhibits beneficial effects to reduce hepatic fat content. As factors regulating the endogenous expression of Dpp4 are unknown, the aim of this study was to examine whether the Dpp4 expression is epigenetically regulated in response to dietary components. Primary hepatocytes were treated with different macronutrients, and Dpp4 mRNA levels and DPP4 activity were evaluated. Moreover, dietary low-protein intervention was conducted in New Zealand obese (NZO) mice, and subsequently, effects on Dpp4 expression, methylation as well as plasma concentration and activity were determined. Our results indicate that Dpp4 mRNA expression is mediated by DNA methylation in several tissues. We therefore consider the Dpp4 southern shore as tissue differentially methylated region. Amino acids increased Dpp4 expression in primary hepatocytes, whereas glucose and fatty acids were without effect. Dietary protein restriction in NZO mice increased Dpp4 DNA methylation in liver leading to diminished Dpp4 expression and consequently to lowered plasma DPP4 activity. We conclude that protein restriction in the adolescent and adult states is a sufficient strategy to reduce DPP4 which in turn contributes to improve glucose homeostasis. (C) 2018 Published by Elsevier Inc.}, language = {en} } @article{WittenbecherOuniKuxhausetal.2019, author = {Wittenbecher, Clemens and Ouni, Meriem and Kuxhaus, Olga and J{\"a}hnert, Markus and Gottmann, Pascal and Teichmann, Andrea and Meidtner, Karina and Kriebel, Jennifer and Grallert, Harald and Pischon, Tobias and Boeing, Heiner and Schulze, Matthias Bernd and Sch{\"u}rmann, Annette}, title = {Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes}, series = {Diabetes : a journal of the American Diabetes Association}, volume = {68}, journal = {Diabetes : a journal of the American Diabetes Association}, number = {1}, publisher = {American Diabetes Association}, address = {Alexandria}, issn = {0012-1797}, doi = {10.2337/db18-0620}, pages = {188 -- 197}, year = {2019}, abstract = {Recent studies suggest that insulin-like growth factor binding protein 2 (IGFBP-2) may protect against type 2 diabetes, but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk.}, language = {en} } @article{BaşaranDuyduUestuendağetal.2019, author = {Ba{\c{s}}aran, Nur{\c{s}}en and Duydu, Yal{\c{c}}{\i}n and {\"U}st{\"u}ndağ, Aylin and Taner, G{\"o}k{\c{c}}e and Aydin Dilsiz, Sevtap and Anlar, Hatice G{\"u}l and Yal{\c{c}}in, Can {\"O}zg{\"u}r and Bacanli, Merve and Golka, Klaus and Schwerdtle, Tanja and Bolt, Hermann M.}, title = {Environmental boron exposure does not induce DNA damage in lymphocytes and buccal cells of females DNA damage in lymphocytes and buccal cells of boron exposed females}, series = {Journal of trace elements in medicine and biology}, volume = {53}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier B.V.}, address = {M{\"u}nchen}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2019.03.004}, pages = {150 -- 153}, year = {2019}, abstract = {Boron (B) compounds are essential for plants and animals and beneficial for humans in nutritional amounts. I animals and humans increasing evidence have shown beneficial effects on B compounds on nutrition and on antioxidant status. The genotoxic effects of environmental B exposure in women living in boron-rich and boronpoor areas was examined in this study. For this purpose, the DNA damage in the lymphocytes and buccal cells of females were assessed by Comet and micronucleus (MN) assays respectively. No significant difference was observed in the DNA damage of the lymphocytes of B exposed groups of female volunteers in Comet assay. Even buccal micronucleus (MN) frequency observed in the high exposure group was significantly lower than the low exposure group (p < 0.05). The results of this study came to the same conclusions of the previous studies that boron does not induce DNA damage even under extreme exposure conditions.}, language = {en} } @article{KehmRueckriemenWeberetal.2019, author = {Kehm, Richard and R{\"u}ckriemen, Jana and Weber, Daniela and Deubel, Stefanie and Grune, Tilman and H{\"o}hn, Annika}, title = {Endogenous advanced glycation end products in pancreatic islets after short-term carbohydrate intervention in obese, diabetes-prone mice}, series = {Nutrition \& Diabetes}, volume = {9}, journal = {Nutrition \& Diabetes}, publisher = {Nature Publ. Group}, address = {London}, issn = {2044-4052}, doi = {10.1038/s41387-019-0077-x}, pages = {5}, year = {2019}, abstract = {Diet-induced hyperglycemia is described as one major contributor to the formation of advanced glycation end products (AGEs) under inflammatory conditions, crucial in type 2 diabetes progression. Previous studies have indicated high postprandial plasma AGE-levels in diabetic patients and after long-term carbohydrate feeding in animal models. Pancreatic islets play a key role in glucose metabolism; thus, their susceptibility to glycation reactions due to high amounts of dietary carbohydrates is of special interest. Therefore, diabetes-prone New Zealand Obese (NZO) mice received either a carbohydrate-free, high-fat diet (CFD) for 11 weeks or were additionally fed with a carbohydrate-rich diet (CRD) for 7 days. In the CRD group, hyperglycemia and hyperinsulinemia were induced accompanied by increasing plasma 3-nitrotyrosine (3-NT) levels, higher amounts of 3-NT and inducible nitric oxide synthase (iNOS) within pancreatic islets. Furthermore, N-epsilon-carboxymethyllysine (CML) was increased in the plasma of CRD-fed NZO mice and substantially higher amounts of arg-pyrimidine, pentosidine and the receptor for advanced glycation end products (RAGE) were observed in pancreatic islets. These findings indicate that a short-term intervention with carbohydrates is sufficient to form endogenous AGEs in plasma and pancreatic islets of NZO mice under hyperglycemic and inflammatory conditions.}, language = {en} } @article{PeresHorningBornhorstetal.2019, author = {Peres, Tanara V. and Horning, Kyle J. and Bornhorst, Julia and Schwerdtle, Tanja and Bowman, Aaron B. and Aschner, Michael}, title = {Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo}, series = {Biological Trace Element Research}, volume = {188}, journal = {Biological Trace Element Research}, number = {1}, publisher = {Human press inc.}, address = {Totowa}, issn = {0163-4984}, doi = {10.1007/s12011-018-1531-7}, pages = {127 -- 134}, year = {2019}, abstract = {Manganese (Mn) is essential for several species and daily requirements are commonly met by an adequate diet. Mn overload may cause motor and psychiatric disturbances and may arise from an impaired or not fully developed excretion system, transporter malfunction and/or exposure to excessive levels of Mn. Therefore, deciphering processes regulating neuronal Mn homeostasis is essential to understand the mechanisms of Mn neurotoxicity. In the present study, we selected two small molecules (with opposing effects on Mn transport) from a previous high throughput screen of 40,167 to test their effects on Mn toxicity parameters in vivo using Caenorhabditis elegans. We pre-exposed worms to VU0063088 and VU0026921 for 30min followed by co-exposure for 1h with Mn and evaluated Mn accumulation, dopaminergic (DAergic) degeneration and worm survival. Control worms were exposed to vehicle (DMSO) and saline only. In pdat-1::GFP worms, with GFP labeled DAergic neurons, we observed a decrease of Mn-induced DAergic degeneration in the presence of both small molecules. This effect was also observed in an smf-2 knockout strain. SMF-2 is a regulator of Mn transport in the worms and this strain accumulates higher Mn levels. We did not observe improved survival in the presence of small molecules. Our results suggest that both VU0063088 and VU0026921 may modulate Mn levels in the worms through a mechanism that does not require SMF-2 and induce protection against Mn neurotoxicity.}, language = {en} } @article{VolkertKiesswetterCederholmetal.2019, author = {Volkert, Dorothee and Kiesswetter, Eva and Cederholm, Tommy and Donini, Lorenzo M. and Egiseer, Doris and Norman, Kristina and Schneider, Stephane M. and Stroebele-Benschop, Nanette and Torbahn, Gabriel and Wirth, Rainer and Visser, Marjolein}, title = {Development of a Model on Determinants of Malnutrition in Aged Persons}, series = {Gerontology and Geriatric Medicine}, volume = {5}, journal = {Gerontology and Geriatric Medicine}, publisher = {Sage Publ.}, address = {Thousand Oaks}, issn = {2333-7214}, doi = {10.1177/2333721419858438}, pages = {8}, year = {2019}, abstract = {In older persons, the origin of malnutrition is often multifactorial with a multitude of factors involved. Presently, a common understanding about potential causes and their mode of action is lacking, and a consensus on the theoretical framework on the etiology of malnutrition does not exist. Within the European Knowledge Hub "Malnutrition in the Elderly (MaNuEL)," a model of "Determinants of Malnutrition in Aged Persons" (DoMAP) was developed in a multistage consensus process with live meetings and written feedback (modified Delphi process) by a multiprofessional group of 33 experts in geriatric nutrition. DoMAP consists of three triangle-shaped levels with malnutrition in the center, surrounded by the three principal conditions through which malnutrition develops in the innermost level: low intake, high requirements, and impaired nutrient bioavailability. The middle level consists of factors directly causing one of these conditions, and the outermost level contains factors indirectly causing one of the three conditions through the direct factors. The DoMAP model may contribute to a common understanding about the multitude of factors involved in the etiology of malnutrition, and about potential causative mechanisms. It may serve as basis for future research and may also be helpful in clinical routine to identify persons at increased risk of malnutrition.}, language = {en} } @phdthesis{Eichelmann2019, author = {Eichelmann, Fabian}, title = {Novel adipokines as inflammatory biomarkers of chronic disease risk}, school = {Universit{\"a}t Potsdam}, pages = {133}, year = {2019}, language = {en} } @phdthesis{Gaballa2019, author = {Gaballa, Mohamed Mahmoud Salem Ahmed}, title = {New pharmacological approaches targeting vascular calcification in chronic kidney disease}, address = {Potsdam}, school = {Universit{\"a}t Potsdam}, pages = {X, 110}, year = {2019}, language = {en} } @misc{HenkelBuchheimDieckowCastroetal.2019, author = {Henkel, Janin and Buchheim-Dieckow, Katja and Castro, Jos{\´e} Pedro and Laeger, Thomas and Wardelmann, Kristina and Kleinridders, Andr{\´e} and J{\"o}hrens, Korinna and P{\"u}schel, Gerhard Paul}, title = {Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {807}, issn = {1866-8372}, doi = {10.25932/publishup-44238}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-442384}, pages = {17}, year = {2019}, abstract = {Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10\% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production.}, language = {en} } @article{Wardelmann2019, author = {Wardelmann, Kristina}, title = {Hormonal regulation of neuronal mitochondrial unfolded protein response and its impact on metabolism}, pages = {108}, year = {2019}, abstract = {The hypothalamus is the main brain area of central regulation of whole body metabolism through impacting food intake and energy expenditure. For the complex regulation, high amounts of energy are needed and mainly provided by mitochondria. Hence, mitochondrial function is crucial for cell homeostasis and modulates central insulin sensitivity. Thus, mitochondrial dysfunction is associated with insulin resistance in the brain and therefore is involved in the pathogenesis of type-2 diabetes (T2D). Mitochondrial health and protein homeostasis is propagated by mitochondrial stress responses like e.g. mitochondrial unfolded protein response (UPRmt). Therefore, studies regarding the regulation of mitochondrial homeostasis are crucial for understanding its effects on the central nervous system (CNS) for the progression of metabolic and nutrition-dependent disorders. One main aim of this thesis was to investigate the metabolic regulation of mitochondrial stress responsiveness in the hypothalamus. The observed results showed that functional ERK-dependent insulin signaling is needed for regulation of mitochondrial stress response (MSR) genes and positively impacted the metabolism by controlling mitochondrial proteostasis without affecting mitochondrial biogenesis. To further explore the role of MSR genes for brain cell homeostasis and its consequences for the metabolism, one of the key players - the mitochondrial chaperone heat shock protein 10 (Hsp10) - was studied in detail. Hsp10 expression was decreased in insulin-resistant, hyperglycemic db/db mice brains along with increased protein oxidation. Leptin, another key hormone in regulating metabolism, was able to induce Hsp10 in neurons. Appropriately, lentiviral-mediated knock down (KD) of Hsp10 introduced into hypothalamic CLU-183 cells induced mitochondrial dysfunction, altered mitochondrial dynamics and increased contact sites between mitochondria and endoplasmic reticulum (ER). In addition, Hsp10 KD caused cellular insulin resistance along with increasing oxidative stress specifically in mitochondrial fraction. Interestingly, acute Hsp10 KD in the arcuate nucleus of the hypothalamus in C57BL/6N male mice did not change body weight or food intake, but it increased plasma leptin concentrations suggesting an effect on global leptin signaling. It increased hepatic markers of gluconeogenesis and hepatic insulin resistance along with features of low-grade inflammation. Long-term studies of hypothalamic Hsp10 KD mice revealed unaltered systemic insulin sensitivity. The demonstrated increase in markers of hepatic gluconeogenesis of acute Hsp10 KD was still exhibited after 13 weeks, but insulin resistance in the liver was no longer observed. In conclusion, hypothalamic insulin action regulates MSR and ensures proper mitochondrial function which positively affects metabolism. In addition, hypothalamic Hsp10 acts as a modulator of both insulin and leptin signaling and is identified as pivotal for the regulation of central mitochondrial function as well as insulin sensitivity in the brain and it impacts liver function. It may present a regulator of brain-liver crosstalk influencing hepatic gluconeogenesis and insulin sensitivity through a novel regulatory signaling mechanism.}, language = {en} } @article{HenkelBuchheimDieckowCastroetal.2019, author = {Henkel, Janin and Buchheim-Dieckow, Katja and Castro, Jos{\´e} Pedro and Laeger, Thomas and Wardelmann, Kristina and Kleinridders, Andr{\´e} and J{\"o}hrens, Korinna and P{\"u}schel, Gerhard Paul}, title = {Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {11}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11112709}, pages = {15}, year = {2019}, abstract = {Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10\% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production.}, language = {en} } @misc{SaguTchewonpiHuschekBoenicketal.2019, author = {Sagu Tchewonpi, Sorel and Huschek, Gerd and B{\"o}nick, Josephine and Homann, Thomas and Rawel, Harshadrai Manilal}, title = {A New Approach of Extraction of α-Amylase/trypsin Inhibitors from Wheat (Triticum aestivum L.), Based on Optimization Using Plackett-Burman and Box-Behnken Designs}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {805}, issn = {1866-8372}, doi = {10.25932/publishup-44222}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-442229}, pages = {20}, year = {2019}, abstract = {Wheat is one of the most consumed foods in the world and unfortunately causes allergic reactions which have important health effects. The α-amylase/trypsin inhibitors (ATIs) have been identified as potentially allergen components of wheat. Due to a lack of data on optimization of ATI extraction, a new wheat ATIs extraction approach combining solvent extraction and selective precipitation is proposed in this work. Two types of wheat cultivars (Triticum aestivum L.), Julius and Ponticus were used and parameters such as solvent type, extraction time, temperature, stirring speed, salt type, salt concentration, buffer pH and centrifugation speed were analyzed using the Plackett-Burman design. Salt concentration, extraction time and pH appeared to have significant effects on the recovery of ATIs (p < 0.01). In both wheat cultivars, Julius and Ponticus, ammonium sulfate substantially reduced protein concentration and inhibition of amylase activity (IAA) compared to sodium chloride. The optimal conditions with desirability levels of 0.94 and 0.91 according to the Doehlert design were: salt concentrations of 1.67 and 1.22 M, extraction times of 53 and 118 min, and pHs of 7.1 and 7.9 for Julius and Ponticus, respectively. The corresponding responses were: protein concentrations of 0.31 and 0.35 mg and IAAs of 91.6 and 83.3\%. Electrophoresis and MALDI-TOF/MS analysis showed that the extracted ATIs masses were between 10 and 20 kDa. Based on the initial LC-MS/MS analysis, up to 10 individual ATIs were identified in the extracted proteins under the optimal conditions. The positive implication of the present study lies in the quick assessment of their content in different varieties especially while considering their allergenic potential.}, language = {en} } @article{SaguTchewonpiHuschekBoenicketal.2019, author = {Sagu Tchewonpi, Sorel and Huschek, Gerd and B{\"o}nick, Josephine and Homann, Thomas and Rawel, Harshadrai Manilal}, title = {A New Approach of Extraction of α-Amylase/trypsin Inhibitors from Wheat (Triticum aestivum L.), Based on Optimization Using Plackett-Burman and Box-Behnken Designs}, series = {molecules}, volume = {24}, journal = {molecules}, number = {19}, publisher = {MDPI}, address = {Basel}, issn = {1420-3049}, doi = {10.3390/molecules24193589}, pages = {18}, year = {2019}, abstract = {Wheat is one of the most consumed foods in the world and unfortunately causes allergic reactions which have important health effects. The α-amylase/trypsin inhibitors (ATIs) have been identified as potentially allergen components of wheat. Due to a lack of data on optimization of ATI extraction, a new wheat ATIs extraction approach combining solvent extraction and selective precipitation is proposed in this work. Two types of wheat cultivars (Triticum aestivum L.), Julius and Ponticus were used and parameters such as solvent type, extraction time, temperature, stirring speed, salt type, salt concentration, buffer pH and centrifugation speed were analyzed using the Plackett-Burman design. Salt concentration, extraction time and pH appeared to have significant effects on the recovery of ATIs (p < 0.01). In both wheat cultivars, Julius and Ponticus, ammonium sulfate substantially reduced protein concentration and inhibition of amylase activity (IAA) compared to sodium chloride. The optimal conditions with desirability levels of 0.94 and 0.91 according to the Doehlert design were: salt concentrations of 1.67 and 1.22 M, extraction times of 53 and 118 min, and pHs of 7.1 and 7.9 for Julius and Ponticus, respectively. The corresponding responses were: protein concentrations of 0.31 and 0.35 mg and IAAs of 91.6 and 83.3\%. Electrophoresis and MALDI-TOF/MS analysis showed that the extracted ATIs masses were between 10 and 20 kDa. Based on the initial LC-MS/MS analysis, up to 10 individual ATIs were identified in the extracted proteins under the optimal conditions. The positive implication of the present study lies in the quick assessment of their content in different varieties especially while considering their allergenic potential.}, language = {en} } @article{RohnRaschkeAschneretal.2019, author = {Rohn, Isabelle and Raschke, Stefanie and Aschner, Michael and Tuck, Simon and Kuehnelt, Doris and Kipp, Anna Patricia and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Treatment of caenorhabditis elegans with small selenium species enhances antioxidant defense systems}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {63}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {9}, publisher = {Wiley}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201801304}, pages = {9}, year = {2019}, abstract = {ScopeSmall selenium (Se) species play a key role in Se metabolism and act as dietary sources of the essential trace element. However, they are redox-active and trigger pro- and antioxidant responses. As health outcomes are strongly species-dependent, species-specific characteristics of Se compounds are tested in vivo. Methods and resultsIn the model organism Caenorhabditis elegans (C. elegans), immediate and sustained effects of selenite, selenomethionine (SeMet), and Se-methylselenocysteine (MeSeCys) are studied regarding their bioavailability, incorporation into proteins, as well as modulation of the cellular redox status. While all tested Se compounds are bioavailable, only SeMet persistently accumulates and is non-specifically incorporated into proteins. However, the protection toward chemically-induced formation of reactive species is independent of the applied Se compound. Increased thioredoxin reductase (TXNRD) activity and changes in mRNA expression levels of antioxidant proteins indicate the activation of cellular defense mechanisms. However, in txnrd-1 deletion mutants, no protective effects of the Se species are observed anymore, which is also reflected by differential gene expression data. ConclusionSe species protect against chemically-induced reactive species formation. The identified immediate and sustained systemic effects of Se species give rise to speculations on possible benefits facing subsequent periods of inadequate Se intake.}, language = {en} } @misc{KoenigGruneOtt2019, author = {K{\"o}nig, Jeannette and Grune, Tilman and Ott, Christiane}, title = {Assessing autophagy in murine skeletal muscle: current findings to modulate and quantify the autophagic flux}, series = {Current opinion in clinical nutrition and metabolic care}, volume = {22}, journal = {Current opinion in clinical nutrition and metabolic care}, number = {5}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {1363-1950}, doi = {10.1097/MCO.0000000000000579}, pages = {355 -- 362}, year = {2019}, abstract = {Purpose of review In addition to the currently available lysosomotropic drugs and autophagy whole-body knockout mouse models, we provide alternative methods that enable the modulation and detection of autophagic flux in vivo, discussing advantages and disadvantages of each method. Recent findings With the autophagosome-lysosome fusion inhibitor colchicine in skeletal muscle and temporal downregulation of autophagy using a novel Autophagy related 5-short hairpin RNA (Atg5-shRNA) mouse model we mention two models that directly modulate autophagy flux in vivo. Furthermore, methods to quantify autophagy flux, such as mitophagy transgenic reporters, in situ immunofluorescent staining and multispectral imaging flow cytometry, in mature skeletal muscle and cells are addressed. To achieve clinical benefit, less toxic, temporary and cell-type-specific modulation of autophagy should be pursued further. A temporary knockdown as described for the Atg5-shRNA mice could provide a first insight into possible implications of autophagy inhibition. However, it is also important to take a closer look into the methods to evaluate autophagy after harvesting the tissue. In particular caution is required when experimental conditions can influence the final measurement and this should be pretested carefully.}, language = {en} } @article{BaeslerKoppPohletal.2019, author = {Baesler, Jessica and Kopp, Johannes Florian and Pohl, Gabriele and Aschner, Michael and Haase, Hajo and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Zn homeostasis in genetic models of Parkinson's disease in Caenorhabditis elegans}, series = {Journal of Trace Elements in Medicine and Biology}, volume = {55}, journal = {Journal of Trace Elements in Medicine and Biology}, publisher = {Elsevier}, address = {M{\"u}nchen}, doi = {10.1016/j.jtemb.2019.05.005}, pages = {44 -- 49}, year = {2019}, abstract = {While the underlying mechanisms of Parkinson's disease (PD) are still insufficiently studied, a complex interaction between genetic and environmental factors is emphasized. Nevertheless, the role of the essential trace element zinc (Zn) in this regard remains controversial. In this study we altered Zn balance within PD models of the versatile model organism Caenorhabditis elegans (C. elegans) in order to examine whether a genetic predisposition in selected genes with relevance for PD affects Zn homeostasis. Protein-bound and labile Zn species act in various areas, such as enzymatic catalysis, protein stabilization pathways and cell signaling. Therefore, total Zn and labile Zn were quantitatively determined in living nematodes as individual biomarkers of Zn uptake and bioavailability with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) or a multi-well method using the fluorescent probe ZinPyr-1. Young and middle-aged deletion mutants of catp-6 and pdr-1, which are orthologues of mammalian ATP13A2 (PARK9) and parkin (PARK2), showed altered Zn homeostasis following Zn exposure compared to wildtype worms. Furthermore, age-specific differences in Zn uptake were observed in wildtype worms for total as well as labile Zn species. These data emphasize the importance of differentiation between Zn species as meaningful biomarkers of Zn uptake as well as the need for further studies investigating the role of dysregulated Zn homeostasis in the etiology of PD.}, language = {en} } @article{BaeslerKoppPohletal.2019, author = {Baesler, Jessica and Kopp, Johannes F. and Pohl, Gabriele and Aschner, Michael and Haase, Hajo and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Zn homeostasis in genetic models of Parkinson's disease in Caenorhabditis elegans}, series = {Journal of trace elements in medicine and biology}, volume = {55}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier GMBH}, address = {M{\"u}nchen}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2019.05.005}, pages = {44 -- 49}, year = {2019}, language = {en} } @misc{HassHerpichNorman2019, author = {Haß, Ulrike and Herpich, Catrin and Norman, Kristina}, title = {Anti-Inflammatory Diets and Fatigue}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {803}, issn = {1866-8372}, doi = {10.25932/publishup-44117}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-441172}, pages = {26}, year = {2019}, abstract = {Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals' use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue.}, language = {en} } @article{HassHerpichNorman2019, author = {Haß, Ulrike and Herpich, Catrin and Norman, Kristina}, title = {Anti-Inflammatory Diets and Fatigue}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {10}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11102315}, pages = {24}, year = {2019}, abstract = {Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals' use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue.}, language = {en} } @article{KoelmanPivovarovaRamichPfeifferetal.2019, author = {Koelman, Liselot A. and Pivovarova-Ramich, Olga and Pfeiffer, Andreas F. H. and Grune, Tilman and Aleksandrova, Krasimira}, title = {Cytokines for evaluation of chronic inflammatory status in ageing research}, series = {Immunity \& Ageing}, volume = {16}, journal = {Immunity \& Ageing}, publisher = {BMC}, address = {London}, issn = {1742-4933}, doi = {10.1186/s12979-019-0151-1}, pages = {12}, year = {2019}, abstract = {Background: There is a growing interest in the role of inflammageing for chronic disease development. Cytokines are potent soluble immune mediators that can be used as target biomarkers of inflammageing; however, their measurement in human samples has been challenging. This study aimed to assess the reliability of a pro- and anti-inflammatory cytokine panel in a sample of healthy people measured with a novel electrochemiluminescent multiplex immunoassay platform (Meso Scale Discovery, MSD), and to characterize their associations with metabolic and inflammatory phenotypes.}, language = {en} } @misc{RawelHuschekSaguTchewonpietal.2019, author = {Rawel, Harshadrai Manilal and Huschek, Gerd and Sagu Tchewonpi, Sorel and Homann, Thomas}, title = {Cocoa Bean Proteins-Characterization, Changes and Modifications due to Ripening and Post-Harvest Processing}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {2}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11020428}, pages = {20}, year = {2019}, abstract = {The protein fractions of cocoa have been implicated influencing both the bioactive potential and sensory properties of cocoa and cocoa products. The objective of the present review is to show the impact of different stages of cultivation and processing with regard to the changes induced in the protein fractions. Special focus has been laid on the major seed storage proteins throughout the different stages of processing. The study starts with classical introduction of the extraction and the characterization methods used, while addressing classification approaches of cocoa proteins evolved during the timeline. The changes in protein composition during ripening and maturation of cocoa seeds, together with the possible modifications during the post-harvest processing (fermentation, drying, and roasting), have been documented. Finally, the bioactive potential arising directly or indirectly from cocoa proteins has been elucidated. The state of the art suggests that exploration of other potentially bioactive components in cocoa needs to be undertaken, while considering the complexity of reaction products occurring during the roasting phase of the post-harvest processing. Finally, the utilization of partially processed cocoa beans (e.g., fermented, conciliatory thermal treatment) can be recommended, providing a large reservoir of bioactive potentials arising from the protein components that could be instrumented in functionalizing foods.}, language = {en} } @misc{KotthoffLisecSchwerdtleetal.2019, author = {Kotthoff, Lisa and Lisec, Jan and Schwerdtle, Tanja and Koch, Matthias}, title = {Prediction of transformation products of monensin by electrochemistry compared to microsomal assay and hydrolysis}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1340}, issn = {1866-8372}, doi = {10.25932/publishup-47326}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-473262}, pages = {12}, year = {2019}, abstract = {The knowledge of transformation pathways and identification of transformation products (TPs) of veterinary drugs is important for animal health, food, and environmental matters. The active agent Monensin (MON) belongs to the ionophore antibiotics and is widely used as a veterinary drug against coccidiosis in broiler farming. However, no electrochemically (EC) generated TPs of MON have been described so far. In this study, the online coupling of EC and mass spectrometry (MS) was used for the generation of oxidative TPs. EC-conditions were optimized with respect to working electrode material, solvent, modifier, and potential polarity. Subsequent LC/HRMS (liquid+ chromatography/high resolution mass spectrometry) and MS/MS experiments were performed to identify the structures of derived TPs by a suspected target analysis. The obtained EC-results were compared to TPs observed in metabolism tests with microsomes and hydrolysis experiments of MON. Five previously undescribed TPs of MON were identified in our EC/MS based study and one TP, which was already known from literature and found by a microsomal assay, could be confirmed. Two and three further TPs were found as products in microsomal tests and following hydrolysis, respectively. We found decarboxylation, O-demethylation and acid-catalyzed ring-opening reactions to be the major mechanisms of MON transformation}, language = {en} } @article{KotthoffLisecSchwerdtleetal.2019, author = {Kotthoff, Lisa and Lisec, Jan and Schwerdtle, Tanja and Koch, Matthias}, title = {Prediction of transformation products of monensin by electrochemistry compared to microsomal assay and hydrolysis}, series = {Molecules}, volume = {24}, journal = {Molecules}, number = {15}, publisher = {MDPI}, address = {Basel}, issn = {1420-3049}, doi = {10.3390/molecules24152732}, pages = {12}, year = {2019}, abstract = {The knowledge of transformation pathways and identification of transformation products (TPs) of veterinary drugs is important for animal health, food, and environmental matters. The active agent Monensin (MON) belongs to the ionophore antibiotics and is widely used as a veterinary drug against coccidiosis in broiler farming. However, no electrochemically (EC) generated TPs of MON have been described so far. In this study, the online coupling of EC and mass spectrometry (MS) was used for the generation of oxidative TPs. EC-conditions were optimized with respect to working electrode material, solvent, modifier, and potential polarity. Subsequent LC/HRMS (liquid chromatography/high resolution mass spectrometry) and MS/MS experiments were performed to identify the structures of derived TPs by a suspected target analysis. The obtained EC-results were compared to TPs observed in metabolism tests with microsomes and hydrolysis experiments of MON. Five previously undescribed TPs of MON were identified in our EC/MS based study and one TP, which was already known from literature and found by a microsomal assay, could be confirmed. Two and three further TPs were found as products in microsomal tests and following hydrolysis, respectively. We found decarboxylation, O-demethylation and acid-catalyzed ring-opening reactions to be the major mechanisms of MON transformation.}, language = {en} } @article{KluthStadionGottmannetal.2019, author = {Kluth, Oliver and Stadion, Mandy and Gottmann, Pascal and Aga-Barfknecht, Heja and J{\"a}hnert, Markus and Scherneck, Stephan and Vogel, Heike and Krus, Ulrika and Seelig, Anett and Ling, Charlotte and Gerdes, Jantje and Sch{\"u}rmann, Annette}, title = {Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans}, series = {Cell reports}, volume = {26}, journal = {Cell reports}, number = {11}, publisher = {Cell Press}, address = {Maryland Heights}, issn = {2211-1247}, doi = {10.1016/j.celrep.2019.02.056}, pages = {3027 -- 3036}, year = {2019}, abstract = {An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MINE beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk.}, language = {en} } @misc{IgualGilOstKaschetal.2019, author = {Igual Gil, Carla and Ost, Mario and Kasch, Juliane and Schumann, Sara and Heider, Sarah and Klaus, Susanne}, title = {Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1090}, issn = {1866-8372}, doi = {10.25932/publishup-46054}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-460541}, pages = {11}, year = {2019}, abstract = {Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.}, language = {en} } @article{HarmsScalbertZamoraRosetal.2019, author = {Harms, Laura M. and Scalbert, Augustin and Zamora-Ros, Raul and Rinaldi, Sabina and Jenab, Mazda and Murphy, Neil and Achaintre, David and Tj{\o}nneland, Anne and Olsen, Anja and Overvad, Kim and Aleksandrova, Krasimira}, title = {Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations}, series = {British Journal of Nutrition}, volume = {123}, journal = {British Journal of Nutrition}, number = {2}, publisher = {Cambridge University Press}, address = {Cambridge}, issn = {0007-1145}, doi = {10.1017/S0007114519002538}, pages = {198 -- 208}, year = {2019}, abstract = {Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 \% CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 \% CI 50, 1) \% lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 \% CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 \% CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 \% CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 \% CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 \% CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 \% CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.}, language = {en} } @article{IgualGilOstKaschetal.2019, author = {Igual Gil, Carla and Ost, Mario and Kasch, Juliane and Schumann, Sara and Heider, Sarah and Klaus, Susanne}, title = {Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice}, series = {Scientific reports}, volume = {9}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-019-56922-w}, pages = {9}, year = {2019}, abstract = {Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.}, language = {en} } @phdthesis{Kehm2019, author = {Kehm, Richard}, title = {The impact of metabolic stress and aging on functionality and integrity of pancreatic islets and beta-cells}, doi = {10.25932/publishup-44109}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-441099}, school = {Universit{\"a}t Potsdam}, pages = {VI, 138}, year = {2019}, abstract = {The increasing age of worldwide population is a major contributor for the rising prevalence of major pathologies and disease, such as type 2 diabetes, mediated by massive insulin resistance and a decline in functional beta-cell mass, highly associated with an elevated incidence of obesity. Thus, the impact of aging under physiological conditions and in combination with diet-induced metabolic stress on characteristics of pancreatic islets and beta-cells, with the focus on functionality and structural integrity, were investigated in the present dissertation. Primarily induced by malnutrition due to chronic and excess intake of high caloric diets, containing large amounts of carbohydrates and fats, obesity followed by systemic inflammation and peripheral insulin resistance occurs over time, initiating metabolic stress conditions. Elevated insulin demands initiate an adaptive response by beta-cell mass expansion due to increased proliferation, but prolonged stress conditions drive beta-cell failure and loss. Aging has been also shown to affect beta-cell functionality and morphology, in particular by proliferative limitations. However, most studies in rodents were performed under beta-cell challenging conditions, such as high-fat diet interventions. Thus, in the first part of the thesis (publication I), a characterization of age-related alterations on pancreatic islets and beta-cells was performed by using plasma samples and pancreatic tissue sections of standard diet-fed C57BL/6J wild-type mice in several age groups (2.5, 5, 10, 15 and 21 months). Aging was accompanied by decreased but sustained islet proliferative potential as well as an induction of cellular senescence. This was associated with a progressive islet expansion to maintain normoglycemia throughout lifespan. Moreover, beta-cell function and mass were not impaired although the formation and accumulation of AGEs occurred, located predominantly in the islet vasculature, accompanied by an induction of oxidative and nitrosative (redox) stress. The nutritional behavior throughout human lifespan; however, is not restricted to a balanced diet. This emphasizes the significance to investigate malnutrition by the intake of high-energy diets, inducing metabolic stress conditions that synergistically with aging might amplify the detrimental effects on endocrine pancreas. Using diabetes-prone NZO mice aged 7 weeks, fed a dietary regimen of carbohydrate restriction for different periods (young mice - 11 weeks, middle-aged mice - 32 weeks) followed by a carbohydrate intervention for 3 weeks, offered the opportunity to distinguish the effects of diet-induced metabolic stress in different ages on the functionality and integrity of pancreatic islets and their beta-cells (publication II, manuscript). Interestingly, while young NZO mice exhibited massive hyperglycemia in response to diet-induced metabolic stress accompanied by beta-cell dysfunction and apoptosis, middle-aged animals revealed only moderate hyperglycemia by the maintenance of functional beta-cells. The loss of functional beta-cell mass in islets of young mice was associated with reduced expression of PDX1 transcription factor, increased endocrine AGE formation and related redox stress as well as TXNIP-dependent induction of the mitochondrial death pathway. Although the amounts of secreted insulin and the proliferative potential were comparable in both age groups, islets of middle-aged mice exhibited sustained PDX1 expression, almost regular insulin secretory function, increased capacity for cell cycle progression as well as maintained redox potential. The results of the present thesis indicate a loss of functional beta-cell mass in young diabetes-prone NZO mice, occurring by redox imbalance and induction of apoptotic signaling pathways. In contrast, aging under physiological conditions in C57BL/6J mice and in combination with diet-induced metabolic stress in NZO mice does not appear to have adverse effects on the functionality and structural integrity of pancreatic islets and beta-cells, associated with adaptive responses on changing metabolic demands. However, considering the detrimental effects of aging, it has to be assumed that the compensatory potential of mice might be exhausted at a later point of time, finally leading to a loss of functional beta-cell mass and the onset and progression of type 2 diabetes. The polygenic, diabetes-prone NZO mouse is a suitable model for the investigation of human obesity-associated type 2 diabetes. However, mice at advanced age attenuated the diabetic phenotype or do not respond to the dietary stimuli. This might be explained by the middle age of mice, corresponding to the human age of about 38-40 years, in which the compensatory mechanisms of pancreatic islets and beta cells towards metabolic stress conditions are presumably more active.}, language = {en} } @article{SchutkowskiKoenigKlugeetal.2019, author = {Schutkowski, Alexandra and K{\"o}nig, Bettina and Kluge, Holger and Hirche, Frank and Henze, Andrea and Schwerdtle, Tanja and Lorkowski, Stefan and Dawczynski, Christine and Gabel, Alexander and Grosse, Ivo and Stangl, Gabriele I.}, title = {Metabolic footprint and intestinal microbial changes in response to dietary proteins in a pig model}, series = {The journal of nutritional biochemistry}, volume = {67}, journal = {The journal of nutritional biochemistry}, publisher = {Elsevier}, address = {New York}, issn = {0955-2863}, doi = {10.1016/j.jnutbio.2019.02.004}, pages = {149 -- 160}, year = {2019}, abstract = {Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15\% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome. (C) 2019 Elsevier Inc. All rights reserved.}, language = {en} } @misc{WiggerGulbinsKleuseretal.2019, author = {Wigger, Dominik and Gulbins, Erich and Kleuser, Burkhard and Schumacher, Fabian}, title = {Monitoring the Sphingolipid de novo Synthesis by Stable-Isotope Labeling and Liquid Chromatography-Mass Spectrometry}, series = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe}, number = {800}, issn = {1866-8372}, doi = {10.25932/publishup-44115}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-441158}, pages = {16}, year = {2019}, abstract = {Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to cellular signaling. De novo sphingolipid synthesis takes place in the endoplasmic reticulum (ER), where the condensation of the activated C₁₆ fatty acid palmitoyl-CoA and the amino acid L-serine is catalyzed by serine palmitoyltransferase (SPT). The product, 3-ketosphinganine, is then converted into more complex sphingolipids by additional ER-bound enzymes, resulting in the formation of ceramides. Since sphingolipid homeostasis is crucial to numerous cellular functions, improved assessment of sphingolipid metabolism will be key to better understanding several human diseases. To date, no assay exists capable of monitoring de novo synthesis sphingolipid in its entirety. Here, we have established a cell-free assay utilizing rat liver microsomes containing all the enzymes necessary for bottom-up synthesis of ceramides. Following lipid extraction, we were able to track the different intermediates of the sphingolipid metabolism pathway, namely 3-ketosphinganine, sphinganine, dihydroceramide, and ceramide. This was achieved by chromatographic separation of sphingolipid metabolites followed by detection of their accurate mass and characteristic fragmentations through high-resolution mass spectrometry and tandem-mass spectrometry. We were able to distinguish, unequivocally, between de novo synthesized sphingolipids and intrinsic species, inevitably present in the microsome preparations, through the addition of stable isotope-labeled palmitate-d₃ and L-serine-d₃. To the best of our knowledge, this is the first demonstration of a method monitoring the entirety of ER-associated sphingolipid biosynthesis. Proof-of-concept data was provided by modulating the levels of supplied cofactors (e.g., NADPH) or the addition of specific enzyme inhibitors (e.g., fumonisin B₁). The presented microsomal assay may serve as a useful tool for monitoring alterations in sphingolipid de novo synthesis in cells or tissues. Additionally, our methodology may be used for metabolism studies of atypical substrates - naturally occurring or chemically tailored - as well as novel inhibitors of enzymes involved in sphingolipid de novo synthesis.}, language = {en} } @article{WiggerGulbinsKleuseretal.2019, author = {Wigger, Dominik and Gulbins, Erich and Kleuser, Burkhard and Schumacher, Fabian}, title = {Monitoring the Sphingolipid de novo Synthesis by Stable-Isotope Labeling and Liquid Chromatography-Mass Spectrometry}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {2296-634X}, doi = {10.3389/fcell.2019.00210}, pages = {16}, year = {2019}, abstract = {Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to cellular signaling. De novo sphingolipid synthesis takes place in the endoplasmic reticulum (ER), where the condensation of the activated C₁₆ fatty acid palmitoyl-CoA and the amino acid L-serine is catalyzed by serine palmitoyltransferase (SPT). The product, 3-ketosphinganine, is then converted into more complex sphingolipids by additional ER-bound enzymes, resulting in the formation of ceramides. Since sphingolipid homeostasis is crucial to numerous cellular functions, improved assessment of sphingolipid metabolism will be key to better understanding several human diseases. To date, no assay exists capable of monitoring de novo synthesis sphingolipid in its entirety. Here, we have established a cell-free assay utilizing rat liver microsomes containing all the enzymes necessary for bottom-up synthesis of ceramides. Following lipid extraction, we were able to track the different intermediates of the sphingolipid metabolism pathway, namely 3-ketosphinganine, sphinganine, dihydroceramide, and ceramide. This was achieved by chromatographic separation of sphingolipid metabolites followed by detection of their accurate mass and characteristic fragmentations through high-resolution mass spectrometry and tandem-mass spectrometry. We were able to distinguish, unequivocally, between de novo synthesized sphingolipids and intrinsic species, inevitably present in the microsome preparations, through the addition of stable isotope-labeled palmitate-d₃ and L-serine-d₃. To the best of our knowledge, this is the first demonstration of a method monitoring the entirety of ER-associated sphingolipid biosynthesis. Proof-of-concept data was provided by modulating the levels of supplied cofactors (e.g., NADPH) or the addition of specific enzyme inhibitors (e.g., fumonisin B₁). The presented microsomal assay may serve as a useful tool for monitoring alterations in sphingolipid de novo synthesis in cells or tissues. Additionally, our methodology may be used for metabolism studies of atypical substrates - naturally occurring or chemically tailored - as well as novel inhibitors of enzymes involved in sphingolipid de novo synthesis.}, language = {en} } @article{FrombachUnbehauenKurniasihetal.2019, author = {Frombach, Janna and Unbehauen, Michael and Kurniasih, Indah N. and Schumacher, Fabian and Volz, Pierre and Hadam, Sabrina and Rancan, Fiorenza and Blume-Peytavi, Ulrike and Kleuser, Burkhard and Haag, Rainer and Alexiev, Ulrike and Vogt, Annika}, title = {Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin}, series = {Journal of controlled release}, volume = {299}, journal = {Journal of controlled release}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-3659}, doi = {10.1016/j.jconrel.2019.02.028}, pages = {138 -- 148}, year = {2019}, abstract = {In reconstructed skin and diffusion cell studies, core-multishell nanocarriers (CMS-NC) showed great potential for drug delivery across the skin barrier. Herein, we investigated penetration, release of dexamethasone (DXM), in excised full-thickness human skin with special focus on hair follicles (HF). Four hours and 16 h after topical application of clinically relevant dosages of 10 mu g DXM/cm(2) skin encapsulated in CMS-NC (12 nm diameter, 5.8\% loading), presence of DXM in the tissue as assessed by fluorescence microscopy of anti-DXM-stained tissue sections as well as ELISA and HPLC-MS/MS in tissue extracts was enhanced compared to standard LAW-creme but lower compared to DXM aqueous/alcoholic solution. Such enhanced penetration compared to conventional cremes offers high potential for topical therapies, as recurrent applications of corticosteroid solutions face limitations with regard to tolerability and fast drainage. The findings encourage more detailed investigations on where and how the nanocarrier and drug dissociate within the skin and what other factors, e.g. thermodynamic activity, influence the penetration of this formulations. Microscopic studies on the spatial distribution within the skin revealed accumulation in HF and furrows accompanied by limited cellular uptake assessed by flow cytometry (up to 9\% of total epidermal cells). FLIM clearly visualized the presence of CMS-NC in the viable epidermis and dermis. When exposed in situ a fraction of up to 25\% CD1a(+) cells were found within the epidermal CMS-NC+ population compared to approximately 3\% CD1a(+)/CMS-NC+ cells after in vitro exposure in short-term cultures of epidermal cell suspensions. The latter reflects the natural percentage of Langerhans cells (LC) in epidermis suspensions and indicated that CMS-NC were not preferentially internalized by one cell type. The increased CMS-NC+ LC proportion after exposure within the tissue is in accordance with the strategic suprabasal LC-localization. More specifically we postulate that the extensive dendrite meshwork, their position around HF orifices and their capacity to modulate tight junctions facilitated a preferential uptake of CMS-NC by LC within the skin. This newly identified aspect of CMS-NC penetration underlines the potential of CMS-NC for dermatotherapy and encourages further investigations of CMS-NC for the delivery of other molecule classes for which intracellular delivery is even more crucial.}, language = {en} } @article{GronkeHernandezZimmermannetal.2019, author = {Gronke, Konrad and Hernandez, Pedro P. and Zimmermann, Jakob and Klose, Christoph S. N. and Kofoed-Branzk, Michael and Guendel, Fabian and Witkowski, Mario and Tizian, Caroline and Amann, Lukas and Schumacher, Fabian and Glatt, Hansruedi and Triantafyllopoulou, Antigoni and Diefenbach, Andreas}, title = {Interleukin-22 protects intestinal stem cells against genotoxic stress}, series = {Nature : the international weekly journal of science}, volume = {566}, journal = {Nature : the international weekly journal of science}, number = {7743}, publisher = {Nature Publ. Group}, address = {London}, issn = {0028-0836}, doi = {10.1038/s41586-019-0899-7}, pages = {249 -- 253}, year = {2019}, abstract = {Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1,2,3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.}, language = {en} } @article{GohlkeZagoriyInostrozaetal.2019, author = {Gohlke, Sabrina and Zagoriy, Vyacheslav and Inostroza, Alvaro Cuadros and Meret, Michael and Mancini, Carola and Japtok, Lukasz and Schumacher, Fabian and Kuhlow, Doreen and Graja, Antonia and Stephanowitz, Heike and J{\"a}hnert, Markus and Krause, Eberhard and Wernitz, Andreas and Petzke, Klaus-Juergen and Sch{\"u}rmann, Annette and Kleuser, Burkhard and Schulz, Tim Julius}, title = {Identification of functional lipid metabolism biomarkers of brown adipose tissue aging}, series = {Molecular Metabolism}, volume = {24}, journal = {Molecular Metabolism}, publisher = {Elsevier}, address = {Amsterdam}, issn = {2212-8778}, doi = {10.1016/j.molmet.2019.03.011}, pages = {1 -- 17}, year = {2019}, abstract = {Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.}, language = {en} } @article{WiesnerReinholdBarknowitzFlorianetal.2019, author = {Wiesner-Reinhold, Melanie and Barknowitz, Gitte and Florian, Simone and Mewis, Inga and Schumacher, Fabian and Schreiner, Monika and Glatt, Hansruedi}, title = {1-Methoxy-3-indolylmethyl DNA adducts in six tissues, and blood protein adducts, in mice under pak choi diet: time course and persistence}, series = {Archives of toxicology : official journal of EUROTOX}, volume = {93}, journal = {Archives of toxicology : official journal of EUROTOX}, number = {6}, publisher = {Springer}, address = {Heidelberg}, issn = {0340-5761}, doi = {10.1007/s00204-019-02452-3}, pages = {1515 -- 1527}, year = {2019}, abstract = {We previously showed that purified 1-methoxy-3-indolylmethyl (1-MIM) glucosinolate, a secondary plant metabolite in Brassica species, is mutagenic in various in vitro systems and forms DNA and protein adducts in mouse models. In the present study, we administered 1-MIM glucosinolate in a natural matrix to mice, by feeding a diet containing pak choi powder and extract. Groups of animals were killed after 1, 2, 4 and 8 days of pak choi diet, directly or, in the case of the 8-day treatment, after 0, 8 and 16 days of recovery with pak choi-free diet. DNA adducts [N-2-(1-MIM)-dG, N-6-(1-MIM)-dA] in six tissues, as well as protein adducts [tau N-(1-MIM)-His] in serum albumin (SA) and hemoglobin (Hb) were determined using UPLC-MS/MS with isotopically labeled internal standards. None of the samples from the 12 control animals under standard diet contained any 1-MIM adducts. All groups receiving pak choi diet showed DNA adducts in all six tissues (exception: lung of mice treated for a single day) as well as SA and Hb adducts. During the feeding period, all adduct levels continuously increased until day 8 (in the jejunum until day 4). During the 14-day recovery period, N-2-(1-MIM)-dG in liver, kidney, lung, jejunum, cecum and colon decreased to 52, 41, 59, 11, 7 and 2\%, respectively, of the peak level. The time course of N-6-(1-MIM)-dA was similar. Immunohistochemical analyses indicated that cell turnover is a major mechanism of DNA adduct elimination in the intestine. In the same recovery period, protein adducts decreased more rapidly in SA than in Hb, to 0.7 and 37\%, respectively, of the peak level, consistent with the differential turnover of these proteins. In conclusion, the pak choi diet lead to the formation of high levels of adducts in mice. Cell and protein turnover was a major mechanism of adduct elimination, at least in gut and blood.}, language = {en} } @article{RancanVolkmannGiulbudagianetal.2019, author = {Rancan, Fiorenza and Volkmann, Hildburg and Giulbudagian, Michael and Schumacher, Fabian and Stanko, Jessica Isolde and Kleuser, Burkhard and Blume-Peytavi, Ulrike and Calderon, Marcelo and Vogt, Annika}, title = {Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels}, series = {Pharmaceutics : Molecular Diversity Preservation International}, volume = {11}, journal = {Pharmaceutics : Molecular Diversity Preservation International}, number = {8}, publisher = {MDPI}, address = {Basel}, issn = {1999-4923}, doi = {10.3390/pharmaceutics11080394}, pages = {14}, year = {2019}, abstract = {Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1\% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1\% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.}, language = {en} } @article{GereckeSchumacherBerndzenetal.2019, author = {Gerecke, Christian and Schumacher, Fabian and Berndzen, Alide and Homann, Thomas and Kleuser, Burkhard}, title = {Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells}, series = {Epigenetics : the official journal of the DNA Methylation Society}, volume = {15}, journal = {Epigenetics : the official journal of the DNA Methylation Society}, number = {3}, publisher = {Taylor \& Francis Group}, address = {Philadelphia}, issn = {1559-2294}, doi = {10.1080/15592294.2019.1666652}, pages = {307 -- 322}, year = {2019}, abstract = {Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of alpha-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116 IDH1(R132H/+) (harbouring a mutated IDH1 allele) and the parental cells HCT116 IDH1(+/+) (wild type IDH1). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumour suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment of IDH1/2 mutated cancers.}, language = {en} } @misc{RancanVolkmannGiulbudagianetal.2019, author = {Rancan, Fiorenza and Volkmann, Hildburg and Giulbudagian, Michael and Schumacher, Fabian and Stanko, Jessica Isolde and Kleuser, Burkhard and Blume-Peytavi, Ulrike and Calder{\´o}n, Marcelo and Vogt, Annika}, title = {Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1339}, issn = {1866-8372}, doi = {10.25932/publishup-47327}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-473270}, pages = {14}, year = {2019}, abstract = {Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1\% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1\% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.}, language = {en} } @article{SolgerKunzFinketal.2019, author = {Solger, Franziska and Kunz, Tobias C. and Fink, Julian and Paprotka, Kerstin and Pfister, Pauline and Hagen, Franziska and Schumacher, Fabian and Kleuser, Burkhard and Seibel, J{\"u}rgen and Rudel, Thomas}, title = {A role of sphingosine in the intracellular survival of Neisseria gonorrhoeae}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {10}, journal = {Frontiers in Cellular and Infection Microbiology}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {2235-2988}, doi = {10.3389/fcimb.2020.00215}, pages = {12}, year = {2019}, abstract = {Obligate human pathogenic Neisseria gonorrhoeae are the second most frequent bacterial cause of sexually transmitted diseases. These bacteria invade different mucosal tissues and occasionally disseminate into the bloodstream. Invasion into epithelial cells requires the activation of host cell receptors by the formation of ceramide-rich platforms. Here, we investigated the role of sphingosine in the invasion and intracellular survival of gonococci. Sphingosine exhibited an anti-gonococcal activity in vitro. We used specific sphingosine analogs and click chemistry to visualize sphingosine in infected cells. Sphingosine localized to the membrane of intracellular gonococci. Inhibitor studies and the application of a sphingosine derivative indicated that increased sphingosine levels reduced the intracellular survival of gonococci. We demonstrate here, that sphingosine can target intracellular bacteria and may therefore exert a direct bactericidal effect inside cells.}, language = {en} } @misc{BeckmannBeckerKadowetal.2019, author = {Beckmann, Nadine and Becker, Katrin Anne and Kadow, Stephanie and Schumacher, Fabian and Kramer, Melanie and K{\"u}hn, Claudine and Schulz-Schaeffer, Walter J. and Edwards, Michael J. and Kleuser, Burkhard and Gulbins, Erich and Carpinteiro, Alexander}, title = {Acid sphingomyelinase deficiency ameliorates Farber disease}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1087}, issn = {1866-8372}, doi = {10.25932/publishup-44128}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-441282}, pages = {20}, year = {2019}, abstract = {Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can't achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients}, language = {en} } @article{DerakhshaniKurzJaptoketal.2019, author = {Derakhshani, Shaghayegh and Kurz, Andreas and Japtok, Lukasz and Schumacher, Fabian and Pilgram, Lisa and Steinke, Maria and Kleuser, Burkhard and Sauer, Markus and Schneider-Schaulies, Sibylle and Avota, Elita}, title = {Measles Virus Infection Fosters Dendritic Cell Motility in a 3D Environment to Enhance Transmission to Target Cells in the Respiratory Epithelium}, series = {Frontiers in immunology}, volume = {10}, journal = {Frontiers in immunology}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.01294}, pages = {14}, year = {2019}, abstract = {Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit.}, language = {en} } @article{FredeSchreinerBaldermann2019, author = {Frede, Katja and Schreiner, Monika and Baldermann, Susanne}, title = {Light quality-induced changes of carotenoid composition in pak choi Brassica rapa ssp. chinensis}, volume = {193}, publisher = {Elsevier}, address = {Lausanne}, issn = {1011-1344}, doi = {10.1016/j.jphotobiol.2019.02.001}, pages = {18 -- 30}, year = {2019}, abstract = {Carotenoids as part of the photosystems are crucial for their assembly, light-harvesting, and photoprotection. Light of different wavelengths impacts the composition and structure of photosystems, thus offering the possibility to influence the carotenoid concentrations and composition in photosystems by illumination with specific narrow-banded light spectra. Key components involved in the regulation of gene transcription are still poorly characterized, particularly in leafy vegetables as compared to model plants. In particular, the effect of different light qualities and its connection to redox control mechanisms, which also determine the photosystem composition and structure, is not yet well understood. Furthermore, light quality effects are species-dependent, and thus, increase the need to perform research on individual vegetable species such as pak choi Brassica rapa ssp. chinensis. Here, we investigated the carotenoid concentrations and composition of pak choi sprouts grown for 6 days under blue, red, or white light emitting diodes (LEDs) as light source. After 6 days, the total carotenoid content was the highest under white and slightly reduced under blue or red LEDs. Blue, red, and white light differently affected the carotenoid composition mainly due to variations of the beta-carotene content which could be correlated to changes in the transcript levels of beta-carotene hydroxylase 1 (beta-OHASE1). Further investigations implied a redox controlled gene expression of beta-OHASE1. In addition, transcription factors related to light signaling and the circadian clock differed in their transcriptional abundance after exposure to blue and red light. RNA-Seq analysis also revealed increased transcript levels of genes encoding the outer antenna complex of photosystem II under red compared to blue light, indicating an adjustment of the photosystems to the different light qualities which possibly contributed to the alternations in the carotenoid content and composition.}, language = {en} } @article{ShiXieQietal.2019, author = {Shi, Jiang and Xie, Dongchao and Qi, Dandan and Peng, Qunhua and Chen, Zongmao and Schreiner, Monika and Lin, Zhi and Baldermann, Susanne}, title = {Methyl jasmonate-induced changes of flavor profiles during the processing of Green, Oolong, and Black Tea}, series = {Frontiers in plant science}, volume = {10}, journal = {Frontiers in plant science}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-462X}, doi = {10.3389/fpls.2019.00781}, pages = {13}, year = {2019}, abstract = {Tea aroma is one of the most important factors affecting the character and quality of tea. Here we describe the practical application of methyl jasmonate (MeJA) to improve the aroma quality of teas. The changes of selected metabolites during crucial tea processing steps, namely, withering, fixing and rolling, and fermentation, were analyzed. MeJA treatment of tea leaves (12, 24, 48, and 168 h) greatly promotes the aroma quality of green, oolong, and black tea products when comparing with untreated ones (0 h) and as confirmed by sensory evaluation. MeJA modulates the aroma profiles before, during, and after processing. Benzyl alcohol, benzaldehyde, 2-phenylethyl alcohol, phenylacetaldehyde, and trans-2-hexenal increased 1.07- to 3-fold in MeJA-treated fresh leaves and the first two maintained at a higher level in black tea and the last two in green tea. This correlates with a decrease in aromatic amino acids by more than twofold indicating a direct relation to tryptophan- and phenylalanine-derived volatiles. MeJA-treated oolong tea was characterized by a more pleasant aroma. Especially the terpenoids linalool and oxides, geraniol, and carvenol increased by more than twofold.}, language = {en} } @article{YadavDreherAthmeretal.2019, author = {Yadav, Heena and Dreher, Doroth{\´e}e and Athmer, Benedikt and Porzel, Andrea and Gavrin, Aleksandr and Baldermann, Susanne and Tissier, Alain and Hause, Bettina}, title = {Medicago TERPENE SYNTHASE 10 is involved in defense against an oomycete root pathogen}, series = {Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants}, volume = {180}, journal = {Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants}, number = {3}, publisher = {American Society of Plant Physiologists}, address = {Rockville}, issn = {0032-0889}, doi = {10.1104/pp.19.00278}, pages = {1598 -- 1613}, year = {2019}, abstract = {In nature, plants interact with numerous beneficial or pathogenic soil-borne microorganisms. Plants have developed various defense strategies to expel pathogenic microbes, some of which function soon after pathogen infection. We used Medicago truncatula and its oomycete pathogen Aphanomyces euteiches to elucidate early responses of the infected root. A. euteiches causes root rot disease in legumes and is a limiting factor in legume production. Transcript profiling of seedlings and adult plant roots inoculated with A. euteiches zoospores for 2 h revealed specific upregulation of a gene encoding a putative sesquiterpene synthase (M. truncatula TERPENE SYNTHASE 10 [MtTPS10]) in both developmental stages. MtTPS10 was specifically expressed in roots upon oomycete infection. Heterologous expression of MtTPS10 in yeast led to production of a blend of sesquiterpenes and sesquiterpene alcohols, with NMR identifying a major peak corresponding to himalachol. Moreover, plants carrying a tobacco (Nicotiana tabacum) retrotransposon Tnt1 insertion in MtTPS10 lacked the emission of sesquiterpenes upon A. euteiches infection, supporting the assumption that the identified gene encodes a multiproduct sesquiterpene synthase. Mttps10 plants and plants with reduced MtTPS10 transcript levels created by expression of an MtTPS10-artificial microRNA in roots were more susceptible to A. euteiches infection than were the corresponding wild-type plants and roots transformed with the empty vector, respectively. Sesquiterpenes produced by expression of MtTPS10 in yeast also inhibited mycelial growth and A. euteiches zoospore germination. These data suggest that sesquiterpene production in roots by MtTPS10 plays a previously unrecognized role in the defense response of M. truncatula against A. euteiches.}, language = {en} } @article{KlopschBaldermannVossetal.2019, author = {Klopsch, Rebecca and Baldermann, Susanne and Voss, Alexander and Rohn, Sascha and Schreiner, Monika and Neugart, Susanne}, title = {Narrow-Banded UVB Affects the Stability of Secondary Plant Metabolites in Kale (Brassica oleracea var. sabellica) and Pea (Pisum sativum) Leaves Being Added to Lentil Flour Fortified Bread: A Novel Approach for Producing Functional Foods}, series = {Foods}, volume = {8}, journal = {Foods}, number = {10}, publisher = {MDPI}, address = {Basel}, issn = {2304-8158}, doi = {10.3390/foods8100427}, pages = {20}, year = {2019}, abstract = {Young kale and pea leaves are rich in secondary plant metabolites (SPMs) whose profile can be affected by ultraviolet B (UVB) radiation. Carotenoids and flavonoids in kale and pea exposed to narrow-banded UVB, produced by innovative light-emitting diodes (LEDs), and subsequently used for breadmaking were investigated for the first time, thus combining two important strategies to increase the SPMs intake. Breads were also fortified with protein-rich lentil flour. Antioxidant activity in the 'vegetable breads' indicated health-promoting effects. Lentil flour increased the antioxidant activity in all of the 'vegetable breads'. While carotenoids and chlorophylls showed a minor response to UVB treatment, kaempferol glycosides decreased in favor of increasing quercetin glycosides, especially in kale. Additionally, breadmaking caused major decreases in carotenoids and a conversion of chlorophyll to bioactive degradation products. In 'kale breads' and 'pea breads', 20\% and 84\% of flavonoid glycosides were recovered. Thus, kale and pea leaves seem to be suitable natural ingredients for producing innovative Functional Foods.}, language = {en} } @article{KlopschBaldermannHanschenetal.2019, author = {Klopsch, Rebecca and Baldermann, Susanne and Hanschen, Franziska S. and Voss, Alexander and Rohn, Sascha and Schreiner, Monika and Neugart, Susanne}, title = {Brassica-enriched wheat bread: Unraveling the impact of ontogeny and breadmaking on bioactive secondary plant metabolites of pak choi and kale}, series = {Food chemistry}, volume = {295}, journal = {Food chemistry}, publisher = {Elsevier}, address = {Oxford}, issn = {0308-8146}, doi = {10.1016/j.foodchem.2019.05.113}, pages = {412 -- 422}, year = {2019}, abstract = {Consumption of Brassica vegetables is linked to health benefits, as they contain high concentrations of the following secondary plant metabolites (SPMs): glucosinolate breakdown products, carotenoids, chlorophylls, and phenolic compounds. Especially Brassica vegetables are consumed as microgreens (developed cotyledons). It was investigated how different ontogenetic stages (microgreens or leaves) of pak choi (Brassica rapa subsp. chinensis) and kale (Brassica oleracea var. sabellica) differ in their SPM concentration. The impact of breadmaking on SPMs in microgreens (7 days) and leaves (14 days) in pak choi and kale as a supplement in mixed wheat bread was assessed. In leaves, carotenoids, chlorophylls, and phenolic compounds were higher compared to those of microgreens. Breadmaking caused a decrease of SPMs. Chlorophyll degradation was observed, leading to pheophytin and pyropheophytin formation. In kale, sinapoylgentiobiose, a hydroxycinnamic acid derivative, concentration increased. Thus, leaves of Brassica species are suitable as natural ingredients for enhancing bioactive SPM concentrations in bread.}, language = {en} } @article{ChenHanschenNeugartetal.2019, author = {Chen, Xiaomin and Hanschen, Franziska S. and Neugart, Susanne and Schreiner, Monika and Vargas, Sara A. and Gutschmann, Bj{\"o}rn and Baldermann, Susanne}, title = {Boiling and steaming induced changes in secondary metabolites in three different cultivars of pak choi (Brassica rapa subsp. chinensis)}, series = {Journal of Food Composition and Analysis}, volume = {82}, journal = {Journal of Food Composition and Analysis}, publisher = {Elsevier}, address = {San Diego}, issn = {0889-1575}, doi = {10.1016/j.jfca.2019.06.004}, pages = {9}, year = {2019}, abstract = {Pak choi (Brassica rapa subsp. chinensis) is a leafy vegetable that is widely available in Asia and consumed in rising quantities in Europe. Pak choi contains high levels of secondary plant metabolites, such as carotenoids, chlorophylls, glucosinolates, phenolic compounds, and vitamin K, which are beneficial for humans if consumed on a regular basis. The evaluation of the genotype-induced variation of secondary plant metabolites revealed that the cultivar 'Amur' contained the highest concentration of secondary plant metabolites. Furthermore, steaming retained more chlorophylls, glucosinolates, phenolic acids and flavonoid compounds than boiling. In contrast, both domestic cooking methods - boiling, and steaming - reduced the formation of glucosinolate breakdown products, especially the undesired epithionitriles and nitriles but less of the health-beneficial isothiocyanates.}, language = {en} }